2021 Volume 85 Issue 9 Pages 1590-1689
ACC | American College of Cardiology |
AHA | American Heart Association |
ARVC | arrhythmogenic right ventricular cardiomyopathy |
ASH | asymmetric septal hypertrophy |
BTT | bridge to transplantation |
CMR | cardiac magnetic resonance imaging |
CPEO | chronic progressive external ophthalmoplegia |
CRT | cardiac resynchronization therapy |
D-HCM | dilated phase of hypertrophic cardiomyopathy |
DCM | dilated cardiomyopathy |
ESC | European Society of Cardiology |
GWAS | genome-wide association studies |
HCM | hypertrophic cardiomyopathy |
HFmrEF | heart failure with mid-range ejection fraction |
HFpEF | heart failure with preserved ejection fraction |
HFrEF | heart failure with reduced ejection fraction |
HOCM | hypertrophic obstructive cardiomyopathy |
ICD | implantable cardioverter defibrillator |
IHSS | idiopathic hypertrophic subaortic stenosis |
ISFC | International Society and Federation of Cardiology |
LAMP-2 | lysosome-associated membrane protein-2 |
LGE | late gadolinium enhancement |
LVNC | left ventricular noncompaction cardiomyopathy |
LVOTO | left ventricular outflow tract obstruction |
MELAS | mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes |
MERRF | myoclonus epilepsy associated with ragged-red fibers |
MVO | midventricular obstruction |
PTSMA | percutaneous transluminal septal myocardial ablation |
RCM | restrictive cardiomyopathy |
S-ICD | sub-cutaneous ICD |
SAM | systolic anterior motion |
SCD | sudden cardiac death |
SRT | septal reduction therapy |
TTR | transthyretin |
VAD | ventricular assist device |
WHO | World Health Organization |
α-Gal | α-galactosidase |
Although cardiomyopathies are the disease with far less evidence than ischemic heart disease, rapid progress has been made in understanding the etiology, which has previously been of unknown cause. In 1961, Goodwin et al described cardiomyopathy as “a subacute or chronic disorder of heart muscle of unknown or obscure aetiology, often with associated endocardial, and sometimes with pericardial involvement, but not atherosclerotic in origin”.1 Subsequently, the 1980 World Health Organization (WHO)/International Society and Federation of Cardiology (ISFC) Joint Committee, defined cardiomyopathy as an “unexplained myocardial disease”.2 However, beginning with identification of genetic mutations in hypertrophic cardiomyopathy (HCM), some etiologies of cardiomyopathies have been elucidated, and thus the concept of “unknown cause” no longer fits the definition of cardiomyopathy. With these advances, “unknown cause” was deleted from the definition of the WHO/ISFC Joint Committee in 1995,3 and a new definition and classification were proposed by the American Heart Association (AHA) in 2006,4 and by the European Society of Cardiology (ESC) in 2008.5 Furthermore, guidelines for HCM were published in 2011 (updated in 2020) by the American College of Cardiology (ACC)/AHA,6 and in 2014 by the ESC.7 In Japan, “Cardiomyopathy: diagnostic guidelines and commentary” were prepared in 2005,8 and a local classification of cardiomyopathy was adopted. Guidelines for the diagnosis and treatment of cardiomyopathy were also prepared, including the 2002 “Guidelines for the treatment of hypertrophic cardiomyopathy” (Junichi Yoshikawa, Group leader), revised in 2007 and 2012 (Yoshinori Doi, Group leader),9 and the “Guidelines for the management of dilated cardiomyopathy and secondary cardiomyopathy” (Japanese Circulation Society (JCS) 2011) (Hitonobu Tomoike, group leader).10
The purpose of these current (2018) revised and integrated guidelines is to incorporate the progress made in HCM and dilated cardiomyopathy (DCM), with the following aims.
1. To specify a new definition of cardiomyopathy based on actual medical practice in Japan, referring to the existing methods of classifying cardiomyopathy.
2. To aid in decision-making in HCM by incorporating evidence from Japan and referring to the aforementioned ACC/AHA and ESC guidelines.
3. To specify the etiology and treatment of cardiomyopathy in compliance with the JCS 2017/Japanese Heart Failure Society (JHFS) 2017 “Guidelines for heart failure”.11
Although cardiomyopathies additional to HCM and DCM, such as restricted cardiomyopathy (RCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC), are known, at this time, however, evidence is lacking for separate guidelines for these diseases. Expecting further accumulation of evidence in the future, we will make this an issue for the subsequent revision. Some guidelines have been revised since the Japanese version was published in 2019; this English version partially incorporates those changes.
The classes of recommendations and levels of evidence in these guidelines were determined and described according to the “Guidelines for the treatment of acute and chronic heart failure” (revised in 2017).11 Recommendations regarding classifications and levels of evidence are described using a style similar to previous heart failure (HF) guidelines and those used in the ACC/AHA and ECS guidelines (Tables 1,2). In Japan, guidelines for cardiovascular diseases have used a common style that is highly consistent with Western guidelines. On the other hand, in its Medical Information Network Distribution Service (MINDS), the Japan Council for Quality Health Care uses a different style to show grades of recommendations and levels of evidence, as described in the “Minds handbook for clinical practice guideline development 2007” (Tables 3,4).12 Accordingly, the present document combines both styles to show the classifications and grades of recommendations and levels of evidence (including MINDS) in the tables.
Class I | Evidence and/or general agreement that a given procedure or treatment is useful and effective |
Class II | Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given procedure or treatment |
Class IIa | Weight of evidence/opinion is in favor of usefulness/efficacy |
Class IIb | Usefulness/efficacy is less well established by evidence/opinion |
Class III | Evidence or general agreement that the given procedure or treatment is not useful/effective, and in some cases may be harmful |
Level A | Data derived from multiple randomized clinical trials or meta-analyses |
Level B | Data derived from a single randomized clinical trial or large-scale non-randomized studies |
Level C | Consensus of opinion of the experts and/or small-size clinical studies, retrospective studies, and registries |
Grade A | Strongly recommended and supported by strong evidence |
Grade B | Recommended with moderately strong supporting evidence |
Grade C1 | Recommended despite no strong supporting evidence |
Grade C2 | Not recommended because of the absence of strong supporting evidence |
Grade D | Not recommended as evidence indicates that the treatment is ineffective or even harmful |
The grade of recommendation is determined based on a comprehensive assessment of the level and quantity of evidence, variation of conclusion, size of effectiveness, applicability to the clinical setting, and evidence on harms and costs. (Adapted from MINDS Treatment Guidelines Selection Committee. 200712)
I | Systematic review/meta-analysis of randomized controlled trials |
II | One or more randomized controlled trials |
III | Non-randomized controlled trials |
IVa | Analytical epidemiological studies (cohort studies) |
IVb | Analytical epidemiological studies (case-control studies and cross-sectional studies) |
V | Descriptive studies (case reports and case series) |
VI | Not based on patient data, or based on opinions from a specialist committee or individual specialists |
(Adapted from MINDS Treatment Guidelines Selection Committee. 200712)
Cardiomyopathy is defined as “diseases of the heart muscles with cardiac dysfunction”. In 2005, a Japanese research group published “Cardiomyopathy: diagnostic guidelines and commentary”.8 In those guidelines, idiopathic cardiomyopathy is defined as “a series of diseases that have no apparent cause, such as hypertension or coronary artery disease (CAD), and have a myocardial lesion.”8 Based on the 1995 WHO/ISFC classification (Table 5),3 the following cardiomyopathy classification was proposed: (1) DCM; (2) HCM; (3) RCM; (4) ARVC; (5) sudden familial death syndrome; (6) mitochondrial cardiomyopathy; (7) Fabry disease; and (8) takotsubo cardiomyopathy.
Definition: |
Cardiomyopathies are defined as diseases of the myocardium associated with cardiac dysfunction. |
Classification: |
1. Dilated cardiomyopathy (DCM) |
2. Hypertrophic cardiomyopahy (HCM) |
3. Restrictive cardiomyopathy (RCM) |
4. Arrhythmogenic right ventricular cardiomyopathy |
5. Unclassified cardiomyopathy |
Specific cardiomyopathies |
WHO/ ISFC, World Health Organization/International Society and Federation of Cardiology. (Adapted from McKenna W, et al. 19963)
On the other hand, “specific cardiomyopathy” is a general term for a cardiomyopathy that is clearly associated with a cause or systemic disease (Table 6).3 Among the specific cardiomyopathies, the terms “ischemic”, “valvular”, and “hypertensive” should be used when the degree of myocardial damage caused by each of the underlying diseases is severe.
Ischemic cardiomyopathy |
Valvular cardiomyopathy |
Hypertensive cardiomyopathy |
Inflammatory cardiomyopathy (myocarditis, etc.) |
Metabolic cardiomyopathy |
Endocrine: thyrotoxicosis, hypothyroidism, adrenal cortical insufficiency, pheochromocytoma, acromegaly, and diabetes mellitus |
Familial storage disease and infiltrations: hemochromatosis, glycogen storage disease, Hurler’s syndrome, Refsum’s syndrome, Niemann-Pick disease, Hand-Schüller-Christian disease, Fabry disease, and Morquio-Ullrich disease |
Deficiency: disturbances of potassium metabolism, magnesium deficiency, and nutritional disorders such as anemia, beriberi, and selenium deficiency |
General systemic disease |
Connective tissue disorders, sarcoidosis and leukemia |
Muscular dystrophies |
Duchenne, Becker-type, and myotonic dystrophies |
Neuromuscular disorders |
Friedreich’s ataxia, Noonan syndrome |
Sensitivity and toxic reactions |
Reactions to alcohol, catecholamines, anthracyclines, irradiation |
Peripartum cardiomyopathy |
(Adapted from McKenna W, et al. 19963)
The AHA proposed a definition and classification system for cardiomyopathy in 2006 (Figure 1).4 The definition of cardiomyopathy in the AHA classification is: “…a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic.”4 Primary cardiomyopathies are those solely or predominantly confined to heart muscle and are relatively few in number. Secondary cardiomyopathies show pathological myocardial involvement as part of a large variety and number of generalized systemic (multi-organ) disorders. Moreover, primary cardiomyopathies are classified into 3 types: genetic, mixed (genetic and acquired), and acquired. Ion channel diseases such as long QT syndrome and Brugada syndrome are also included as genetic conditions.
Contemporary definitions and classifications of the cardiomyopathies in AHA. Primary cardiomyopathies in which the clinically relevant disease processes solely or predominantly involve the myocardium. The conditions have been segregated according to their genetic or nongenetic etiologies. *Predominantly nongenetic; familial disease with a genetic origin has been reported in a minority of cases. (Adapted from Maron BJ, et al. 20064) ©2006 American Heart Association, Inc.
By contrast, the classification published by the ESC in 2008 (Figure 2)5 was an extension of the WHO/ISFC classification published in 1995. According to that classification, the definition of cardiomyopathy is “a myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of CAD, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality”, and the concept of secondary cardiomyopathy was excluded. This classification was based on the concept of morphological and functional abnormalities and hereditary/nonhereditary disease.
Proposed classification system of cardiomyopathies in ESC. (Adapted from Elliott P, et al. 20085) Translated and reproduced by permission of Oxford University Press on behalf of the European Society of Cardiology. Please visit: www.escardio.org/Guidelines/Consensus-and-Position-Papers/Myocardial-and-Pericardial-Diseases OUP and the ESC are not responsible or in any way liable for the accuracy of the translation. The Japanese Circulation Society is solely responsible for the translation in this publication/reprint.
In recent years, many gene mutations related to cardiomyopathy have been identified, and the families and functions containing these mutations continue to be clarified. In the ESC and ACC guidelines, the notion that a “primary cardiomyopathy” is probably due to known or unknown genetic abnormalities or autoantibodies has become mainstream. However, because various environmental factors combine with genetic predisposition, the phenotypes would be different. Under such circumstances, the MOGE (S) classification system has been proposed as a method of integrating and expressing the morphofunctional phenotype (M), organ/system involvement (O), genetic inheritance pattern (G), etiology (E), and stage and severity (S) (Table 7).13 This classification received attention as a new diagnostic method that provided a better understanding of disease risk and severity over time, resulting in the selection of more appropriate treatments.
M Morphofunctional Phenotype* |
O Organ/System Involvement† |
G Genetic‡ |
E Etiological Annotation§ |
S Stage; ACC/AHA Stage, NYHA Functional Class|| |
---|---|---|---|---|
(D) Dilated (H) Hypertrophic (R) Restrictive (A) ARVC (NC) LVNC Overlapping (H+R), (D+A), (NC+H), (H+D), (D+NC) or more complex combinations such as (H+R+NC) (E) Early, with type in parentheses (NS) Nonspecific phenotype (NA) Information not available (0) Unaffected |
(H) Heart (M) Muscle, skeletal (N) Nervous (C) Cutaneous (E) Eye (A) Auditory (K) Kidney (G) Gastrointestinal (S) Skeletal (0) Absence of organ/system involvement, e.g., in family members who are healthy mutation carriers; the mutation is specified in E and inheritance in G |
(N) Family history negative (U) Family history unknown (AD) Autosomal dominant (AR) Autosomal recessive (XLR) X-linked recessive (XLD) X-linked dominant (XL) X-linked (M) Matrilineal (DN) De novo (0) Family history not investigated |
(G) Genetic etiology–add gene and mutation; (NC) Individual noncarrier plus the gene that tested negative (OC) Obligate carrier (ONC) Obligate noncarrier (DN) De novo (C) Complex genetics when >1 mutation (provide additional gene and mutation) (Neg) Genetic test negative for the known familial mutation (NA) Genetic test not yet available (N) Genetic defect not identified (0) No genetic test, any reason (no blood sample, no informed consent, etc.) Genetic amyloidosis (A-TTR) or hemochromatosis (HFE) Nongenetic etiologies: (M) Myocarditis (V) Viral infection (add the virus identified in affected heart) (AI) Autoimmune/immune-mediated; suspected (AI-S), proven (AI-P) (A) Amyloidosis (add type of amyloidosis: A-K; A-L, A-SAA) (I) Infectious, nonviral (add the infectious agent) (T) Toxicity (add toxic cause/drug) (Eo) Hypereosinophilic heart disease |
ACC/AHA stage represented as letter (A, B, C, D) To be followed by NYHA functional class represented in Roman numerals (I, II, III, IV) |
MD, MH, MR, MA, MNC, M0, MH+R, MD+A |
OH, OM, OK, OC | GN, GU, GAD, GAR, GXLR, GXLD, GXD, GM, GDN |
EG–MYH7 [R403E], EG–HFE [Cys282Tyr+/+], EV–HCMV, EG–A–TTR [V30M], EM–sarcoidosis |
SA–I, SA–II |
*The morphofunctional phenotype description (M) may contain more information using standard abbreviations, such as AVB, atrioventricular block; WPW, Wolff-Parkinson-White syndrome; LQT, prolongation of the QT interval; AF, atrial fibrillation; ↓R, low electrocardiogram voltages; ↓PR, short PR interval. †Organ (O) involvement in addition to the H subscript (for heart) should be expanded for the involvement of M, skeletal muscle; O, ocular system; A, auditory system; K, kidney; L, liver; N, nervous system; C, cutaneous; G, gastrointestinal system, and other comorbidities, including MR, mental retardation. ‡Genetic (G) describes the available information about inheritance of the disease. It also provides complete information if the family history is not proven or unknown, and if genetic testing has not been performed or was negative for the mutation/mutations identified in the family. §The etiologic annotation (E) provides the facility for the synthetic description of the specific disease gene and mutation, as well as description of nongenetic etiology. ||The functional annotation or staging (S) allows the addition of ACC/AHA stage and NYHA functional class. ACC/AHA, American College of Cardiologye-American Heart Association; NYHA, New York Heart Association. (Adapted from Arbustini E, et al. 201313) © 2013 by the American College of Cardiology Foundation, with permission from Elsevier.
Consequently, as described above, the terminology, definitions, and classifications of cardiomyopathies used in Japan, the USA, and Europe remain inconsistent and confused.
2. Definition and Classification of CardiomyopathyThese guidelines emphasize the basic decision-making process for correctly diagnosing cardiomyopathy in daily medical practice while complying with the definitions and classifications in conventional diagnostic guidance in Japan.
As shown in Figure 3, if ventricular hypertrophy, dilatation of the heart chamber, or declining systolic and/or diastolic function is observed, cardiomyopathy should be suspected. Next, an examination of family history should be conducted, together with a search for the presence or absence of gene mutations in consideration of the cause. In this sense, the present guidelines are similar to the 2008 ESC classification. However, the difference between the present guidelines and the 2008 ESC classification is that here, primary cardiomyopathies are diagnosed by distinguishing them from secondary cardiomyopathies (“specific cardiomyopathy”) as much as possible. After this process, “primary” (formerly “idiopathic”) cardiomyopathies are classified into the following 4 types: HCM, DCM, ARVC, and RCM. Some of the phenotypes of these 4 basic pathologies of primary cardiomyopathy overlap, so they are sometimes difficult to distinguish. This is one of the most important points in the definition and classification of cardiomyopathy in this guideline.
Definitions and classifications of the cardiomyopathies in this Japanese guideline. Cases that cannot be classified into the four pathological groups are classified as unclassifiable cardiomyopathy.
1.1 Definition
HCM is a disease characterized by (1) left ventricular (LV) or right ventricular (RV) hypertrophy, and (2) LV diastolic function based on cardiac hypertrophy, similar to the classification of the 2005 Idiopathic Cardiomyopathy Research Group.8 To confirm the diagnosis, it is necessary to exclude HCM phenocopies (secondary cardiomyopathy) resulting from underlying disease or systemic abnormalities and showing a similar disease state.6 That is, HCM is defined as a case in which a pathogenic mutation has been identified mainly in genes coding for sarcomere proteins, or in which LV hypertrophy (LVH) is associated with other cardiac diseases, including storage, infiltrative or systemic disease, has been excluded. However, in the field of pediatrics, because cardiac hypertrophy due to other causes has also been referred to as HCM in Japan, LVH in children is described as HCM in these guidelines.
Clinically, HCM is defined by echocardiography or cardiac magnetic resonance imaging (CMR) as a maximum LV wall thickness ≥15 mm (≥13 mm if there is a family history of HCM) (Figure 4).6,7,14,15
Definition of HCM.
Specific diagnostic criteria are proposed in the ESC 2014 guidelines.7 The important points are summarized below.
1. HCM is defined by a wall thickness ≥15 mm in ≥ one LV myocardial segment as measured by any imaging technique (echocardiography, CMR, or computed tomography [CT]).
2. When the LV wall thickness is 13–14 mm, a diagnosis of HCM requires the evaluation of other features, including family history, noncardiac symptoms and signs, ECG abnormalities, laboratory tests, and multimodality cardiac imaging.
3. The clinical diagnosis of HCM in 1st-degree relatives of patients with unequivocal disease (LVH ≥15 mm) is based on the presence of otherwise unexplained increased LV wall thickness ≥13 mm in ≥ one LV myocardial segment as measured using any cardiac imaging technique (e.g., echocardiography, CMR, CT).
If a wall thickness ≥15 mm is observed, as described above, the possibility of HCM increases, and in the case of a wall thickness of 13–14 mm, the importance of making an exclusion diagnosis with the possibility of HCM and adding tests that support HCM, such as genetic testing, is emphasized.
LVH as a storage and systemic disease with extracardiac lesions is classified as a secondary cardiomyopathy and has a pathophysiology similar to HCM. It should be noted that treatment for secondary cardiomyopathy is disease-specific, depending on the cause (see Chapter III.2 Etiology). For Fabry disease, more than 10 years have passed since the introduction of enzyme-replacement therapy, and its usefulness has been established.16 New therapies for amyloidosis are also advancing rapidly.17 Therefore, this guideline emphasizes that the appropriate diagnosis of secondary cardiomyopathy is becoming increasingly important.
1.2 Classification
Although various types of HCM have been described, in these guidelines, HCM is defined based on the classification of the 2005 Idiopathic Cardiomyopathy Research Group and recent findings6–9,14,18 (Table 8).
1. Hypertrophic obstructive cardiomyopathy (HOCM) |
• HOCM (basal obstruction) |
Presence of basal LVOT pressure gradient ≥30 mmHg at rest |
• HOCM (labile/provocable obstruction) |
LVOT pressure gradient <30 mmHg at rest, but pressure gradient ≥30 mmHg on provocation including exercise |
2. Nonobstructive HCM |
Intraventricular pressure gradient <30 mmHg at rest or on provocation |
3. Midventricular obstruction (MVO) |
Presence of systolic LV cavity obliteration at the midventricle creating MVO with a peak systolic gradient ≥30 mmHg |
4. Apical HCM |
Hypertrophy confined to the LV apex |
5. Dilated phase of HCM (D-HCM) / End-stage HCM |
LV systolic dysfunction of global ejection fraction <50% |
LVOT, left ventricular outflow tract.
1.2.1 Hypertrophic Obstructive Cardiomyopathy (HOCM)
In the past, HOCM has been defined as a disease in which the LV outflow tract (LVOT) pressure gradient is ≥30 mmHg at rest. However, in HOCM, if not observed at rest, a significant pressure gradient is provoked after physiological stimuli such as exercise. Many such cases have been reported,19–23 so in these guidelines, HOCM is defined as follows:
• HOCM (basal obstruction)
LVOT pressure gradient ≥30 mmHg is observed at rest
• HOCM (labile/provocable obstruction)
LVOT pressure gradient at rest <30 mmHg, but a pressure gradient ≥30 mmHg is observed after physiological stimuli such as exercise or the Valsalva maneuver.
1.2.2 Nonobstructive HCM
A pressure gradient ≥30 mmHg is not observed at rest or after provocation.
1.2.3 Midventricular Obstruction (MVO)
Marked hypertrophy in the middle LV, giving an hourglass-like LV morphology, is observed, as is a pressure gradient. MVO has been reported in approximately 10% of Japanese patients with HCM.24 MVO is often difficult to treat and pharmacotherapy tends to be ineffective. During the course of the disease, approximately 25% of patients develop an apical LV aneurysm, which may lead to ventricular tachycardia (VT) or an LV thrombus, resulting in embolism.25,26
1.2.4 Apical HCM
Hypertrophy is limited to the apex of the LV. It was first reported in Japan by Sakamoto et al in 197627 and Yamaguchi et al in 1979.28 Later, cases of this disease were reported in Europe and the USA. However, reports differed between Japan and Western countries in terms of the prevalence and clinical features of the disease. In Japan, many sporadic cases with no or only minor symptoms were identified in middle-aged men, whereas in Western countries, familial and severe cases were seen. One of the reasons for this difference may be that the diagnostic methods and criteria for apical HCM are not consistent. In these guidelines, apical HCM is defined as LVH limited to the level of the apex below the papillary muscle.29,30 Using this criterion, the prevalence of apical HCM among all HCM patients in Japan is approximately 15%, compared with 3% in the USA.31 Cases of HCM in which hypertrophy extends beyond the papillary muscles to the middle of the ventricle may be diagnosed as apical HCM (broadly defined as apical HCM) in clinical practice. Familial history and severe HF symptoms are often observed in this patient population compared with the former definition of apical HCM.29,30
1.2.5 Dilated-Phase HCM (D-HCM; Also Known as End-stage HCM)
In a part of HCM patients, the thickness of the hypertrophied ventricular wall is decreased and thinned, resulting in decreased LV contractility (LV ejection fraction [LVEF] <50%), accompanied by dilatation of the LV cavity, DCM-like morphology, and clinical symptoms.32,33 The diagnosis is certain if the patient is followed up, but if no follow-up is done, it includes cases in which a reliable diagnosis of HCM has previously been made. Around the world, the terms “end-stage HCM” and “burned-out HCM” are sometimes used. However, in Japan, this condition is referred to as D-HCM, and thus all terms have been unified as D-HCM in this guideline.
1.3 HCM as a Lifelong Disease and Recommendations for Follow-up
The phenotype and clinical condition of HCM changes over lifelong LV remodeling,34 and cardiovascular events often occur according to the disease stage35 (Figure 5). Therefore, long-term follow-up is very important. If HCM is diagnosed and the condition remains stable, regular follow-up about once every 1–2 years is desirable. If HCM, but not LVH, is present in the family history, follow-up at least once every 3–5 years for adults and once every 1–1.5 years for those <20 years of age, in whom hypertrophy may progress rapidly, is recommended.6,7,14
Lifelong LV remodeling and HCM-related cardiovascular events. (Source: Prepared based on Olivotto I, et al. 201234)
2.1 Sarcomere Gene Mutations
Approximately 60% of patients with HCM have a family history showing autosomal dominant inheritance of the disease. Mutations in genes encoding myocardial components such as the sarcomere account for 40–60% of HCM with autosomal dominant inheritance (Figure 6).7 The etiology of HCM includes over 1,400 mutations in at least 11 genes.14,15 The typical sarcomere genes that cause HCM are shown in Table 9. Of these mutations, those in the cardiac myosin heavy chain (MYH7) and cardiac myosin-binding protein C (MYBPC3) genes are the most frequently observed, followed by those in the cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), tropomyosin (TPM1), and ventricular myosin essential light chain (MYL3) genes.7,36
Diverse etiology of the diseases presenting cardiac hypertrophy. (Source: Prepared based on Elliott PM, et al. 20147)
Gene | Location | Protein | OMIM gene number | Frequency | |
---|---|---|---|---|---|
Giant filament | TTN | 2q31.2 | Titin | 188840 | <5% |
Thick filament | MYH7 | 14q11.2 | Myosin-7 (β-myosin heavy ch) | 160760 | 10–20% |
MYL2 | 12q24.11 | Myosin regulatory light chain 2 | 160781 | – | |
MYL3 | 3q21.31 | Myosin light chain 3 | 160790 | 1% | |
Intermediate filament | MYBPC3 | 11p11.2 | Myosin-binding protein C, cardiac-type | 600958 | 15–30% |
Thin filament | TNNT2 | 1q32.1 | Troponin T, cardiac muscle | 191045 | 3–5% |
TNNI3 | 19q13.42 | Troponin I, cardiac muscle | 191044 | 1–5% | |
TPM1 | 15q22.2 | Tropomyosin alpha-I chain | 191010 | <5% | |
ACTC1 | 15q14 | Actin, alpha cardiac muscle I | 102540 | – | |
Z-disc | CSPR3 | 11p15.1 | Cysteine and glycine-rich protein 3, muscle LIM protein | 600824 | – |
Calcium-Handling | PLN | 6q22.31 | Cardiac phospholamban | 172405 | – |
(Source: Prepared based on Elliott PM, et al. 20147)
The sarcomere is the contractile unit of the heart muscle and has a structure in which actin and myosin filaments (thick filaments) fold in parallel between adjacent Z-bands (Z-disks). Mutations in sarcomere genes result in abnormal amino acid sequences and deficiencies in sarcomeric constituent proteins. These abnormalities cause structural damage to the sarcomere in the myocardium, increased calcium sensitivity, and decreased adenosine triphosphate hydrolase (ATPase) activity, followed by calcineurin, mitogen-activated protein kinase (MAPK), and transforming growth factor-β, etc., the activation of multiple signal transduction pathways involved in cardiac muscle hypertrophy and fibrosis, and mitochondrial dysfunction. Taken together, these findings show that mutations in sarcomere genes contribute to HF and arrhythmia through myocardial hypertrophy, disarray, and interstitial fibrosis.7,14,15,37,38
Mutations in the angiotensin-1 converting enzyme (ACE) gene have also been reported to modulate the HCM phenotype.39 It is presumed that changes in various modifiers, including blood ACE concentration, are involved in HCM onset and progression.
HCM with sarcomere gene mutations is associated with an increased severity of LVH, more advanced microcirculatory disturbance, and myocardial fibrosis.40 Approximately 5% of patients with HCM and sarcomere gene mutations have multiple sarcomere mutations and exhibit more severe phenotypes.41 A multicenter study in Japan showed that the incidence of cardiovascular events was significantly higher in patients with HCM and sarcomere gene mutations than in those without sarcomere gene mutations.42
Although numerous HCM genotype–phenotype correlation reports have been published, there is insufficient evidence for the application of this approach to long-term prognostic management of individual cases.14 Many issues remain regarding risk stratification and prognosis prediction by genetic diagnosis. Future comprehensive analyses of genetic information using next-generation sequencing (NGS) will allow new information about the genetic basis of the observed phenotypes to be accumulated.
2.2 Differentiation of Secondary Cardiomyopathy and HCM Phenocopies
Differentiating secondary cardiomyopathy from HCM is important because specific treatments may be effective depending on the cause. Table 10 shows secondary cardiomyopathies with a phenotype similar to HCM.7,23
Inherited metabolic diseases |
Glycogen storage diseases |
Pompe disease, PRKAG2 mutation, Danon disease, Forbes disease |
Lipid metabolism abnormality |
Systemic carnitine deficiency |
Lysosomal disease |
Fabry disease |
Mitochondrial disease |
MELAS, MERRF |
Neuromuscular disease |
Friedreich’s ataxia, FHL-1 gene abnormality |
Malformation Syndromes |
Ras/MAPK syndrome |
Noonan syndrome, LEOPARD syndrome, Castello syndrome |
Infiltrative diseases |
Cardiac amyloidosis |
Hereditary ATTR amyloidosis, Systemic ATTR wild type amyloidosis, AL amyloidosis |
Inflammatory diseases |
Acute myocarditis |
Endocrine diseases |
Infant of diabetic mother |
Pheochromocytoma, acromegaly |
Drug-induced |
Steroid, tacrolimus, hydroxychloroquine |
(Source: Prepared based on Elliott PM, et al. 20147)
The frequency of secondary cardiomyopathy among all patients with clinically suspected HCM is considered to be 5–10%. Many metabolic disorders are known to exhibit cardiac hypertrophy.
Fabry disease (also known as Anderson–Fabry disease) is most commonly seen in metabolic disorders with cardiac hypertrophy. The frequency of Fabry disease has been reported as 0.5–1.0% among patients with HCM aged ≥35 years,43 and 1–3% among Japanese patients with cardiac hypertrophy.44,45 Fabry disease is an X-linked inherited disease caused by a mutation in the GLA gene at Xq22.1, resulting in reduced or defective activity of α-galactosidase (α-Gal), one of the lysosomal hydrolases. In men, the diagnosis is made by measuring plasma and leukocyte α-Gal activity, whereas in women, diagnosis based on enzyme activity alone may not be easy because of heterozygosity, so evaluation of familial history or genetic testing might be needed.
Mutations in the adenosine monophosphate (AMP)-activated protein kinase (PRKAG2) gene cause glycogen storage disease, which resembles HCM with Wolff–Parkinson–White (WPW) syndrome.46–48 Danon disease is a rare X-linked genetic disease characterized by myopathy, mental retardation, and myocardial damage caused by mutations in the LAMP-2 gene.49,50 Danon disease demonstrates cardiac hypertrophy similar to HCM.50,51 Myocardial hypertrophy is recognized as one of the systemic symptoms in mitochondrial diseases, such as mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and neuromuscular diseases such as Friedreich’s ataxia. Cardiac hypertrophy is also observed in Noonan syndrome, LEOPARD syndrome, and Castello syndrome, all of which are caused by abnormal proteins associated with the Ras/MAPK signal transduction pathway, which is related to cardiac hypertrophy.51–53
The most common type of cardiac amyloidosis is immunoglobulin light chain (AL) amyloidosis, which is caused by abnormalities in bone marrow plasma cells, or transthyretin (TTR) amyloidosis (ATTR).54–57 ATTR consists of hereditary ATTR (ATTRv), which is caused by a TTR gene mutation (traditionally called familial amyloid polyneuropathy), and systemic wild-type ATTR (ATTRwt; also known as senile systemic amyloidosis), which is caused by deposition of wild-type TTR without a TTR mutation. A definitive diagnosis of amyloidosis requires histopathological evidence of amyloid deposition in tissue, but a biopsy of abdominal fat or upper gastrointestinal mucosa is performed instead of an endomyocardial biopsy because it is a low-risk test, especially for older patients. Technetium-99 m-labeled pyrophosphate (99 mTc-PYP) scintigraphy has attracted attention as a screening tool for ATTR cardiac amyloidosis (see III.4.5 Nuclear Imaging and CT). When these examinations show deposition of TTR in the heart, genetic testing is needed to differentiate ATTRv from ATTRwt.
Acute myocarditis induces cardiac hypertrophy because of inflammatory cell infiltration and myocardial edema.58 Endocrine disorders, such as pheochromocytoma and acromegaly,59–61 and drugs such as corticosteroids may also result in cardiac hypertrophy.62
To differentiate these types of HCM-like cardiac hypertrophy, it is necessary to carefully evaluate medical history, family history, extracardiac symptoms, ECG, blood sampling, and special tests.63 Table 11 shows the extracardiac symptoms that are useful for differentiating secondary cardiomyopathy from HCM.
Finding | Main echocardiographic phenotype | |||
---|---|---|---|---|
HCM | DCM | ARVC | RCM | |
Learning difficulties, mental retardation |
Mitochondrial diseases Noonan syndrome Danon disease |
Dystrophinopathies Mitochondrial diseases Myotonic dystrophy FKTN mutations |
Noonan syndrome | |
Sensorineural deafness | Mitochondrial diseases Anderson–Fabry disease LEOPARD syndrome |
Epicardin mutation Mitochondrial diseases |
||
Visual impairment | Mitochondrial diseases (retinal disease, optic nerve) TTR-related amyloidosis (vitreous opacities, cotton wool type) Danon disease (retinitis pigmentosa) Anderson–Fabry disease (cataracts, corneal opacities) |
CRYAB (polar cataract) Type 2 myotonic dystrophy (subcapsular cataract) |
||
Gait disturbance | Friedreich’s ataxia | Dystrophinopathies Sarcoglycanopathies Myofibrillar myopathies |
||
Myotonia (involuntary muscle contraction with delayed relaxation) |
Myotonic dystrophy (type 1 and type 2) |
|||
Paraesthesiae/sensory abnormalities/ neuropathic pain |
Amyloidosis Anderson–Fabry disease |
Amyloidosis | ||
Carpal tunnel syndrome (bilateral) |
TTR-related amyloidosis | Amyloidosis | ||
Muscle weakness | Mitochondrial diseases Glycogenosis FHL1 mutation |
Dystrophinopathies Sarcoglycanopathies Laminopathies Myotonic dystrophy Desminopathy |
Desminopathies (generally distal progressing to proximal) |
|
Palpebral ptosis | Mitochondrial diseases Myotonic dystrophy |
|||
Lentigines/caféau lait spots |
LEOPARD syndrome | |||
Angiokeratomata Hypohidrosis |
Anderson–Fabry disease | |||
Pigmentation of skin and scars |
Haemochromatosis | |||
Palmoplantar keratoderma and woolly hair |
Carvajal syndrome | Naxos and Carvajal syndromes |
ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; RCM, restrictive cardiomyopathy; TTR, transthyretin. (Source: Prepared based on Rapezzi C, et al. 201363)
3.1 Prevalence
The prevalence of HCM varies widely depending on the patient and the method used. A nationwide epidemiological survey based on a questionnaire conducted on hospitals by the Ministry of Health, Labour and Welfare’s Special Diseases Idiopathic Cardiomyopathy Research Group in 1998 estimated the total number of patients to be 21,900 and the prevalence to be 17.3/100,000 patients. The ratio of men to women with HCM was 2.3 : 1, and the distribution peaked at 60–69 years of age for both sexes.64,65
However, because HCM often progresses without symptoms, it is necessary to estimate the prevalence from a general cohort study. Globally, cohort studies have estimated the prevalence of HCM as about 1 in 500, with only weak racial differences.66–72
On the other hand, in recent years, diagnostic imaging techniques using ECM and CMR have advanced, and genetic screening technology has improved the diagnostic rate; therefore, the prevalence is expected to be slightly higher.73
3.2 Prognosis
The major causes of disease-related death in HCM are sudden death, death from HF, and stroke mainly due to embolism caused by atrial fibrillation (AF).
In the early days, the 5- and 10-year survival rates for HCM were 91.5% and 81.8%, respectively,74 and annual mortality rates of 4–6% have been reported in Europe and the USA.75,76
However, these reports are from tertiary centers with many severe cases. In a large epidemiological study conducted in Japan in 2002, the annual mortality rate for HCM was 2.8%, and the most common causes of death were arrhythmia (31.9%) and HF (21.3%).66 The prognosis of female patients is worse than that of males.77 Currently, mortality rates of approximately 0.5–1.5%/year have been reported in unselected patient populations, coupled with advances in treatment.14,78,79
4. Diagnosis and Examination
4.1 Symptoms and Physical Examination (Table 12)
Clinical symptoms |
(I) Symptoms associated with hypertrophy |
Chest pain, shortness of breath, dyspnea, palpitation |
(II) Symptoms associated with LVOTO |
Faint, near-syncope, syncope |
(III) Arrhythmia |
Palpitation, faint, dizziness, near-syncope, syncope, sudden death |
(IV) Symptoms associated with embolism |
Paralysis (limb, face), dysarthria, pain due to impaired blood flow |
Physical findings |
(I) Palpation |
Double apical impulses, bisferiens pulse in carotid artery |
(II) Auscultation |
S4, S3, paradoxically split S2, systolic ejection murmur |
LVOTO, left ventricular outflow tract obstruction.
4.1.1 Symptoms
In general, HCM patients are often asymptomatic, and this disease has no characteristic symptoms. However, LVOTO often causes symptoms, which provides important information in relation to treatment strategies. The subjective symptoms of patients with HCM can be divided into chest symptoms and cerebral symptoms.
a. Chest Symptoms
Shortness of breath and dyspnea during exertion are common complaints in patients with HCM. An increase in pulmonary capillary pressure due to an increase in LV end-diastolic pressure with LV diastolic dysfunction and/or obstruction of the LV cavity and a low cardiac output may be related to the appearance of dyspnea. Chest pain and tightness, possibly caused by relative myocardial ischemia or may be due to coronary spasms and coronary artery stenosis,80 are also common symptoms in patients with HCM
Palpitations are caused by arrhythmias or hypercontraction of the LV. Palpitations often accompany supraventricular or ventricular arrhythmias. Palpitations caused by paroxysmal or persistent AF also occur, so it is important to make an appropriate diagnosis using Holter ECG. In particular, AF affects cardiac function and is frequently associated with thromboembolism.81
b. Cerebral Symptoms
Symptoms due to cerebral ischemia, such as light-headedness, faintness, and syncope, are important to note in patients with HCM, and are also important predictors of sudden death.82 These symptoms may be caused by severe arrhythmias such as VT/ventricular fibrillation (VF),83 or to decreased cerebral blood flow resulting from a decrease in blood pressure due to LVOTO. The frequency of these symptoms is high in patients with a small LV cavity or LV pressure gradient.84 These symptoms are provoked by vasodilators, standing position, and drinking alcohol.
4.1.2 Physical Examination
a. Inspection and Palpation
The most important finding in patients with HCM is a strong atrial kick associated with poor LV compliance, which can be palpated as a double apical impulse.85 This finding is more prominent in the left lateral position. A double apical impulse is a common finding in patients with HOCM and is often recognized in patients with nonobstructive HCM. Bisferiens pulse in the carotid artery is also palpable (Figure 7).
Systolic ejection murmur and bisferiens pulse in carotid artery in hypertrophic cardiomyopathy (HCM).
b. Auscultation
The abnormal sound most frequently heard in patients with HCM is the IVth sound, which is a left atrial (LA) contraction sound due to reduced LV compliance that is especially heard in patients with HCM with good contractility. The IIIrd sound is also frequently heard. In patients with nonobstructive HCM, systolic murmurs sometimes are heard due to the accelerated flow of the LVOT.
A characteristic feature of auscultation in patients with LVOTO is a systolic murmur heard from the apex to the left edge of the 4th intercostal sternum, with a peak from middle to late systole. In contrast to the systolic murmur heard in aortic stenosis, the one in HOCM shows weak radiation to the neck. It is important that this systolic murmur is easily enhanced by the Valsalva maneuver or a standing load that increases the pressure gradient. This murmur is significantly enhanced in premature systolic heart beats.86 In patients with LVOTO, mitral regurgitation is often complicated. Because LVOTO leads to prolongation of LV ejection time, decreased IIa and IIp intervals or reversal of 2 sounds can occur (paradoxical splitting). The characteristic auscultation finding in the midventricular obstruction type is a soft systolic murmur near the apex.
4.2 Electrocardiography (ECG)
4.2.1 Standard ECG
ECG is a sensitive and useful screening tool, and 75–96% of patients with HCM show abnormal ECG findings, such as an abnormal Q wave, ST–T change, a negative T wave, and high voltage in the left precordial lead.87 Individual ECG findings are related to the type, degree, and stage of hypertrophy. On the other hand, the ECG findings are diverse and nonspecific, so it is not possible to make a definitive diagnosis of HCM or to discriminate between obstructive and nonobstructive HCM using ECG alone.
a. P Wave
Left atrial (LA) load due to LV diastolic dysfunction is observed.
b. QRS Wave
High voltage in the left precordial leads is frequently observed. In nonobstructive HCM, high voltage is more prominent in leads V3 and V4 than in leads V5 and V6.88 LVH findings are more common in HCM and in cases of diffuse hypertrophy and apical HCM.89 In addition, an increase in R waves in the right precordial lead is considered to be a reflection of septal thickening. It has been reported that the frequency of cardiac events is high if the QRS wave increases by ≥1.0 mV over a 5-year period.90 On the other hand, a decrease in the QRS wave reflects degeneration and fibrosis of the myocardium.89,91 A sustained decline in the QRS wave is often seen in D-HCM, and the prognosis is poor if new intraventricular conduction disturbances or abnormal Q waves appear.92
i. Disappearance of Abnormal and Septal Q Waves
Abnormal Q waves are observed in 25–31% of adult cases of HCM.89 There are 2 possible causes of abnormal Q wave formation: unequal hypertrophy of the septum, and myocardial degeneration, which indicates a deep and narrow Q wave. The frequency of abnormal Q waves is high in younger patients with hypertrophy confined to the septum.89 The Q wave decreases and sometimes disappears when the hypertrophy extends to the LV free wall or fibrosis occurs in the septal myocardium. Apical HCM and RV hypertrophy are not accompanied by abnormal Q waves.
ii. Other QRS Abnormalities
Axial deviation is observed in 20–30% of cases. Left axis deviation is common, and reflects impairment of the conduction system. Pre-excitation (WPW syndrome) is observed in 1–5% of cases.93,94
c. ST–T Segment
ST depression and negative T waves are seen in most cases of HCM. It is presumed that these changes are due to relative myocardial ischemia of the subendocardial myocardium. These changes are associated with ventricular hypertrophy, primary changes associated with a delay in the repolarization process of the hypertrophic myocardium, and secondary changes associated with changes in the depolarization process. Strain patterns are also frequently observed.
A giant negative T wave with high voltage in the left precordial lead, seen in apical HCM, is symmetric at ≥1.0 mV, locating in leads V3–5, and is often accompanied by ST depression; the thicker the apex wall, the deeper it becomes. High voltage and giant negative T waves often decrease or disappear over time and may be a sign of poor prognosis.95
Occasionally, the left precordial leads, II, III, and aVF, or leads I, aVL show ST elevation with reduced R waves or wide abnormal Q waves, suggesting progression of myocardial degeneration. This is often seen in patients with D-HCM or apical ventricular aneurysm.
d. QT Interval
In HCM, the QT or heart rate-corrected QT (QTc) interval is often prolonged,96 but no evidence has been reported that this is directly related to the occurrence of fatal arrhythmias, or that increased QT dispersion in the 12-lead ECG could be a predictor of fatal arrhythmias or sudden death.96,97
4.2.2 Holter ECG
A variety of arrhythmias, such as ventricular or supraventricular tachyarrhythmia and bradyarrhythmia, can occur, and can cause syncope, sudden death, and cardiogenic thromboembolism. Because most arrhythmias are asymptomatic, Holter ECG should be recorded in all cases. Guidelines in Europe and the USA recommend that recording is performed at least once a year for at least 48 h.
a. Ventricular Arrhythmias
Holter ECG shows premature ventricular contraction in 50–85% and nonsustained VT in 20–28% of HCM cases.98,99 Most of these arrhythmias are asymptomatic, the tachycardia rate is often ≤180 beats/min, and typically no difference is seen in the frequency of occurrence between obstructive and nonobstructive HCM. Most cases of sustained VT are polymorphic, and result in poor hemodynamic status and syncope or sudden death. On the other hand, sustained monomorphic VT may be associated with D-HCM or HCM with LV apical ventricular aneurysm.100 Nonsustained VT is considered a risk factor for sudden death.100,101 The sensitivity and specificity are both approximately 70%, and the negative predictive value is as high as 95% or more, but the positive predictive value is as low as 20–25%.101 Many children, and cases of young sudden deaths from HCM, do not show ventricular arrhythmias.
b. Supraventricular Arrhythmias
Atrial tachyarrhythmia is observed in 30–50% of cases, and the detection rate of paroxysmal AF is 5–15%.101 Supraventricular tachyarrhythmia in HCM is a prognostic factor.
c. Signal-Averaging ECG
The frequency of late potential detection on signal-averaged ECG is 15–30%, and is reported to be related to VT; however, no consensus has been reached regarding its usefulness.102,103
4.2.3 Exercise Test and Cardiopulmonary Test (Table 13)
Recommendation | COR | LOE | GOR (MINDS) |
LOE (MINDS) |
---|---|---|---|---|
CPET to assess the severity of exercise intolerance and change in systolic blood pressure |
IIa | C | B | IVb |
CPET to plan invasive therapies for LVOT obstruction and to assess the response to the therapy |
IIa | C | C1 | IVb |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence; LVOT, left ventricular outflow tract.
Unexplained syncope associated with exercise is a very strong risk factor for sudden death. In addition, an abnormal blood pressure increase response (<25 mmHg) during exercise, accompanied by a persistent decrease in blood pressure, or abnormal blood pressure responses with a temporary decrease in blood pressure in the early stage of recovery, are observed in young patients or those with a family history of sudden death, and is thus one of the major risk factors for sudden death.104,105
In most cases of HCM there are only relatively minor symptoms, but many patients have reduced exercise capacity.106 Impaired exercise capacity in HCM is associated with many factors, including LV diastolic dysfunction, LVOT pressure gradient, myocardial ischemia, reduced systolic function, and AF. Decreases in maximal oxygen uptake and ventilatory response in cardiopulmonary exercise tests have been reported to be associated with all-cause death, worsening of HF symptoms,107,108 and sudden death.109 It has been reported that exercise tolerance is improved by reducing the pressure gradient by myocardial resection or percutaneous transluminal septal ablation (PTSMA). Therefore, the evaluation of exercise tolerance in HCM is useful for predicting prognosis, determining treatment strategies for reducing pressure gradients, and evaluating responsiveness to treatment.21 However, complications such as severe arrhythmias and decreased blood pressure during exercise have been reported in patients with HCM.
4.2.4 Electrophysiological Study
Extra-atrial or high-frequency stimulation may induce persistent AF or atrial flutter, or reentrant supraventricular tachycardia. In asymptomatic HCM, the rate of induction of persistent VT is not high. The rate of induction of sustained VT in HCM patients with syncope, a history of cardiopulmonary resuscitation, or nonsustained VT has been reported to be 15–18% with double early stimulation, and 27–44% with triple early stimulation, most cases of which are polymorphic VT.110,111 The induction of sustained VT is one of the predictors of cardiac accidents,112 but the accuracy of prediction of sudden death by electrophysiological tests remains limited.
4.3 Echocardiography
The role of echocardiography in HCM is to evaluate cardiac morphology, which contributes to the diagnosis and classification of HCM, cardiac function, hemodynamics, and complications, which contribute to severity. The details of echocardiography for cardiomyopathy are also described in “JCS 2021 Guideline on the Clinical Application of Echocardiography”.113
4.3.1 Transthoracic Echocardiography (TTE; Table 14)
COR | LOE | GOR (MINDS) |
|
---|---|---|---|
Echocardiography to evaluate morphology and LV wall thickness in patients with suspected HCM |
I | B | B |
1) Establish the diagnosis of HCM and identification of morphologic subtype, evaluation of hemodynamics, LV function, and comorbidities |
|||
2) Evaluation of severity and distribution of LV hypertrophy | |||
3) Evaluation of LV systolic function and LV diastolic function | |||
4) Detection and quantification of LVOT obstruction | |||
5) Detection and quantification of mitral regurgitation | |||
Echocardiography to evaluate severity of heart failure, cardiac function and hemodynamics |
I | C | B |
Echocardiography in patients with HCM | I | C | C1 |
1) Reevaluation in patients with obvious change in clinical status | |||
2) Echocardiography for detection of echocardiographic findings suggesting infective endocarditis such as vegetation for patients in the clinical situations which infective endocarditis is suspected |
|||
*Transesophageal echocardiography should be considered if necessary | |||
Stress echocardiography (Valsalva maneuver, standing) for detection of dynamic LVOT obstruction in patients with a peak LVOT gradient <50 mmHg at rest |
I | C | C1 |
Exercise echocardiography for detection of dynamic LVOT obstruction in symptomatic patients with a peak LVOT gradient <50 mmHg at rest |
IIa | B | C1 |
Echocardiography as a follow-up procedure for patients with HCM without any change in clinical status |
IIa | C | C1 |
Exercise echocardiography for detection of dynamic LVOT obstruction in asymptomatic patients with maximum provoked peak LVOT gradient <50 mmHg after Valsalva maneuver or during standing stress echocardiography |
IIb | C | C2 |
Echocardiography as a screening tool for family members of patients with HCM | IIb | C | C2 |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence; LV, left ventricular; LVOT, left ventricular outflow tract.
a. Morphology
The characteristic hypertrophic mode of HCM is a nonuniform LV wall, which cannot be explained by pressure load, and is ≥15 mm (≥13 mm in patients with a family history) anywhere in the LV.6 Hypertrophy may be localized in not only the ventricular septum, but also the posterior, anterior, and lateral walls of the LV, and even the RV. Apical HCM is more common in Japan than in other countries.31 Maron et al’s classification is thickening limited to the anterior septum (type I), thickening of the entire septum (type II), thickening from the septum to the LV anterior and lateral walls (type III), and thickening of parts other than the anterior septum (type IV).114 The hypertrophy pattern is based on the parasternal short-axis view, the parasternal long-axis view, and apical 2- and 4-chamber cross-sectional images, which are observed so as not to be overlooked. The apical type may be difficult to depict on echocardiography and is comprehensively diagnosed using other diagnostic imaging methods such as CMR and CT.
Caution must be taken because nonuniform LV wall thickening is also seen in severe RV overload, hypertensive cardiac hypertrophy, aortic stenosis, etc., and symmetric wall thickening is not rare, even in HCM.115 Fabry disease must be differentiated because it shows circumferential LVH due to glycosphingolipid accumulation in myocardial cells. Left ventricular and atrial enlargement, LV diastolic dysfunction, and mitral regurgitation are also seen in combination.116,117
b. Cardiac Function and Hemodynamics
i. LV Systolic Function
In HCM, a normal or mild increase in the LVEF is typically seen. However, stroke volume is considered to have decreased, especially in cases where the lumen is narrowed, and caution is required when the heart rate is low. At first glance, the LVEF is maintained in some cases; however, the global longitudinal strain value is sometimes decreased and in these cases patients are reported to have a poor prognosis. Therefore, LV systolic function should not always be considered normal.118
In some cases, hypertrophic ventricular thinning, reduced wall motion, and LV expansion are observed during the course of the disease. DCM-like pathophysiology, such as congestive HF is also observed.119 These patients are considered to have a poor prognosis and account for almost 10% of heart transplant cases in Japan.
ii. LV Diastolic Function
LV diastolic function is impaired in HCM. Typical LV inflow abnormalities in HCM include decreased early diastolic waves (E waves), prolonged deceleration, and increased atrial systolic waves (A waves). Further deterioration of LV diastolic function results in a so-called pseudo-normalized or restrictive pattern,120 the waveforms of which are due in part to an increase in LA pressure. However, in most cases of HCM, normal LVEF is maintained, which makes it difficult to predict LV diastolic pressure using LV inflow blood flow waveforms.121 Therefore, LV diastolic dysfunction is usually assessed by tricuspid regurgitation velocity, the presence or absence of LA volume expansion, or the ratio between the early expansion rate of the mitral annulus velocity (E’) and the maximum blood flow velocity of the E wave (E/E’) using the tissue Doppler method (Figure 8).122 LV diastolic dysfunction and AF often lead to LA enlargement.
Assessment of diastolic function in HFpEF. HFpEF, heart failure with preserved ejection fraction; LA, left atrial; LVEF, left ventricular ejection fraction; TR, tricuspid regurgitation. (Source: Prepared based on Nagueh SF, et al. 2016122)
iii. LVOT Gradient and Mitral Complex Abnormalities
HCM often presents with a functional obstruction between the LV septum and the anterior mitral valve leaflet. This is classified as HOCM and thus distinguished from nonobstructive HCM.
LVOTO causes an increase in LV systolic pressure, resulting in prolonged LV relaxation time, increased LV end-diastolic pressure, mitral regurgitation due to systolic anterior motion (SAM), myocardial ischemia, and reduced cardiac output. Previously, the main underlying mechanism of SAM has been explained by the Venturi effect, in which the mitral valve is pulled into the septum by the negative pressure generated by the rapid passage of blood through the obstructed outflow tract. However, its effect is thought to be minimal. In recent years, it has been reported that: (1) the mitral valve is pulled to the septal side during LV contraction because of anterior deviation of the papillary muscle, and then displaced into the outflow tract; (2) an extra portion is created at the tip of the anterior cusp because of the junction with the cusp; and (3) narrowing between the papillary muscles causes slack in the chords attached to the central part of the anterior cusp, and the tip of the mitral valve (particularly the central part) loses tension and is affected by the blood flow in the outflow tract. Through these mechanisms, the main one being the mechanism that results in blockage of the outflow tract, the position of the mitral valve complex shifts during LV systole, which causes a further shift of the anterior leaflet to the outflow tract by drag force (flow drag [pushing] mechanism), resulting in obstruction of the outflow tract.123–125 The evidence for this is that in many cases, at the onset of SAM of the anterior cusp, the flow rate in the LVOT is in the normal range; in addition, dissociation has been found between the actual phenomenon and the Venturi effect theory.126–128 The pressure gradient in the LVOT is extremely variable because of various factors. In particular, increased contractility, reduced preload, and reduced afterload cause a reduction in ventricular volume, bring the mitral valve closer to the septum, and increase the pressure gradient.
SAM is confirmed using the M-mode method. For cases in which LVOTO disrupts ejection flow, mid-systolic half-closure of the aortic valve is seen. High-speed blood flow through the LVOT is observed as a mosaic signal in color Doppler images, and as an ejection flow velocity waveform with a peak in the middle to late systole using the continuous wave Doppler method. The LVOT and mitral regurgitation blood flow waveforms are very similar, except that the former spans from the aortic valve opening to the aortic valve closing, the latter from the mitral valve closing to the mitral valve opening, and these are differentiated by their duration. If the blood flow signals overlap and become difficult to distinguish, the high pulse repetition frequency method is used.
The pressure gradient due to LVOTO is important in the risk assessment of sudden death. Therefore, it is necessary to try to detect the pressure gradient by having the patient rest and perform a Valsalva maneuver in a seated or semi-seated position (Figure 9).129 In patients with a pressure gradient <50 mmHg using the modified Bernoulli equation, yearly follow-up is sufficient for asymptomatic cases, but if symptomatic, exercise stress testing using a treadmill or ergometer is recommended (Figure 10).7,19,20 However, because a unified protocol has not been established and risks are involved in exercise testing, each laboratory requires sufficient training.130 Pressure gradient induction with dobutamine or nitrate under echocardiography is not a physiological test, and should only be used for patients with difficult exercise loads. SAM may cause mitral valve leaflet distortion and mitral regurgitation. In D-HCM, functional mitral regurgitation is observed with LV dilatation and reduced systolic function, so a more careful evaluation is needed because this affects the prognosis.
Assessment and treatment of LV outflow tract obstruction. (Adapted from Braunwald E. 1997129) ©Elsevier (1997)
Protocol for the assessment and treatment of left ventricular outflow tract obstruction. (Adapted from Elliott PM, et al. 20147)
iv. Midventricular Obstruction (MVO)
In this type of HCM, the enlarged papillary muscles deviate during systole and create an obstruction. Specifically, the middle of the LV is obstructed by the septum, side wall, and papillary muscle, the degree of thickening of each part, and the positional relationship during mid-systole. In apical HCM, hypertrophy around the apex leads to lumen obstruction, which may be accompanied by a ventricular aneurysm.30 Severity is influenced by contractility, preload, and afterload. It has been reported that prognosis is poor in patients with apical HCM associated with obstruction and a ventricular aneurysm in the apex. Apical ventricular aneurysms cannot be diagnosed from transthoracic echocardiograms in 40% of cases, and it has been reported that diagnosis is possible only after CMR.25
4.3.2 Transesophageal Echocardiography (Table 15)
COR | LOE | GOR (MINDS) |
|
---|---|---|---|
TEE in patients strongly suspected as HCM by clinical symptoms or transthoracic echocardiography, but unclear if LVOT or hemodynamics due to poor TTE windows. Or in patients undergoing septal myectomy, perioperative TEE should be used to guide the surgical strategy |
I | C | B |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
Transesophageal echocardiography (TEE) is useful in the cases as shown below. First, TTE does not provide sufficient images. Second, the blood velocity of LVOTO is difficult to differentiate from that of mitral regurgitation. Finally, TEE is necessary in myocardial resection.131,132
4.4 Cardiac Magnetic Resonance Imaging (Table 16)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Cine CMR affords greater accuracy than echocardiography in identifying regions of LV hypertrophy (anterolateral free wall and apex), mitral valve or papillary muscle abnormalities not readily recognized by echocardiography |
I | A | B | II |
Late gadolinium enhancement (LGE) pattern on CMR is useful to distinguish hypertrophic cardiomyopathy or other LV hypertrophy disease |
I | B | B | IVa |
The presence and extent of LGE is significantly associated with sudden cardiac death, all cardiac death and all-cause death in patients with HCM |
I | A | B | IVa |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
TTE has long been used for diagnostic imaging of HCM, but in recent years, with the remarkable development of CMR hardware and software, high spatial and temporal resolution has made it possible to capture the morphology and functions of the heart using CMR. Of several imaging methods, cine magnetic resonance imaging (MRI) is capable of capturing moving images with high spatial resolution on any cross-section. It is also excellent for identifying the location and degree of hypertrophy in HCM, and for evaluating the presence or absence of LVOTO and SAM. Furthermore, delayed-contrast MRI using a gadolinium contrast agent has high contrast discrimination ability between damaged and normal myocardium, and is able to depict the damaged myocardium and site of fibrosis more clearly than can contrast-enhanced CT. It provides valuable information for not only the diagnosis of HCM, but also the judgment of severity, including risk assessments of sudden death.
4.4.1 Cine MRI
a. Evaluation of Hypertrophy Site and Wall Thickness
In actual imaging, steady-state free precession sequences are recommended. Cine MRI is widely recognized as the standard for evaluating LV volume, RV volume, cardiac output, cardiac weight, and regional wall motion in the heart.133,134
Patients for whom a sufficient number of images to confirm hypertrophy by echocardiography cannot be achieved are good indications for CMR. Because of its high spatial and temporal resolution, CMR not only obtains a high contrast between blood flow and the myocardium, but also has no limitations on the imaging screen or imaging plane. That is, in anatomical evaluations, CMR provides additional information beyond that obtained by echocardiography.135,136 In addition, cine MRI can provide a better assessment of LVH and anatomic abnormalities of the mitral valve and papillary muscles in areas that are difficult to observe on echocardiography (e.g., anterior wall and apex)135,137,138 (Figure 11).
Cine MRI in HCM. (A) Asymetric septal hypertrophy. (B) Apical HCM. (C) Mid-ventricular obstruction with apical aneurysm.
b. Anatomic Evaluation of LVOT, Papillary Muscles, and Subvalvular Lesions
LVOTO is an important phenotype of HCM that is determined by complex anatomic relationships of the septum, LVOT, mitral valve, and papillary muscles. TTE or TEE is the standard for dissection of the LVOT and evaluation of the flow profile; however, the advantages of CMR include the ability to observe presystolic movement of the ventricular septum and subvalvular lesions. MVO associated with midventricular hypertrophy can also be evaluated. In addition, in HCM, papillary muscle abnormalities are common, so the dissection of subvalvular lesions can be observed on both long- and short-axis cine MRI. This is particularly effective in patients with dynamic LVOTO without classical septal asymmetric thickening. CMR also contributes to the assessment of structural abnormalities of the mitral valve and papillary muscles in patients undergoing invasive catheterization therapy or surgery. In addition, CMR may be able to identify additional sites of hypertrophy, structural abnormalities of the mitral valve and papillary muscles, or the functional cause of the LVOTO, which cannot be identified by echocardiography.135,139
Therefore, when examining the indication for PTSMA or surgical resection for LVOTO, it is advisable to conduct an evaluation.60,135,140–143 In addition, cine MRI can be used for the quantitative evaluation of LV weight,144 the extension of hypertrophy to the RV myocardium,145 and discontinuous cardiac hypertrophy.134,141
4.4.2 Apical HCM and MVO
CMR is effective for observing apical HCM, which is difficult to observe on TTE because of the restriction and shortening of the acoustic window.145 It has been reported that 40% of apical ventricular aneurysms are missed on noncontrast TTE,25 but in many cases are easy to identify with CMR. Apical aneurysms present with thinned myocardium showing reduced or no contraction, and delayed-contrast MRI often shows positive transmural fibrosis, which is associated with adverse events. In addition, MVO with ventricular aneurysm is often accompanied by severe arrhythmias, and delayed-contrast MRI is useful for diagnosis.146
4.4.3 Late Gadolinium Enhancement (LGE) CMR
In HCM, many of the sites that show high-intensity signals on delayed-enhanced MRI may indicate myocardial fibrosis. A site showing such a high signal is judged to be LGE-positive, and quantitative evaluation can be performed based on the percentage of the total LV volume. LGE positivity is found in approximately 70% of patients with HCM, mainly in the thickened part of the LV wall and at the junction between the ventricular septum and the free wall of the RV (Figure 12). Such LGE patterns are useful for the differential diagnosis of HCM and other hypertrophic diseases.147,148
LGE in HCM. (A) Asymmetric septal hypertrophy. (B) Apical HCM. (C) Midventricular obstruction with apical aneurysm.
a. Stratification of Sudden Death Risk
In HCM, the relationship between LGE and prognosis remains a topic of debate, but the prognosis is generally good in patients without LGE. A study of the relationship between the presence of LGE and prognosis in 711 patients with HCM reported finding no association between LGE and the risk of sudden death over a 3.5-year period.149 On the other hand, in a study using quantitative contrast-enhanced MRI in 1,300 patients with HCM, widespread LGE positivity was an independent predictor of sudden death, and LGE levels accounted for 15% of the LV weight. In addition, the risk of sudden death has been shown to double even in HCM without a general risk of sudden death.150 In an observational study comparing the risk of VT based on 24-h Holter ECG with or without LGE in HCM, the risk of VT was high in HCM with vs. without LGE, suggesting that myocardial fibrosis is a structural lesion in the development of potentially fatal reentrant VT.151 A meta-analysis152 of 7 studies showed that the presence of LGE increased the risk of sudden death (SCD by 3.41-fold, total death by 1.8-fold, and cardiac death by 2.93-fold). In addition, the extent of LGE was associated with an increase in SCD. In the 10% LGE range, the risk of SCD was 1.56-fold higher, HF death 1.61-fold, all-cause death 1.29-fold, and cardiac death 1.57-fold. Even when adjusted for the baseline values, the extent of LGE was strongly associated with a 1.57-fold higher risk of SCD at 10% LGE. The presence and extent of LGE was strongly associated with sudden, cardiac, and all-cause death in HCM.153,154
4.4.4 Differential Diagnosis
a. Hypertensive Heart Disease and Aortic Stenosis
In both diseases, the hypertrophy is often concentric. HCM and hypertensive heart disease can be sometimes difficult to differentiate, but in hypertensive heart disease, the LV wall thickness is often <15–16 mm. LGE positivity has been considered to be rare in hypertensive heart disease and aortic stenosis, but recent reports indicate that more than 50% of patients with severe LVH have patchy fibrosis in both cases.155 There are reports that HCM can be accurately distinguished from hypertensive heart disease using native T1 mapping.156
b. Athlete’s Heart
The characteristics of athlete’s heart are mild dilatation of the LV, symmetric thickening of the LV wall (<15 mm), and normal diastolic function on Doppler echocardiography. CMR is complementary to TTE because it can accurately and reproducibly measure LV volume, weight, and function.
c. Left Ventricular Noncompaction
CMR is excellent at delineating the compacted and noncompacted layers of LVNC. It has been proposed that the ratio of layers of noncompaction to compaction at the end of diastole should be 2.4, with ≥1.0 used as a diagnostic criterion for imaging diagnosis of LVNC.
d. Infiltrative Disease
i. Fabry Disease
Delayed-contrast MRI is associated with the extent of LVH and is typically found in the middle layer or below the epicardium of the inferolateral wall of the heart.157 The native T1 value in e T1 mapping is characterized by a low value compared with high native T1 values in LVH caused by other diseases.158 In particular, before the onset of hypertrophy, moderate decrease is seen in the native T1 value because of lipid accumulation in the myocardium.159 CMR is used to monitor the regression of LVH associated with enzyme-replacement therapy.160
ii. Eosinophilia Syndrome
In Loeffler endocarditis associated with eosinophilia syndrome, subendocardial fibrosis and mural thrombus are observed. Delayed-contrast MRI shows the fibrosis and inflammation and is useful for identifying mural thrombi.161
iii. Sarcoidosis
Normally, this cardiomyopathy is a form of RCM, especially in the acute phase of inflammation, where the site of inflammation is hypertrophic and shows asymmetric septal thickening. In addition, the LGE distribution pattern varies.162
iv. Amyloidosis
Preserved systolic function, diffuse LVH, and thickening of the free wall and septum of the atrium are observed. CMR reveals circumferential LGE below the endocardium from the base to the middle of the LV. The characteristic feature is that the time to zero signal of the myocardium after administration of the gadolinium contrast agent is short, and if delayed imaging is not started earlier than normal imaging, the time of positive delayed imaging may be missed.163 The native T1 value is extremely high.164
4.5 Nuclear Imaging and CT
4.5.1 Nuclear Imaging (Table 17)
COR | LOE | GOR (MINDS) |
|
---|---|---|---|
Radionuclide angiography to assess left ventricular function in patients who cannot be assessed with echocardiography |
IIa | C | C1 |
99m-Tc pyrophosphate scintigraphy to rule out transthyretin-related cardiac amyloidosis (ATTRv and ATTRwt) |
I | B | B |
Gallium scintigraphy or FDG-PET to differentiate HCM from cardiac sarcoidosis | IIa | C | C1 |
Myocardial perfusion imaging to assess abnormal left ventricular hypertrophy and predict the prognosis of patients with HCM |
IIb | C | C2 |
Myocardial fatty acid metabolism imaging to assess myocardial damage and predict the prognosis of patients with HCM |
IIb | C | C2 |
Myocardial sympathetic nerve imaging to assess myocardial damage and predict the prognosis of patients with HCM |
IIb | C | C2 |
Radionuclide angiography to assess left ventricular morphology and function in patients who can be assessed with echocardiography |
IIb | C | C2 |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
At present, advances in echocardiography and CMR, with excellent temporal and spatial resolution, have reduced the usefulness of nuclear imaging in the morphological and functional diagnoses of HCM. However, nuclear imaging can be used to evaluate myocardial blood flow, metabolism, and sympathetic nervous function, which are useful for estimating prognosis.
a. Perfusion Imaging
The accumulation of thallium chloride and 99 mTc-labeled sestamibi and tetrofosmin in myocardial tissue depends on myocardial blood flow and the number of myocardial cells. Because hypertrophy is depicted as a high accumulation of tracers, morphological asymmetric hypertrophy can be diagnosed. If ECG-gated acquisition is performed, the contractility of the LV can be evaluated.
In HCM, the finding of myocardial perfusion abnormalities such as redistribution phenomena and fixed defects seen in stress thallium myocardial scintigraphy indicate not only by coronary atherosclerotic lesions, but also reduced coronary blood flow reserve, cardiomyocyte necrosis, and myocardial fibrosis, scarring, etc.165–167
Fixed defects are associated with a history of syncope, enlargement of the LV cavity and LA diameter, decreased LV contractility, and decreased maximal oxygen uptake. In addition, a relationship has been reported between fixed defects and LGE as evaluated by CMR.168 Although redistribution is not necessarily associated with anginal symptoms, it is associated with increases in the LA diameter and LV wall thickness, and is often seen in patients with preserved LV contractility.169,170
Young patients with reversible defects are at high risk of fatal arrhythmias.171 On the other hand, no consensus has been reached regarding whether stress myocardial perfusion imaging and prognosis are actually related in adult cases.172
b. Myocardial Fatty Acid Metabolism Imaging
123I-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (123I-BMIPP) is taken up and retained by cardiomyocytes depending on the state of fatty acid metabolism in the myocardium. In HCM, the defect is most common in the RV free wall attachments on the anterior and posterior sides of the ventricular septum, and the extent of the defect reflects the degree of myocardial cell damage.173 A lower level of 123I-BMIPP uptake compared with myocardial perfusion tracers (mismatch phenomenon) is often seen in HCM (Figure 13), but not in other diseases that cause LVH, such as hypertensive heart disease; therefore, it is useful for discriminating diseases.174–177 The greater the severity of the defects, the greater their extent, the greater the incidence of subsequent cardiac accidents, and the poorer lifetime prognosis.178,179
Myocardial perfusion imaging (Left) and BMIPP imaging (Right) in patients with hypertrophic cardiomyopathy.
c. Cardiac Sympathetic Nerve Imaging
123I-metaiodobenzylguanidine (123I-MIBG) is an analog of norepinephrine thought to be able to evaluate sympathetic nerve function and the density of nerve distribution to the heart muscle. The defect site coincides with the hypertrophy site, and the stronger the defect, the greater the myocardial damage.180 Clearance is enhanced in the apical portion of the septum compared with healthy subjects,181 and the clearance increases with decreases in the contractile and diastolic function, and increases with the degree of hypertrophy.182 A relationship between enhanced clearance of the entire LV and VT has also been reported.183,184
d. Radionuclide (RI) Angiography
Multigated acquisition (MUGA) RI angiography can detect morphologically asymmetric septal hypertrophy (ASH), narrowing of the LV lumen during systole, and LVOTO by visualizing the LV and RV chambers. Deterioration of the LV diastolic index (e.g., decreased maximum filling rate, prolonged time to maximum filling rate, prolonged isovolumetric dilation time) can also be detected, which may also be a predictor of death.185
e. Other
Positron emission tomography (PET) using fluorodeoxyglucose (FDG) can be used to evaluate myocardial glucose metabolism, but it has been reported that FDG uptake can be either decreased186–188 or increased189 in the hypertrophic ventricular septum. In cardiac amyloidosis due to mutation or wild-type TTR deposition, abnormal accumulation of 99 mTc-PYP in the myocardium is observed, which has been reported to be particularly sensitive and useful for diagnosis;190–192 no accumulation is seen in HCM, which is useful for differentiation.
4.5.2 Cardiac CT (Table 18)
COR | LOE | GOR (MINDS) |
|
---|---|---|---|
Assessment of coronary stenosis in patients with HCM | I | C | B |
Assessment of which septal branch is the target vessel for PTSMA in patients with HOCM |
IIa | C | B |
Morphological and functional assessment in patients with suspected HCM when echocardiography is inadequate for evaluation and CMR is not feasible |
IIa | C | C1 |
Assessment of myocardial properties based on late enhancement in patient with HCM in whom CMR is not feasible |
IIb | C | C2 |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
Contrast-enhanced CT is mainly used in clinical practice to evaluate cardiac morphology, wall motion, myocardial tissues, and coronary arteries, the purpose of which is to assess coronary artery stenosis by multi-row, multi-slice CT and visualize the septal branch before PTSMA. Although myocardial tissue evaluation by delayed-contrast imaging with CMR using a gadolinium contrast agent has become the gold standard, there have been reports of evaluations by cardiac CT with excellent spatial resolution in recent years.
a. Morphology/Function Evaluation
Echocardiography is essential for the morphological diagnosis of HCM, but CT and CMR are useful when echocardiographic images are difficult to visualize. In recent years, CT has been able to obtain images with better spatial resolution, and can be used to evaluate functions such as wall motion abnormalities. However, evaluation using LV long- and short-axis images is difficult, as is obtaining arbitrary cross-sectional images compared with echocardiography or CMR. In addition, CT and CMR require ECG synchronization, which makes it difficult to scan patients with AF or arrhythmia. Respiratory artifacts also require attention.
b. Coronary Artery Evaluation
Using multi-slice CT, coronary artery imaging is possible in sinus rhythm patients with adequate heart rate control. Although the number of cases is small, coronary artery imaging is also useful for evaluating the site of hypertrophy and coronary arteries in surgical resection of the ventricular septum with HOCM, as well as the ventricular septal perforator, which is the target of percutaneous septal myocardial ablation.193–195
c. Tissue Characterization
In HCM, tissue characterization by delayed-imaging MRI is commonly performed. However, in recent years, tissue characterization by cardiac CT with similar types of delayed imaging has also been performed.196–198 CT can be used even in difficult cases such as after the implantation of a device such as a pacemaker.
4.6 Cardiac Catheterization (Table 19)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Right and left heart catheterization to assess hemodynamics when considering indications for mechanical circulatory support and heart transplantation |
I | B | B | IVa |
Coronary angiography in adult survivors of sudden cardiac arrest, in patients with sustained ventricular tachyarrhythmia and in patients with severe stable angina (Canadian Cardiovascular Society (CCS) Class ≥3) |
I | C | B | IVa |
Right and left heart catheterization to accurately assess the severity of left ventricular outflow tract and mid obstruction, and left ventricular filling pressure in patients with symptomatic heart failure who cannot be assessed adequately with echocardiography, CMR, or other procedures |
IIa | C | B | IVa |
Coronary angiography to assess the ventricular septal perforator to be treated when considering indications for percutaneous septal myocardial ablation or surgical septal reduction |
IIa | C | B | V |
Coronary angiography in patients with typical exertional chest pain (CCS Class <3) who have an intermediate pre-test probability of atherosclerotic coronary artery disease |
IIa | C | B | V |
Left ventriculography to assess ventricular morphology and mitral regurgitation in patients for whom there are inadequate echocardiographic imaging and insufficient CMR and CT or other procedures |
IIb | C | C1 | V |
CCS, Canadian Cardiovascular Society; CMR, cardiac magnetic resonance imaging; COR, class of recommendation; CT, computed tomography; GOR, grade of recommendation; LOE, level of evidence.
The purposes of cardiac catheterization in the diagnosis of HCM are as follows: (1) evaluate LV morphology by LV angiography and regurgitation in the presence of mitral regurgitation; (2) measure LV pressure and accurately evaluate the LV pressure gradient by left heart catheterization; (3) measure cardiac output and right heart pressure; (4) identify secondary cardiomyopathy by endocardial myocardial biopsy; (5) evaluate CAD by coronary angiography in the case of suspected ischemic heart disease; and (6) perform catheter ablation and electrophysiological examinations based on consideration of pacemaker treatment when tachycardia or bradyarrhythmias such as palpitations or syncope are suspected.
4.6.1 LV Angiography
LV angiography in patients with suspected HCM has been performed for some time, but at present, cardiac morphology is often evaluated by noninvasive echocardiography, CMR, and cardiac CT. However, LV angiography is considered when it is difficult to conduct an evaluation by echocardiography or to perform CMR or cardiac CT because of arrhythmic complications such as AF, to place an implantable cardioverter-defibrillator (ICD), or to deliver cardiac resynchronization therapy (CRT).
LV angiography shows thickening of the LV wall and obstruction of the LV cavity. In obstructive HCM, a W- or V-shaped transparent image is observed (W or V sign, respectively). In apical HCM, the cavity suddenly narrows at the apex and shows a spade-like configuration.28 In MVO, characteristic findings such as an hourglass or gourd shape with a narrow neck at the center are obtained.199 In the case of transition to D-HCM, decreased LV wall motion, decreased LVEF, and enlarged LV cavity are observed.
4.6.2 Left Heart Catheterization
By directly measuring the intracardiac pressure, it is possible to accurately evaluate the decrease in diastolic compliance and the difference in systolic pressure in the LV. Although measurement of the pressure differential in the LVOT or the central part of the LV is often performed using the continuous wave Doppler method in echocardiography, it is reasonable to evaluate intracardiac pressure and the pressure gradient for accurate assessment of severity. The reasons for evaluation with left heart catheterization are that accurate evaluation is difficult by echocardiography, and that it is considered better than medical treatment, such as β-blockers, calcium antagonists, and Class Ia antiarrhythmic drugs, and invasive treatments such as PTSMA, myocardial resection, or pacemaker implantation.
In patients with a systolic pressure gradient, the aortic pressure waveform rises sharply, forms a spike at the early stage of ejection, descends, rises again in a dome shape, and finally becomes bimodal (spike-and-dome type). Even if a significant pressure gradient (≥30 mmHg) is not seen at rest, a significant pressure gradient may be induced by the Valsalva maneuver or the Brockenbrough phenomenon after ventricular extrasystole.15,200
4.6.3 Right Heart Catheterization
The usefulness of routine right heart catheterization in HCM has not been proven. Right heart catheterization is performed for the purpose of hemodynamic evaluation if HF symptoms are present and noninvasive evaluations such as echocardiography are difficult, if standard treatment does not improve HF symptoms, if invasive treatment for HOCM is considered, or if it is necessary to consider mechanical circulatory support or heart transplantation. In HCM, it has been reported that a pressure gradient may also occur in the RV outflow tract (RVOT) and the RV,201 and catheterization may be performed for the purpose of accurately evaluating the pressure gradient.
4.6.4 Endomyocardial Biopsy
(See III.4.7 Endomyocardial Biopsy and Pathology)
4.6.5 Coronary Angiography
If one of the main symptoms of HCM is chest pain or tightness during exertion or rest, and if CAD is suspected, coronary angiography is considered. By substituting coronary CT, patients with mild to moderate CAD may be excluded from diagnosis after considering characteristics such as age, sex, and risk factors for CAD, and pretest probabilities. As a poor prognosis has been reported for patients with HCM and CAD,202 coronary angiography is recommended for patients with a high probability of pre-examination, post-cardiac arrest resuscitation and persistent VT, and for symptomatic patients who have previously undergone percutaneous coronary intervention. Coronary angiography in HCM may show myocardial bridging stenosis in which the left anterior descending coronary artery narrows because of myocardial compression coincident with systole, but no relationship with SCD has been established.203–205
In addition, when considering the indications for PTSMA or surgical septal myocardial resection in HOCM, coronary angiography or CT is considered for identifying the perfusion area and the ventricular septal perforator to be treated.193,206
4.6.6 Electrophysiological Tests
(See III.4.2.4 Electrophysiological Study)
4.7 Endomyocardial Biopsy and Pathology
4.7.1 Endomyocardial Biopsy
a. Indications
Developed by Sakakibara and Konno in 1962,207 endomyocardial biopsy by cardiac catheterization is currently performed around the world. It is about the only way to obtain histological information regarding the myocardium in vivo without performing a surgical procedure. Endomyocardial biopsy is not always required for a definitive diagnosis of cardiomyopathy; however, it is not only essential for monitoring allograft rejection, but also beneficial for differential diagnoses between primary cardiomyopathies, myocarditis, and secondary cardiomyopathies, and is potentially useful for the diagnosis of cardiac tumors.208–210
In 2007, the ACC, AHA, and ESC jointly advocated for classification based on clinical scenarios as the international guidelines for the indication of endomyocardial biopsy.209 A joint statement by the European Association for Cardiovascular Pathology and the Society for Cardiovascular Pathology has also been published:208 Table 20 outlines the former. According to these guidelines, immunosuppressive therapy such as steroids is recommended for new-onset HF (clinical scenario 1), in which hemodynamics are disrupted in the acute phase because of fulminant/necrotizing eosinophilic myocarditis or giant cell myocarditis. As eosinophilic infiltration into the myocardial tissue does not necessarily accompany eosinophilia in blood tests, endomyocardial biopsy is helpful for selecting treatment.209 Other cases that are relatively frequent and for which biopsy is highly useful involve the differentiation of sarcoidosis, amyloidosis, Fabry disease, and drug-induced cardiomyopathy due to anthracyclines, etc.208–210 In Japan, prior to the registration of a cardiac transplantation recipient, it is essential to differentiate secondary cardiomyopathies, except for definitive ischemic cardiomyopathy, by endomyocardial biopsy.211 A total of 5,260 endomyocardial biopsies have been performed at the National Cerebral and Cardiovascular Center over 12 years, and the highest indication rate (31.5%) was seen for rejection monitoring after heart transplantation, followed by differential diagnoses of DCM, HCM, and myocarditis, at 23.8%, 14.9%, and 7.5%, respectively.210
Scenario Number |
Clinical Scenario | Representative conditions | COR (I, IIa, IIb, III) |
LOE (A, B, C) |
Grading of ECP Recommendation |
---|---|---|---|---|---|
1 | New-onset heart failure of <2 weeks’ duration associated with a normal-sized or dilated left ventricle and hemodynamic compromise |
Myocarditis (Viral, Eosinophilic, Giant cell)·Cardiomyopathy |
I | B | S |
2 | New-onset heart failure of 2 weeks’ to 3 months’ duration associated with a dilated left ventricle and new ventricular arrhythmias, second- or third- degree heart block, or failure to respond to usual care within 1 to 2 weeks |
Myocarditis · Cardiomyopathy · Cardiac sarcoidosis |
I | B | S |
3 | Heart failure of >3 months’ duration associated with a dilated left ventricle and new ventricular arrhythmias, second- or third-degree heart block, or failure to respond to usual care within 1 to 2 weeks |
Cardiomyopathy (DCM, HCM, etc) |
IIa | C | M |
4 | Heart failure associated with a DCM of any duration associated with suspected allergic reaction and/or eosinophilia |
Löffler endocarditis, Eosinophilic myocarditis |
IIa | C | S |
5 | Heart failure associated with suspected anthracycline cardiomyopathy |
Drug-induced myocarditis/ cardiomyopathy |
IIa | C | M |
6 | Heart failure associated with unexplained restrictive cardiomyopathy |
RCM, Cardiac amyloidosis, Storage disorders, i.e., Fabry disease |
IIa | C | M |
7 | Suspected cardiac tumors | Sarcoma, Cancer metastasis, Lymphoma |
IIa | C | S |
8 | Unexplained cardiomyopathy in children | Congenital metabolic diseases | IIa | C | M |
9 | New-onset heart failure of 2 weeks’ to 3 months’ duration associated with a dilated left ventricle, without new ventricular arrhythmias or second- or third-degree heart block, that responds to usual care within 1 to 2 weeks |
IIb | B | ||
10 | Heart failure of >3 months’ duration associated with a dilated left ventricle, without new ventricular arrhythmias or second- or third-degree heart block, that responds to usual care within 1 to 2 weeks |
IIb | C | ||
11 | Heart failure associated with unexplained HCM | HCM, Cardiac amyloidosis, Storage disases, i.e., Fabry disease |
IIb | C | |
12 | Suspected ARVC/D | ARVC/D | IIb | C | S |
13 | Unexplained ventricular arrhythmias | Various secondary cardiomyopathies |
IIb | C | |
14 | Unexplained atrial fibrillation | III | C |
ARVC/D, arrhythmogenic right ventricular cardiomyopathy/dysplasia; COR, class of recommendation; ECP, European Cardiovascular Pathology; LOE, level of evidence; M, mixture of supported and non supported; S, supported. (Adapted from Leone O, et al. 2012,208 Cooper LT, et al. 2007209) © 2007 by the American College of Cardiology Foundation, with permission from Elsevier.
b. Sample Collection and Complications
In endomyocardial biopsy, specimens are obtained from the wall of the RV or LV, but superiority is not apparent from the usefulness of histological information and the frequency of complications. Because blinded sampling is performed, sampling errors cannot be avoided because of the location of the lesions,212 and it is usually desirable to collect 3–5 samples. In recent years, especially in cases of suspected sarcoidosis, attempts to increase the diagnostic accuracy through identifying the lesion using MRI,213 FDG-PET,214 and electroanatomical mapping215 have been reported.
Endomyocardial biopsy includes a risk of complications such as cardiac tamponade and bloody pericardial effusion due to myocardial penetration by the biopsy catheter (bioptome), vagal reflex, vascular injury, ventricular or supraventricular arrhythmias, bundle branch block, pneumothorax, pulmonary embolism and cerebral infarction, valvular regurgitation due to injury of the tricuspid or mitral chordae, and hematoma or infection at the puncture site.208,209 The frequency of serious complications in endomyocardial biopsy is reportedly less than 1%, and a study in Japan showed that the rate of ventricular perforation was 0.7% (147/19,964) for both the left and right approaches, with a mortality rate of 0.05%. The mortality rate for cardiac perforation was 12.9% in the LV and 5.2% in the RV.216 According to a 2010 report from Germany, cases of perforation requiring pericardial drainage were 0.8% (4/490) in the RV and 0.3% (2/622) in the LV, and no deaths occurred.217 When a patient shows hypotension and tachycardia after endomyocardial biopsy, pericardial effusion should be ruled out by echocardiography. In definitive cases, drainage must be performed promptly by puncture under echocardiographic guidance or pericardiotomy under direct vision.218
c. Tissue Handling and Histological Method (Table 21)
• Obtaining samples ranged from 3 to 5 pieces to reduce sampling error, if possible |
• Fix samples immediately in 10% neutral buffered formalin at room temperature (Contraction band artifact emerges at low tempreture.) |
• Making deep cut sections, in the cases with negative histological findings irrespective of suggestive clinical information (e.g., sarcoidosis) |
• Careful handling of the samples to minimize artifacts (It is important to understand artifacts characteristic of EMB and handling methods.) |
EMB, endomyocardial biopsy.
Tissue samples obtained by endomyocardial biopsy are fixed overnight in a 10% neutral buffered formalin solution (at room temperature) and used for conventional light microscopy. Hematoxylin and eosin (H&E) and Masson’s trichrome staining, which are excellent for demonstrating fibrosis, are basic staining methods, and special staining methods such as periodic acid-Schiff (PAS; with or without diastase digestion), Congo red (for amyloid material), elastica van Gieson (for elastic fibers), or Berlin blue (for iron), may be added. In cases in which there are concerns about sampling errors, especially in cases of suspected sarcoidosis, additional deep cut sections may improve sensitivity.
It is recommended that at least one piece of the tissue sample is fixed in a 2.5% glutaraldehyde solution for electron microscopy, especially in cases of severe myocardial vacuolation under light microscopy (e.g., Fabry disease). Transmission electron microscopy is also useful for confirming morphological changes in mitochondria and detecting amyloid fibrils.
d. Microscopic Observation and Interpretation
Histopathological findings observed in endomyocardial biopsies are generally nonspecific, and therefore, systematic evaluation and the use of tissue parameters such as those shown in Table 22 are helpful for interpretation.219,220 In Japan, a 4-point evaluation (from − to +++) of cardiomyocyte hypertrophy, fibrosis, and (inflammatory) cell infiltration is required as an evaluation of candidates for heart transplantation.221 In endomyocardial biopsies, artifacts such as contraction bands produced by tissue overshrinkage (Figure 14A), crush artifacts caused by handling with biopsy forceps, and the invagination of small vessels (telescope phenomenon), which is easily mistaken for thrombosis (Figure 14B), are frequently observed, and care must be taken to avoid overestimation. When mesothelial cells overlay pericardial fatty connective tissue (Figure 14C), bioptome penetration into the pericardium is suggested.219
Histological parameters | Grading | |||
---|---|---|---|---|
Transverse diameter of cardiomyocyte (μm) | ||||
Degree of hypertropy* | − | + | 2+ | 3+ |
Size variation of cardiomyocytes | − | + | ||
Nuclear deformity (Enlargement, Pyknosis, Irregularity, binucleation, etc.) |
− | + | 2+ | 3+ |
Lipofuscin deposition | − | + | 2+ | 3+ |
Myofibrillar loss | − | + | 2+ | 3+ |
Vacuolar change | − | + | 2+ | 3+ |
Basophilic degeneration | − | + | ||
Contraction band artifact | − | + | 2+ | 3+ |
Myocardial disarrangement | − | + | 2+ | 3+ |
Myocardial Disarray | − | + | 2+ | 3+ |
Fibrosis | ||||
Perivascular | – | + | 2+ | 3+ |
Interstitial | – | + | 2+ | 3+ |
Replacemental | – | + | 2+ | 3+ |
Others characteristic distributions | Focal | Scarring | ||
Endocardial thickening | − | + | 2+ | 3+ |
Fat infiltration | − | + | 2+ | 3+ |
Amyloid deposition | − | + | ||
Inflammatory (exogenous) cell infiltration | ||||
Lymphocytes, Macrophages, Eosinophils, Neutrophils, Multinucleated giant cells, etc. |
− | + | 2+ | 3+ |
Epithelioid granuloma | − | + | ||
Vascular (arterial) wall thickening | − | + | 2+ | 3+ |
Others (additional comments) |
*The degree of hypertrophy by transverse diameter of Cardiomyocytes.219 Right ventricle (hypertrophy 0; <15 μm, 1+; 16~20 μm, 2+; 21~25 μm, 3+; >26 μm). Left ventricle (hypertrophy 0; <18 μm, 1+; 19~23 μm, 2+; 24~28 μm, 3+; >29 μm).
Representative artifacts and findings related to complications in endomyocardial biopsy. (A) Contraction band artifact (H&E, bar=100 μm). (B) Telescopic phenomenon (Masson trichrome, bar=50 μm). (C) Pericardial tissue covered by mesothelial cells (H&E, bar=100 μm).
The main purpose of endomyocardial biopsy in daily practice is to exclude specific secondary cardiomyopathies. Histopathological findings from endomyocardial biopsy alone cannot make a definitive diagnosis of primary (idiopathic) cardiomyopathy. However, a definitive diagnosis can be made clinicopathologically when accompanied by histological information. With endomyocardial biopsy, it is rather rare to obtain specific histopathological findings for each disease state, even in the various secondary cardiomyopathies. Thus, interpretation is performed comprehensively while revealing characteristic findings and keeping the relationship with other possible etiologies in mind. In general, among patients with advanced-stage cardiomyopathies, distinct retrograde degeneration can be seen under light microscopy (Figure 15A,B);222 a good example is D-HCM (i.e., end-stage HCM) (Figure 15E). Fat infiltration often occurs with fibrosis, but fibro-fatty change in ARVC is thought to be a characteristic finding (Figure 15F). Notably, severe or irreversible cardiomyopathy cannot be ruled out, even if the histological degeneration is modest (Figure 15C,D). It has been reported that some histological parameters, such as compensative hypertrophy, myofibrillar loss, and interstitial fibrosis, may be useful in indicating reduced systolic function and a poor prognosis.223 On the other hand, it has also been reported that it is difficult to estimate prognosis based on histological findings obtained from endomyocardial biopsy.224,225 Generally, the method for estimating prognosis based on endomyocardial biopsy findings has not been established. For evaluating allograft rejection for follow-up after transplantation, endomyocardial biopsy is essential (see published guidelines211).
Histopathology observed in endomyocardial biopsy. (A–D) Differential morphology in dilated cardiomyopathy (DCM). Severe compensative hypertrophy and fibrosis are seen in A and B. However, the case showing C and D also represent dilated heart failure with equivalent degree of left ventricular dysfunction with the case showing A and B. (E) Dilated phase hypertrophic cardiomyopathy (D-HCM); (F) Arrhythmogenic right ventricular cardiomyopathy (ARVC). (A,C,E,F: H&E; B,D: Masson trichome.) Bar=100 μm.
4.7.2 Endomyocardial Biopsy and Pathology in HCM
a. Indications
Although HCM has characteristic pathological findings, clinical evaluation and noninvasive examinations, such as CMR, are prioritized, and routine endomyocardial biopsy is not always necessary for a definitive diagnosis. However, endomyocardial biopsy is useful for differential diagnosis if secondary cardiomyopathies cannot be excluded by noninvasive testing (Table 23).
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
In the patient showing LVH in whom secondary cardiomyopathy is suspected and cannot be defined by other clinical examinations |
IIa | C | C1 | V |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
b. Pathology of HCM and Secondary Cardiomyopathies
i. Gross Pathological Findings
HCM is clinically diagnosed as involving a large volume of cardiac mass and an increase in ventricular wall thickness without any definitive cause such as aortic stenosis or severe hypertension. Hypertrophy of the myocardium in HCM often shows a wall thickness ≥15 mm, but it usually occurs asymmetrically as opposed to diffusely (Figure 16A,B). The characteristic myocardial disarray often occurs in the ventricular septum and anterior wall near the base of the heart, which typically corresponds to ASH. A pathological study of sudden juvenile deaths revealed that focal ischemic scars due to microvascular disease are often involved in HCM.226 Such fibrotic areas are suggested by LGE areas on MRI.
Hypertrophic cardiomyopathy (HCM) (macroscopic findings in autopsy cases). (A) Concentric left ventricular hypertrophy with septal wall thickening >2 cm. (B) Marked septal hypertrophy and relatively thin apex. Box shows estimated region for endomyocardial biopsy sampling.
ii. Histopathological Findings
Characteristic histological findings in HCM are myocardial disarray, cardiomyocyte hypertrophy, and nuclear abnormalities. It should be kept in mind that in normal hearts, myocardial disarray is physiologically observed in the attachment of the papillary muscle and connecting region of the septum and the anterior/posterior wall. The disarrangement of myofibers is represented by overlapping, whorls, intertwining, and abnormal branching. In a typical case of HCM, the histological features, namely severely hypertrophic cardiomyocytes, nuclear deformities, and stereographical myocardial disarray, are referred to as bizarre myocardial hypertrophy with disorganization (BMHD). At the site of disarray, fibrosis is interknitted among the myofibers, which is called plexiform fibrosis (Figure 17A,B). In the thickened ventricular wall, irregular thickening of the intima and media of the small arteries (small intramural coronary artery dysplasia) may be observed (Figure 17C).
Histology of hypertrophic cardiomyopathy (HCM) and related cardiomyopathies for major differential diagnosis. (A) HCM, Masson trichrome (MT) section of an autopsy case. Typical disarray is seen. (B) HCM, MT stain of endomyocardial biopsy specimen. In such case showing patchy and plexiform fibrosis, progression to dilated phase is suspicious. (C) HCM, MT stain of endomyocardial biopsy specimen showing small intramural arterial dysplasia (SICAD) is seen. (D) Cardiac amyloidosis, H&E and Congo red (inset) stains. Endomyocardial biopsy obtained from a senile patient (an ATTR case). (E) Fabry disease, H&E stain and immunohistochemistry for Gb3 (inset) of endomyocardial biopsy specimen. Severe vacuolation is noted in the cardiomyocytes. (F) Fabry disease (same case as E), Lamellar bodies observed in electron microscopy.
As a rule, such typical histological findings are found in autopsied hearts, but not in endomyocardial biopsy specimens, which usually display nonspecific hypertrophy of the heart muscle. Final decisions should be made using clinical data such as from echocardiography. Nevertheless, endomyocardial biopsy is valuable for differential diagnosis from the other forms of cardiomyopathies, as described below.15,219
iii. Restricted Cardiomyopathy (RCM) Requiring Differentiation From HCM
Among the primary cardiomyopathies, it is important to differentiate HCM from RCM. Unlike pediatric cases, primary RCM is a rare disease in adults; however, in recent years, specific genetic abnormalities have been reported.227 The symptoms of RCM are caused by LV diastolic dysfunction without reduced systolic function. Similar restrictive hemodynamics can be seen in HCM, hypertensive heart disease, and various diseases with endocardial thickening, such as endocardial fibroelastosis and Löffler endocarditis with eosinophilia. Histologically, RCM cases that cannot be distinguished from HCM often occur. In addition, cardiac amyloidosis, hemochromatosis, and storage diseases such as glycogenosis may present restrictive hemodynamics. Major histopathological criteria for differentiating HCM, RCM, and related secondary cardiomyopathies are listed in Table 24.
Hypertrophic cardiomyopathy |
Restrictive cardiomyopathy |
Cardiac amyloidosis |
Fabry disease | Glycogenosis | Mitochondrial cardiomyopathy |
Other secondary cardiomyopathies |
|
---|---|---|---|---|---|---|---|
Macroscopic findings |
Typical case shows unproportional thickening of the ventricular wall representing asymmetric septal hypertrophy (ASH). Subtypes include obstructive type with severe stenosis of LV outflow track, apical hypertrophy, etc. Characteric ASH would be lost in dilated phase (Figure 16). |
Dilastolic heart failure is seen without obvious left ventricular hypertrophy or dilated chambers. Severe fibrous thickening of the endocardium may suggest endomyocardial fibroelastosis or Löffler endocarditis. Both atrium would be severely enlarged. |
Usually, severe biventricular hypertrophy is circumferentially seen with marked wall thickening. Cut-surface shows glossy and waxy appearance. The case with severe amyloid depotion becames rubber- like rigidity. |
Usually, it represents cardiac hypetrophy and some cases represent restrictive heart failure. If left ventricular dysfunction is progressed, the chamber would be dilated. |
Usually, hypertrophy with ventricular wall thickening is seen. In Pompe disease, left ventricular free wall and papillary muscle represent more severe hypertrophy and the chamber would be narrowing. Cut-surface shows light pink color with rubber-like rigidity. Some cases are associated with endocardial fibroelastosis. |
Some cases represent severe left ventricular hypertrophy similarly with hypertrophic cardiomyopathy. The other cases may represent dilated cardiomyopthy-like or left ventricular non-compaction- like morphology. |
Symmetric hypertrophy can be seen in hypertension and aortic stenosis with pressure overload. However, the cases with asymmetric hypertrophy require the differentiation from hypertrophic cardiomyopathy. Diabetic, uremic and steroid-induced cardiomyopathy may also represent hypertrophic heart. Many of athelic heart are recognized as adaptation but there is a risk for enhancement of pathologic background, which is sometimes difficult to differetiate pathologic hypertrophy. |
Microscopic findings |
Typical case represents disarray of the hypertrophic cardiomyocytes with bizarre nuclei (i.e., Bizarre myocardial hypertrophy with disorganization: BMHD). Plexiform fibrosis and thickening of small arterial wall may be associated. Disarray of myofibers can be also seen by electron microscopy. Severe retrograde degeneration with severe fibrosis is seen in the advanced stage, especially in dilated phase (Figure 17A–C). |
Hypertrophic cardiomyocytes, fibrosis and disarrangement of the myofibrils may be seen, of which findings are usually mild and there is no specific changes. In the diagnosis of primary restrictive cardiomyopathy, histology is useful for differentiating from the other cardiomyopathies that potentially represent ristrictive heart failure. |
Amyloid deposits as eosionphilic and amorphous materials surrounding vessels and in the interstitium (Figure 17B). It is stained positively by Congo red dye, which is confirmed by apple green birefringence under polarization. Major types of cardiac amyloidosis are AL, ATTR, AA and Aβ in the pateints with hemodialysis. |
Cardiomyocytes represent marked vaculation in the light microscopy and typical case shows net-work pattern (Figure 17E,F). In the thick section (observed prior to electron microscopy) with toluidine blue staining, the part of vaculation is darkly stained. In the electron microscopy, myelin-like concentric multilayer structures (myelin figure, zebra body) are observed. For definitive diagnosis, enzymatic and/ or genetic analysis for α-galactocidase is required. |
Cardiomyocytes represent marked vacuolation with glycogen deposition. Myofibers are excluded by large amount of deposition and exhibit a unique lacy architecture, which are positive by PAS staining. In pediatric case, differential diagnosis against rhabdomyoma may be required in histology. |
Cardiomyocytes may represent vacuolation. Otherwise, increased number of mitochondria may be resulted in red granular apperance in the cytoplasm. In the electron microscopy, various abnormalities in mitochondrial morphology are possibly observed such as ring-shaped giant mitochondria. |
In hypertensive heart, thickening of the small artery wall and perivascular fibrosis are seen. Same changes are also seen in the obesity and diabetes. In the uremic cardiomyopathy, pathopysiology may be affected by co-exisetd hypertension. However, there is no specific histology in hypertensive, diabetic and uremic cardiomyopaties and clinicopathological decision is needed for diagnosis. In CD36 deficiency, some cases may represent HCM-like morophology and immunohistochemically, CD36 expression in microvessels surronding the cardiomyocytes are disapperared. |
Supplementary notes |
In the endomyocardial biopsy, it is ususally difficult to recognize characteritic findings which are observed in autopsy and nonspecific histology is often obsered. Diagnosis should be made clnicopathologically with exclusion of the other cardiomyopathies. Diarray is not a specific finding and it can be seen physiologically and also pathologically in the different conditions. |
Restrictive cardiomyopathy mainly occures in childhood and is rare in the adult. However, endomyocardial biopsy is useful for differentiating from hypertrohic cardiomyopathy, amyloidosis, Löffler endocarditis, etc. |
Confirming amyloid precursor protein is critical for estimation of prognosis and choice of treatment. Immunohistochemistry is initially performed. However, amino acid and/or genetic analysis should be further considerd, if decision is difficult. |
For the differential diagnosis in the cases observed marked vaculation in the light microscopy, electron microscopic is useful. In the prepartion process of light microscopy, lipophilic matrials are eluted but they are preserved in the samples for electron microscopy. Thus at least one specimen is recommended to keep for the electron microscopy, in the endomyocardial biopsy. |
Type I, II, and III glycogenosis may exhibit cardiac symptoms. Almost of them are pediatric cases but some are rarely found in the adulthood. In the electron microscopy, marked glycogen deposion is seen. As a differential diagnosis, Danon’s disease caused by LAMP2 gene mutation can be detected by immunohistochemistry and autophagic vacuoles are seen in the electron microscopy. |
Morphological alterations of mitochondria observed by electron microscopy are geneally due to nonspecific compensation or cellular injury in the failing heart, which does not always mean mitochondrial cardiomyopathy. Analysis of mitochondrial enzyme and/or gene is needed for definitive diagnosis. |
In pure hypertensive cardiomyopathy, size variation of myofibril and disarray similar with hypertrophic cardiomyopathy are rarely observed. However, both conditions are often co-existed. Endocrine disorders such as hyperthyroidium may complicate secondary hypertension and thus cardiac injury may be occured based on both primary endocrine disease and hypertension. Takotsubo cardiomyopathy-like condition may be seen in the case of Pheochromocytoma. |
iv. Major Secondary Cardiomyopathies Requiring Differentiation From HCM
a) Cardiac Amyloidosis In H&E-stained sections, amyloidosis is revealed as deposition of eosinophilic and amorphous material in the interstitium. Congo red or direct fast scarlet staining highlights amyloid as orange, which shows apple-green birefringence under polarization (Figure 17D). In electron microscopy, amyloid is observed as microfibrils of 8–15 nm width.57,219,228 At least 30 amyloid precursor proteins have been identified to date. AL amyloidosis, ATTR, amyloid A (AA) amyloidosis, and β2-microglobulin amyloidosis (Aβ2M) in patients undergoing hemodialysis are major causes of cardiac amyloidosis. AL amyloidosis is usually a sequela of hematopoietic disorders or myeloma, and HF often progresses rapidly. Most cases of cardiac ATTR are due to the deposition of wild-type TTR. In conditions with chronic inflammation, such as rheumatoid arthritis or tuberculosis, AA amyloidosis may involve the heart. The identification of amyloid precursor proteins is closely related to the estimation of prognosis and choice of treatment. Immunohistochemical staining is initially chosen for the identification of amyloid precursor proteins, followed by specialized analysis of amino acid or genetics, as needed.57
b) Fabry Disease (Also Known as Anderson–Fabry Disease) Fabry disease is an inherited glycosphingolipid metabolism disorder with a congenital lack or reduction of α-Gal (the metabolic enzyme of ceramide trihexoside). Fabry disease is an X-linked lysosomal storage disease, but also affects female carriers, and heterozygotes show large individual differences. The severe form develops in childhood. In other cases, for which a familial history is often unclear, the accumulation of ceramide trihexoside progresses after middle age. Endomyocardial biopsy may be performed for differential diagnosis. On histological findings, the myocardium shows marked vacuolation, and in advanced cases, a spider-web/network pattern. Although immunostaining for globotriaosylceramide (Gb3 or GL3) may be useful, the staining method has not been popularized (Figure 17E). In electron microscopy, deposits with a myelin-like concentric multilayer structure (i.e., myelin figure, zebra body) are observed in the myocardium as a result of the deposition of ceramide on lysosomes (Figure 17F). In addition, toluidine blue-stained sections observed prior to the preparation of ultra-thin sections for electron microscopy are also useful for screening, as they can show osmiophilic deposition of Gb3 in cardiomyocytes. However, swirl deposits observed in electron microscopy are a common finding among various lysosomal storage diseases. Enzymatic or genetic analysis to confirm abnormal α-Gal activity is therefore required for definitive diagnosis.
c) Glycogen Storage Disease Although glycogen storage disease is rare, types II, III, and V are known to exhibit cardiac symptoms. Of these, type II (Pompe disease) is the most important in terms of cardiac involvement. Glycogen deposition occurs throughout the body because of an innate acid α-1,4-glucosidase deficiency, but severe deposition is mainly seen in the heart and liver. Marked cardiomegaly with various cardiac symptoms is found. In endomyocardial biopsy specimens, cardiomyocytes are vacuolated and exhibit a unique lacy architecture, which is positive by PAS staining. Electron microscopy shows glycogen granules in the lysosome. In recent years, Danon disease (type IIb, autophagic vacuolar myopathy) showing HCM-like pathophysiology has been reported to have a mutation of lysosomal membrane protein 2 (LAMP-2) or PRKAG-2. Thus, it is desirable to differentiate these diseases in young patients suspected to have HCM.219,229
d) Mitochondrial Cardiomyopathy The intramyocardial mitochondria are organelles that increase in number in response to various pathologic conditions such as ischemia and cardiac hypertrophy. Therefore, morphological changes of the mitochondria observed in electron microscopy are generally nonspecific, but mitochondrial cardiomyopathy may be associated with myopathy, diabetes, hearing impairment, etc.230 Enzymatic or genetic analysis of mitochondrial enzymes is required to confirm the diagnosis.
4.8. Genetic Testing and Family Screening (Including Genetic Counseling) (Tables 25–27)
Recommendations | COR | LOE | GOR (MINDS) |
LOE (MINDS) |
---|---|---|---|---|
Genetic counseling for all patients with HCM regardless of family screening | I | B | A | IVa |
Genetic counseling in genetic testing | I | B | A | IVa |
Genetic counseling should be performed by professionals trained in genetics | IIa | C | C1 | IVa |
COR, class of recommendation; GOR, grade of recommendation; HCM, hypertrophic cardiomyopathy; LOE, level of evidence.
Recommendations | COR | LOE | GOR (MINDS) |
LOE (MINDS) |
---|---|---|---|---|
Genetic testing to confirm the diagnosis in the presence of symptoms and findings of disease suggestive of secondary cardiomyopathy |
I | B | A | IVa |
Genetic testing in HCM patients, when it enables cascade genetic screening of their family members |
IIa | B | B | IVa |
Genetic testing in HCM patients, if family screening is difficult to perform | IIb | B | C2 | IVa |
Genetic testing for the assessment of risk of SCD in HCM patients | IIb | B | C2 | III |
COR, class of recommendation; GOR, grade of recommendation; HCM, hypertrophic cardiomyopathy; LOE, level of evidence; SCD, sudden cardiac death.
Recommendations | COR | LOE | GOR (MINDS) |
LOE (MINDS) |
---|---|---|---|---|
Creating a family tree for patients with HCM | I | C | C1 | V |
Clinical evaluation of first-degree relatives | I | C | A | IVa |
Clinical evaluation for long-term follow-up in first-degree relatives who have the same definite disease-causing mutation as the proband |
I | C | A | IVa |
Cascade genetic screening in first-degree relatives of patients with a definite disease-causing mutation |
IIa | B | B | IVa |
Discontinuance of ongoing clinical follow-up in genotype-negative relatives of patients with a definite disease-causing mutation |
IIa | B | B | IVa |
Genetic testing in relatives when the HCM proband does not have a definitive disease-causing mutation. (However, family screening including clinical evaluation and genetic testing is recommended to determine whether the variant identified in HCM proband is disease-causing or not) |
III | C | D | V |
COR, class of recommendation; GOR, grade of recommendation; HCM, hypertrophic cardiomyopathy; LOE, level of evidence.
4.8.1 For Genetic Diagnosis
The elucidation of the mechanisms underlying cardiovascular disease has been progressing rapidly. In particular, due to advances in molecular genetics, the causative genes of cardiomyopathy, which were previously unknown, have been identified, and numerous mutations have been reported.
In 2003, 10 societies and research groups related to genetic medicine in Japan proposed unified guidelines for genetic testing (“Guidelines for genetic testing”), which is regarded as a medical practice.231 These guidelines stipulate that it is essential to conduct “genetic counseling” before conducting a genetic test, and this is treated similarly in other guidelines as well.232–236 The need for counseling is becoming more important than ever.
In addition, it is a major premise that sufficient informed consent is required, and because genetic information is the highest level of personal information, it needs to be handled under strict protocols. In 2011, the Japanese Medical Association published the “Guidelines for genetic testing and diagnosis in health care”, which summarize the basic issues and principles that doctors and others should keep in mind when conducting genetic tests and diagnoses in medical settings.237 The JCS previously published the “Guidelines for genetic test and genetic counseling in cardiovascular disease”, followed by a partially revised version in 2010.238 In the genetic diagnosis of cardiomyopathy, it is strongly recommended that the contents of the guidelines should be understood and adhered to. In the clinical application of genetic diagnoses, it is also important to consider carefully whether the identified variant is pathogenic. At present, instead of being determined as disease-causing or not, identified variants are classified into the following 5 categories: pathogenic, likely pathogenic, variant of uncertain significance, likely benign, or benign.
4.8.2 Disease-Causing Genes of HCM
Since the discovery of a missense mutation in the MYH7 gene in HCM by Seidman and Seidman,239 causative genes of cardiomyopathy have been reported around the world. In HCM, mutations have been reported in genes encoding sarcomere components in almost half of the patients with a clear family history, and in nearly 15% of patients with no or unknown family history.240–242 Approximately half of the cases of HCM are familial with autosomal dominant inheritance, and many of these are considered to be myocardial sarcomere diseases. More than 1,000 mutations of more than 16 genes have been reported.14,15,38,239 Among the identified mutations, mutations in the MYH7 and MYBPC3 genes account for the majority.240,243 However, a genetic test may not detect a previously reported gene mutation if it is unidentified or if no mutation has been identified in the previously reported gene. It is also possible that pathogenic mutations exist in other genes.
4.8.3 Gene Analysis and Clinical Application
Although genetic analysis of cardiomyopathy has been performed and the etiology of the disease has been elucidated, many of these analyses are still in the research stage in a limited number of facilities, and thus are not routinely performed in clinical settings in Japan. However, in the future, an increase in the number of genetic diagnosis facilities (including private commercial bases) and the use of NGS is expected to enable the rapid sequencing of multiple samples in many targeted genes.
The benefits of genetic testing in patients with suspected HCM include the following. (1) Genetic testing of a proband can identify the etiological mutation and determine the need for diagnosis and follow-up of family members, and confirmation of a genetic diagnosis of a proband is also expected to promote family screening. (2) Genetic testing is useful for discriminating specific cardiomyopathies that may have a similar form to that of HCM, and particularly important for diagnosing specific cardiomyopathies with available disease-specific treatments. (3) Genetic diagnosis may be useful for estimating the prognosis of patients with HCM. A recent report demonstrated that patients with HCM who have sarcomere mutations have a worse prognosis than those without any identified mutations or a family history of HCM.244
5. Evaluation by Disease State5.1 Chest Pain
Chest pain is likely to occur at the time of tachycardia, such as during exercise, but may also appear at rest. It may worsen with food or alcohol consumption. Chest pain appears even in patients without significant stenosis on coronary angiography, and is thought to be caused by relative ischemia or a microcirculation abnormality in which the blood flow is not sufficient to meet the increase in myocardial oxygen demand due to cardiac hypertrophy.
5.2 Heart Failure
5.2.1 Pathology
HCM often presents with HF symptoms, such as shortness of breath and dyspnea on exertion. In many cases, these symptoms are attributed to an elevation in LA pressure secondary to LV diastolic dysfunction, leading to the pathology of HF with preserved ejection fraction (HFpEF). On the other hand, in HCM with LVOTO, HF symptoms due to reduced cardiac output are more pronounced.22,245 In the case of transition to D-HCM, HF with reduced EF (HFrEF) is prominent, HF death and sudden death occur frequently, and the prognosis is poor.23,33 Additionally, VT and tachycardia due to AF significantly deteriorate the hemodynamics of HCM and may be exacerbating factors for HF.246
5.2.2 Diagnosis and Severity Assessment
The diagnosis and assessment of HF due to HCM follow the standard medical practice for HF due to other causes. If HF is suspected based on symptoms and physical findings, blood tests, including plasma brain (B-type) natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) urinalysis, ECG, and chest radiography, should be performed to determine the validity of the diagnosis. In particular, BNP, which has been established as an auxiliary diagnostic method for HF, is also useful for HCM.247 BNP levels have been reported to be related to not only LVH and LV pressure differences,248,249 but also the severity of HF,250 exercise tolerance,251 and clinical prognosis.252 In addition, the assessment of cardiac function and hemodynamics by echocardiography, the evaluation of exercise tolerance by an exercise stress test, and the evaluation of hemodynamics by a Swan-Ganz catheter are used to determine the overall severity of HCM.
5.3 Syncope
Approximately 20% of patients experience syncope, and the causes vary (e.g., tachycardia and bradyarrhythmia, dehydration, reduced blood pressure due to LVOTO, abnormal vascular reactions). Syncope due to unknown cause is a particularly important risk factor for sudden death.
5.4 Diagnostic Flowchart
Figure 18 shows a diagnostic flowchart.
Diagnostic flowchart of hypertrophic cardiomyopathy (HCM).
6.1 General Treatment
A flowchart of treatment for HCM is shown in Figure 19. Treatments for LVOTO (see III.6.3) and supraventricular arrhythmia (see III.6.4) are described separately.
Treatment flowchart of hypertrophic cardiomyopathy (HCM). *In case of HCM, there is no established pharmacological therapy for completely asymptomatic patient.
In nonobstructive HCM, β-blockers and calcium antagonists (verapamil and diltiazem) are used as symptomatic treatments to improve subjective symptoms caused by diastolic dysfunction in HCM, although little evidence has been established.253,254 It has been confirmed that β-blockers increase the diastolic time by decreasing the heart rate (negative chronotropic action) and suppress the increase in LV end-diastolic pressure associated with tachycardia during exercise;255,256 however, they cannot suppress LV myocardial injury (transition to D-HCM) and no evidence that they improve the prognosis has been presented. The classification of β-blockers is based on the selectivity of the β-receptor subtype, the intrinsic sympathomimetic activity (ISA), the membrane stabilizing activity, and the α-blocking action. Although it remains unclear whether β1-selective or nonselective is more appropriate for HCM, β1-selective is preferred in HCM patients complicated with bronchial asthma. In addition, those with α-blocking action or ISA are not indicated in HCM. Considering the tissue penetration of β-blockers, lipid solubility is preferable to water solubility.
Calcium antagonists (verapamil and diltiazem) are used to improve diastolic function by negative chronotropic action, similar to β-blockers, and are also useful in cases where β-blockers do not improve symptoms.257–260 However, no clear consensus has been reached regarding whether calcium antagonists or β-blockers should be preferentially used, or whether concomitant or single use is better. Verapamil suppresses calcium overload in cardiomyocytes, improves relaxation properties,261 and locally improves the diastolic asynchronous motion in the LV that causes relaxation abnormalities.262,263 Verapamil mitigates myocardial ischemia during exercise by improving coronary blood flow in the early diastolic phase.264 In addition, verapamil has a coronary dilatation effect, suppresses coronary spasms, and improves subendocardial ischemia in hypertrophic hearts.265 However, caution is required because the negative inotropic effect of verapamil may worsen contractility and exacerbate HF. Diltiazem (intravenous and oral administration) improves diastolic function, such as by shortening the LV isovolumetric expansion time, increasing the maximum LV filling rate, and improving the time constant for the LV pressure drop (t); it also improves subjective symptoms, exercise tolerance, and myocardial ischemia equivalent to verapamil.266–269 On the other hand, dihydropyridine calcium antagonists such as nifedipine have been reported to impair hemodynamics as indicated by an increase in the LVOT pressure gradient due to peripheral vasodilation,270 an increase in pulmonary artery wedge pressure, a drop in systolic blood pressure,271 and an increase in LV end-diastolic pressure.272 Therefore, dihydropyridine calcium antagonists are not recommended in HCM.
If pulmonary congestion is severe and shortness of breath is persistent, even when using β-blockers, calcium antagonists, or a combination of both, the use of low-dose diuretics (loop or thiazide) in the acute and chronic phases should be considered.6,7 However, attention must be paid to an excessive reduction of preload, and it is not generally used in patients with HOCM because the reduction in preload causes an increase in the pressure gradient.
ACE inhibitors/angiotensin II receptor blockers (ARBs) may be an effective treatment for nonobstructive HCM. These agents were reported to have an inhibitory effect on cardiac fibrosis in a transgenic mouse model of HCM, and the AT1-receptor A/C273 polymorphism has been shown to be associated with the degree of cardiac hypertrophy in HCM patients.274 However, the effect of ACE inhibitors/ARBs on improving symptoms or long-term prognosis remains to be established. On the other hand, in HOCM, drugs with vasodilation such as ACE inhibitors and ARBs are more likely to enhance LVOTO and thus, their use is undesirable.
Little evidence of treatment in D-HCM has been presented, but guideline-directed medical therapy for heart failure with mid-range EF or HFrEF is recommended.11 In brief, ACE inhibitors/ARBs, β-blockers, and mineral corticoid receptor antagonist (MRA) are used. For patients with New York Heart Association (NYHA) Class III–IV who are refractory to these standard medical therapies, CRT, ventricular assist devices (VADs), and heart transplantation are indicated according to the indication criteria in the Japanese guidelines.11
No evidence of pharmacotherapy has been presented for patients with completely asymptomatic HCM, especially those with nonobstructive HCM who do not exhibit a pressure gradient, even after provocation. Treatment for comorbidities may be helpful in maintaining the stage of HF. In addition, regular follow-up is necessary even for patients with HCM who are asymptomatic at that time. Table 28 shows the recommendations and levels of evidence for HF due to HCM.
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Use of β-blockers and calcium antagonists (verapamil) in patients with nonobstructive HCM (HFpEF) and who have NYHA Class I symptoms to improve diastolic function |
IIb | C | C2 | V |
Use of β-blockers and calcium antagonists (verapamil/diltiazem) in patients with nonobstructive HCM and who have NYHA Class II–IV symptoms to improve symptoms |
I | B | B | III |
Use of low-dose diuretics (loop or thiazide) in patient with nonobstructive HCM (HFpEF) who have NYHA Class II–IV symptoms to improve congestive symptoms |
I | C | C1 | VI |
Use of ACE inhibitor or ARB and β-blockers in patient with dilated-phase HCM (HFmrEF, HFrEF) | I | C | C1 | VI |
Use of MRA in patient with dilated-phase HCM (HFmrEF, HFrEF) who have NYHA Class II–IV symptoms |
IIa | C | C1 | VI |
Use of diuretics in patient with dilated-phase HCM (HFmrEF, HFrEF) who have NYHA Class II–IV symptoms to improve congestive symptoms |
I | C | C1 | VI |
ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence; MRA, mineral corticoid receptor antagonist.
6.2 Sudden Death
Sudden death has been reported to account for about 40% of HCM-related deaths,79,275 and is one of the most devastating events. The frequency of sudden death associated with HCM is reported to be ≤1% per year.79,275–277 Although not many HCM patients are at high risk of sudden death, a certain number of patients are. Many sudden death cases have been observed predominantly in the young (especially those aged <25 years). However, sudden death can occur after middle age.79,275
The risk factors for sudden death, resuscitation from cardiac arrest, VF, and sustained VT have a high risk of recurrence (≈10% annually).278,279 In addition, 5 established risk factors are known: (1) family history of sudden death associated with HCM; (2) syncope of unknown cause; (3) extreme LVH (≥30 mm); (4) nonsustained VT on Holter ECG; and (5) abnormal blood pressure response during exercise.279,280 In the previous Japanese guidelines for the treatment of HCM (2012 revised version),9 it was recommended to consider the indication for an ICD to prevent sudden death based on these 5 risk factors with equal importance. On the other hand, it has been pointed out that the weighting of these risk factors is not equal, and the degree of association with sudden death differs for each factor. For example, although nonsustained VT is reported to be an independent risk factor for young people (age <30 years),281 it is considered to have a weak relation to sudden death on its own.280 Furthermore, recent studies have shown that LVOTO, extensive LGE on CMR, D-HCM, and apical aneurysm formation in the LV (including those associated with MVO) may be risk factors for sudden death.24,25,147,280,282 There is a limit to the predictability of sudden death in the presence of AF or the inducing of sustained VT/VF by electrophysiological tests. Although the relationship between genetic mutations and clinical outcomes has been investigated, the predictability of sudden death has not yet been established.283
The 2011 ACCF/AHA guidelines emphasized that a family history of sudden death in 1st-degree relatives, recent syncope of unknown cause, and extreme LVH (≥30 mm) were the most important risk factors.6 On the other hand, the existence of nonsustained VT or abnormal blood pressure response during exercise are regarded to be less important, and decisions regarding ICD implantation should be made in consideration of other conditions (e.g., LVOTO, extent of LGE on CMR, apical aneurysm, genetic mutations strongly associated with sudden death).
The 2014 ESC guidelines7 proposed a calculation formula (the HCM Risk-SCD Calculator) that consists of 7 risk factors: age, maximum LV wall thickness, LA diameter, LVOT pressure gradient (at rest or on provocation), family history of sudden death, nonsustained VT, and history of syncope. By inputting a total of 7 items, the estimated sudden death rate is calculated for 5 years, and the degree of recommendation for ICD implantation is shown.
Although these 2 guidelines are very important and informative for identifying patients at a high risk of sudden death, the limitations of each guideline have been pointed out. The 2011 ACCF/AHA guidelines were criticized that the negative predictive value of a sudden death event is high, but the positive predictive value is low, and no improvement in the area under the receiver-operating characteristic curve has been reported compared with the 2003 ACC/ESC guidelines.284 Regarding the 2014 ESC guidelines, a critical study noted that the event occurrence rate was high for patients judged to be at high risk, but more than half of the patients with a sudden death event were judged to be at low risk.285 Another validation study involving 206 Japanese patients showed that although the HCM Risk-SCD Calculator was useful for predicting events in the high-risk group, a considerable number of sudden deaths also occurred in patients judged to be in the low–mediate risk group.286
Therefore, identification of patient groups at high risk of sudden death (especially those requiring an ICD) is not yet sufficient, and more knowledge needs to be accumulated, especially in Japanese patients.27,79,287–289 The risk factors for sudden death in HCM in the guidelines are shown in Table 29, and a flowchart showing indications for ICD implantation is shown in Figure 20. Among the major risk factors reported to date, recent cardiogenic syncope or unexplained syncope (especially a history of syncope within 6 months that has been reported to be at high risk) and extreme LVH with a thickness ≥30 mm are regarded as particularly high risk factors. If one of these risks is present, the patient is considered to be eligible for ICD implantation (primary prevention). In addition, if patients are judged as being at high risk (estimated event rate for 5 years >6%) by the HCM Risk-SCD Calculator in the 2014 ESC guidelines mentioned above, ICD implantation should be considered.
Major risk factors |
• History of recovery from cardiac arrest due to VF or sustained VT |
• History of sustained VT |
• Recent cardiogenic syncope or unexplained syncope, within 6 months |
• Maximum LV wall thickness ≥30 mm |
• High-risk patient judged by HCM Risk-SCD model proposed by 2014 ESC guidelines (estimated 5-year risk of sudden death ≥6%) |
• Family history of SCD, including successful recovery from cardiac arrest and appropriate ICD therapy: one or more first- or second-degree relatives have died suddenly aged <40 years with or without a diagnosis of HCM, or when SCD has occurred in a first- or second-degree relative at any age with an established diagnosis of HCM |
• Documented nonsustained VT |
• Abnormal blood pressure response during exercise |
Risk modifiers |
• LV outflow tract obstruction (≥30 mmHg at rest or during exercise) |
• Extensive LGE on CMR imaging |
• Dilated-phase HCM |
• Ventricular aneurysm |
CMR, cardiac magnetic resonance [imaging]; ESC, European Society of Cardiology; ICD, implantable cardioverter defibrillator; LGE, late gadolinium enhancement; VF, ventricular fibrillation; VT, ventricular tachycardia.
The flowchart for indications for ICD implantation in patients with HCM. The family history of sudden death of first-degree relatives is a particularly high-risk factor in 2011ACC/AHA guidelines. On the other hand, in the reports on the prognosis of HCM in Japanese, it was not possible to clarify whether the sudden death of first-degree relatives was a single criterion for ICD implantation.287,288,289
Patients with the following other multiple risk factors are also recommended for placement of an ICD (primary prevention): family history of sudden death (sudden death likely due to HCM in 1st- and 2nd-degree relatives; note: the risk of sudden death is not yet fully known for those with a family history of sudden death), nonsustained VT, and abnormal blood pressure response during exercise. ICD implantation also should be considered in HCM patients who have one of several other risk factors (family history of SCD events, nonsustained VT, or abnormal blood pressure response during exercise) and the following risk modifiers: LVOTO, extensive LGE on CMR imaging, D-HCM, and LV aneurysm.
According to an observational study of 334 patients with HCM who received an ICD (92% primary prevention), appropriate therapy was observed in 8% (2.3% annually) and inappropriate therapy was seen in 16% (4.6% per annum). Moreover, complications associated with implantation were observed in 18% (5.1% per annum).290 Careful management is needed for not only the indications for an ICD, but also its handling (e.g., avoiding inappropriate therapy, preventing long-term device complications).
Amiodarone has an arrhythmia-suppressing effect, but is limited in preventing sudden death.276,291,292 Therefore, an ICD is most effective for those at high risk.6,7,280 Subcutaneous ICDs may be more beneficial than transvenous ICDs, especially in young people, but their long-term efficacy needs to be clarified.293 Table 30 shows the recommendations and levels of evidence for the prevention of sudden death in HCM.
Recommendations | COR | LOE | GOR (MINDS) |
LOE (MINDS) |
---|---|---|---|---|
Avoidance of competitive sports | I | C | B | IVa |
ICD implantation in HCM patients who had successful recovery from cardiac arrest due to ventricular fibrillation or sustained ventricular tachycardia or had a history of sustained ventricular tachycardia |
I | B | A | IVa |
ICD implantation in HCM patients who have at least 1 of the following major risk factors: recent cardiogenic syncope or unexplained syncope, maximum LV wall thickness ≥30 mm, high-risk patient judged by HCM Risk-SCD model proposed by 2014 ESC guidelines |
IIa | C | B | IVa |
ICD implantation in HCM patient with several of the following risk factors: family history of SCD events, nonsustained ventricular tachycardia, abnormal blood pressure response during exercise |
IIa | C | B | IVa |
ICD implantation in HCM patient with 1 of the following risk factors: family history of SCD events, nonsustained ventricular tachycardia, abnormal blood pressure response during exercise, and also with the following risk modifiers: LV outflow tract obstruction, extensive LGE on CMR imaging, dilated-phase HCM, ventricular aneurysm |
IIa | C | B | IVa |
ICD implantation in HCM patient with 1 of the following risk factors: family history of SCD events, nonsustained ventricular tachycardia, abnormal blood pressure response during exercise, and without the following any risk modifiers: LV outflow tract obstruction, extensive LGE on CMR imaging, dilated-phase HCM, ventricular aneurysm |
IIb | C | C1 | IVa |
ICD implantation in HCM patient without the following risk factors: family history of SCD events, nonsustained ventricular tachycardia, abnormal blood pressure response during exercise, but with the following risk modifiers: LV outflow tract obstruction, extensive LGE on CMR imaging, dilated-phase HCM, ventricular aneurysm |
IIb | C | C1 | IVa |
ICD implantation in HCM patients who do not have any risk factors or risk modifiers | III | C | D | IVa |
Assessment of SCD risk at first evaluation and re-evaluation at 1–2-year intervals or whenever there is a change in clinical status |
I | B | B | IVa |
Beta-blockers and/or amiodarone in patients with an ICD, who have recurrent shocks | I | C | B | IVa |
CMR, cardiac magnetic resonance [imaging]; COR, class of recommendation; ESC, European Society of Cardiology; GOR, grade of recommendation; ICD, implantable cardioverter defibrillator; LGE, late gadolinium enhancement; LOE, level of evidence; VF, ventricular fibrillation; VT, ventricular tachycardia.
6.3 LVOTO/MVO
6.3.1 Pharmacotherapy (Table 31)
Recommendations | COR | LOE | GOR (MINDS) |
LOE (MINDS) |
---|---|---|---|---|
Non-vasodilating β-blockers, titrated to maximum tolerated dose, to improve symptoms in patients with resting or provoked LVOTO |
I | B | B | IVa |
Verapamil, titrated to maximum tolerated dose, to improve symptoms in patients with resting or provoked LVOTO, who are intolerant or have contraindications to β-blockers |
I | B | B | IVa |
Cibenzolin or disopyramide, titrated to maximum tolerated dose, in addition to a β-blocker(or, if this is not possible, with verapamil) to improve symptoms in patients with resting or provoked LVOTO |
I | B | B | IVa |
Oral or IV β-blockers and vasoconstrictors in patients with severe provocable LVOTO presenting with hypotension and pulmonary edema |
IIa | C | C1 | V |
β-blockers or verapamil in asymptomatic adults with resting or provoked LVOTO, to reduce left ventricular pressures |
IIb | C | C1 | V |
Low-dose loop or thiazide diuretics with caution in symptomatic LVOTO, to improve exertional dyspnea |
IIb | C | C1 | V |
Diltiazem, titrated to maximum tolerated dose, in symptomatic patients with resting or provoked LVOTO, who are intolerant or have contraindications to β-blockers and verapamil, to improve symptoms |
IIb | C | C1 | V |
Vasodilating or positive inotropic drugs in patients with resting or provocable LVOTO (e.g. digoxin) | III | C | C2 | V |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence; LVOTO, left ventricular outflow tract obstruction.
Appropriate pharmacotherapy can relieve subjective symptoms in many cases, but the persistence of the effect and the effect of improving long-term prognosis are unknown.
a. β-Blockers
β-blockers have negative inotropic and chronotropic effects, and are expected to be effective in reducing the pressure gradient in the LV. β-blockers are considered to be especially effective in patients with HOCM, where the obstruction activates the sympathetic nerve and causes hypercontraction. In other words, β-blockers can be expected to reduce the pressure gradient during exertion more than at rest.294 In addition, β-blockers improve diastolic dysfunction and myocardial ischemia, and are effective for relieving subjective symptoms such as chest pain and shortness of breath during exertion.
β-blockers are highly tolerated, but attention must be paid to bradycardia and hypotension with regard to side effects. It is usually desirable to start with a low dose and increase as much as possible, taking the effects and side effects into account. The final dose for each case is determined based on blood pressure and heart rate. No clear evidence has been presented, but it is desirable to use β1-selective β-blockers that do not have an α-blocking action (vasodilatory action).
b. Calcium Antagonists
Calcium antagonists are administered to patients who cannot take β-blockers for reasons such as side effects and are used to reduce the LV pressure gradient due to negative inotropic and chronotropic effects. Calcium antagonists are expected to reduce the pressure gradient at both rest and exertion, and to improve diastolic dysfunction. When verapamil is used, it is desirable to increase the dose to the maximum tolerated dose while paying attention to the side effects. A previous report noted an increase in the LV pressure gradient associated with a decrease in systolic blood pressure due to the administration of verapamil;295 in that study, the appropriate dose was determine while checking for side effects, blood pressure, and heart rate, similarly to β-blockers.
Regarding diltiazem, hardly any evidence has been presented,268 and consideration should be given only to patients who cannot receive β-blockers or verapamil.7 In addition, dihydropyridine calcium antagonists such as nifedipine, which have high vascular affinity and strong vasodilator action, should not be used to increase the LV pressure gradient.271
c. Sodium-Channel Inhibitors (Class Ia Antiarrhythmic Drugs)
Sodium-channel inhibitors (Class Ia antiarrhythmic drugs) have a strong negative inotropic effect and reduce the LV pressure gradient. Outside of Japan, disopyramide is often used, whereas in Japan cibenzoline is often used, as reported by Hamada et al.296,297 Compared with β-blockers, which are effective for reducing the LV pressure gradient during exercise, disopyramide and cibenzoline are effective for reducing the pressure gradient at both rest and during exercise. Therefore, subjective awareness is greater than that of β-blockers and calcium antagonists. Disopyramide has been reported to improve long-term prognosis.298,299 Its efficacy has been demonstrated, but its prescription rate is not always high because of side effects such as anticholinergic effects (e.g., dry eyes/mouth, constipation, dysuria) and a prolonged QT interval. It has been reported that the long-term administration of cibenzoline results in a continuous reduction in the LV pressure gradient.298,299 Before starting disopyramide and cibenzoline, an ECG should be performed to check the QTc interval. In prescribing, concomitant use with other oral medications that cause QTc prolongation and whether patients have dehydration and/or electrolyte abnormalities should be confirmed.
Monitoring blood levels of disopyramide and cibenzoline is extremely important for management. Cibenzoline is used more frequently in Japan because it has less anticholinergic activity than disopyramide. Hypoglycemia is one of the side effects of both cibenzoline and disopyramide.
6.3.2 Invasive Therapy
Surgical septal myectomy and PTSMA (or alcohol septal ablation [ASA]) are regarded as invasive treatments for symptomatic drug-resistant HOCM. In the 2011 ACCF/AHA guidelines6 and 2014 ESC guidelines,7 these are referred to as septal reduction therapy (SRT).
Pacing therapy is distinguished from SRT and is another invasive treatment. Pacing therapy should be considered in the following cases.
(1) The patient is not indicated for SRT for some reason.
(2) Pacemaker implantation is required for purposes other than reducing the LVOT pressure gradient.
(3) An ICD is implanted in a patient with HOCM with preserved LV contractility for the primary or secondary prevention of sudden death, and the effect of dual-chamber (DDD) pacing is confirmed.
a. Indications for SRT6,7,300 (Table 32)
Recommendations | COR | LOE | GOR (MINDS) |
LOE (MINDS) |
---|---|---|---|---|
Septal reduction therapies performed by experienced operators, working as part of a multidisciplinary team expert in the management of HCM (experienced operators are defined as an individual operator with a cumulative case volume of at least 10 procedures and individual operator who is working in a dedicated HCM program with a cumulative total of at least 20 procedures) |
I | C | C1 | VI |
Septal reduction therapy to improve symptoms in patients with a resting or maximum provoked LVOT gradient of ≥50 mmHg, who are in NYHA functional Class III–IV, despite maximum tolerated medical therapy |
I | B | B | IVb |
Septal reduction therapy in patients with chest pain or recurrent exertional syncope caused by a resting or maximum provoked LVOTO gradient ≥50 mmHg despite optimal medical therapy |
I | B | B | IVb |
Septal myectomy, rather than PTSMA, in patients with an indication for septal reduction therapy | IIa | C | C1 | IVb |
Septal myectomy, rather than PTSMA, in patients with other lesions requiring surgical intervention (e.g., mitral valve repair/replacement, papillary muscle intervention) |
IIa | C | C1 | VI |
Mitral valve repair or replacement in patients with a resting or maximum provoked LVOTO gradient ≥50 mmHg and moderate-to-severe mitral regurgitation not caused by SAM of the mitral valve alone |
IIa | C | C1 | V |
PTSMA in eligible adult patients with HCM with LVOTO and severe drug-refractory symptoms when surgery is contraindicated or the risk is considered unacceptable because of serious comorbidities or advanced age |
IIa | C | C1 | V |
Mitral valve repair or replacement in patients with a resting or maximum provoked LVOTO gradient ≥50 mmHg and a maximum septal thickness ≤16 mm at the point of the mitral leaflet-septal contact or when there is moderate-to-severe mitral regurgitation following isolated myectomy |
IIb | C | C1 | V |
PTSMA in patients with midventricular-obstruction, who are in NYHA functional Class IIm–IV, despite optimal medical therapy if there is no other treatment |
IIb | C | C1 | V |
Septal reduction therapy for adult patients with HCM who are asymptomatic with normal exercise tolerance or whose symptoms are controlled or minimized on optimal medical therapy |
III | C | C2 | V |
Septal reduction therapy for adult patients with no evidence of resting or provoked LVOTO, even if they have symptoms |
III | C | C2 | V |
Mitral valve replacement for relief of LVOTO in patients with HCM in whom septal reduction therapy is an option |
III | C | C2 | V |
PTSMA in patients with HCM with concomitant disease that independently warrants surgical correction (e.g., coronary artery bypass grafting for CAD, mitral valve repair for ruptured chordae) in whom surgical myectomy can be performed as part of the operation |
III | C | C2 | V |
PTSMA in patients with HCM who are less than 21 years of age, and discouraged in adults less than 40 years of age if myectomy is a viable option |
III | C | C2 | V |
Septal reduction therapy unless performed as part of a program dedicated to the longitudinal and multidisciplinary care of patients with HCM |
III | C | C2 | V |
CAD, coronary artery disease; COR, class of recommendation; GOR, grade of recommendation; HCM, hypertrophic cardiomyopathy; LOE, level of evidence; LVOTO, left ventricular outflow tract obstruction; PTSMA, percutaneous transluminal septal myocardial ablation.
The following 3 indications for SRT should be present: (1) HCM with a significant pressure gradient in the LV (with LVOT and MVO); (2) drug-refractory; and (3) symptomatic.
b. Selection of Treatment
i. PTSMA ? Septal Myectomy?
First, the indications for surgical septal myectomy should be considered. If comorbid heart disease is present that can be repaired at the same time with a thoracotomy, septal myocardial resection is selected. Mitral regurgitation may be the most frequent comorbid condition.
Surgical septal myectomy should be positively considered in the following cases:
(1) structural abnormality of the LVOT or mitral complex requiring surgical treatment
(2) organic aortic or mitral valve disease requiring surgery
(3) young and middle-aged adults, especially in HOCM, except for (1) and (2) above
(4) wall thickness of the LV septum at obstruction is ≥30 mm
(5) insufficient septal reduction by PTSMA.
It is very important to check for structural abnormalities in the mitral chordae complex in performing SRT. This should be checked using various imaging modalities.301 Surgical myectomy or PTSMA should be performed after discussions with cardiologists and cardiac surgeons who are well-versed in treating HCM and other multidisciplinary heart teams. SRT should be conducted in hospitals with a low rate of complications.302
ii. Surgical Septal Myectomy
The basic procedure for myocardial resection is the transaortic valve approach by Morrow et al.303,304 In the cases of abnormal attachment of chordae to the anterior mitral valve leaflet, and direct attachment of the fused anterior papillary muscle head to the anterior mitral valve leaflet, with abnormal fiber continuity from the anterior mitral valve leaflet to the septum, ingenious myectomy or valvuloplasty or valve replacement will be required.305 Recently, in patients with MVO or apical hypertrophy, a transaortic valve approach and extended resection of the myocardium at the transapical portion have been performed.306
As diagnostic imaging technologies advances, the causes of intra-LV pressure gradient are not only myocardial hypertrophy, but also the extension of the mitral valve leaflets, abnormal muscle bundles between the mitral valve leaflet and interventricular septum, and abnormal muscle bundles from apical displacement of the papillary muscles and abnormal chordae from the papillary muscles.307–309 Because patients usually have an obstruction not only in the LVOT, but also in the mid-LV, the concept of RPR repair, which involves resection of the hypertrophic myocardium, plication of the mitral valve leaflets, and release of abnormal muscle bundles and chordae, is popular.310
After septal myectomy, improvements are seen in not only the symptoms, but also survival rate, and a prognosis equivalent to that of nonobstructive HCM can be expected.311,312 LVOTO is relieved in such patients, and recurrence is rarely seen. In ≥70% of patients, HF and exercise capacity are improved for more than 5 years, and the 10-year survival rate has been reported as 72–88%. The results of the surgery are good, especially in younger cases, and should be the first choice in younger cases. The surgical death rate is 3.2–4.6% (0–2% in experienced centers), and the risk factors include old age, preoperative NYHA Class IV, and pulmonary hypertension.311,313,314
Perioperative complications include death, bradyarrhythmia represented by atrioventricular block, cerebral infarction, cardiac tamponade, lethal VT (sustained VT/VF), ventricular septal perforation, aortic valve injury, and coronary fistula.315
iii. PTSMA/ASA
In PTSMA, a type of SRT, ethanol is injected into the coronary artery that perfuses the hypertrophic myocardium, which often causes the pressure gradient in the LVOT or mid-LV in HOCM, and induces thinning of the hypertrophied myocardium, ultimately reducing the pressure gradient.
There are many reports of treatment results from the USA and Europe.316–327 The rate of need for new permanent pacemaker insertion is 10–30%, for hospital mortality 1–2%, and for re-PTSMA 5–15%, and the 5- to 10-year survival rate is 80–95%.317–324 According to reports from the largest registry (The Euro-ASA registry), perioperative complications associated with PTSMA were rare, and long-term mortality was low. They concluded that PTSMA is an effective treatment for reducing symptoms and relieving LVOTO in HOCM.323 However, the exacerbation of LVOTO after surgery is associated with a worse prognosis, and appropriate treatment should be selected to relieve LVOTO.
Complications include tachyarrhythmias (VT/VF) and bradyarrhythmias (e.g., complete atrioventricular block), as well as those associated with ethanol infusion, catheterization, and temporary pacemaker insertion.
Septal myectomy should be considered for young adults (PTSMA should not be considered as a treatment option except in special circumstances). For patients aged ≥40 years, after evaluating their background and various findings (e.g., TTE or TEE, cardiac CT, CMR), it is desirable for a heart team to consider which is the most effective treatment.325–327
Regarding experience, Class I is defined as personal procedure experience of >20 patients, and in this guideline the treatment experience of hospitals should be at least 20 patients, the same as in previous guidelines.6,7,300
iv. DDD Pacing (Table 33)
Recommendations | COR | LOE | GOR (MINDS) |
LOE (MINDS) |
---|---|---|---|---|
Sequential AV pacing in patients who are at high risk of developing heart block following PTSMA or septal myectomy |
IIb | C | C1 | VI |
Sequential AV pacing, with optimal AV interval to reduce the LV outflow tract gradient or to facilitate medical treatment with β-blockers and/or verapamil, may be considered in selected patients with resting or provocable LVOTO ≥50 mmHg, sinus rhythm and drug-refractory symptoms, who have contraindications for PTSMA or septal myectomy |
IIb | C | C1 | V |
In patients with resting or provocable LVOTO ≥50 mmHg, sinus rhythm and drug-refractory symptoms, in whom there is an indication for an ICD, a dual-chamber ICD |
IIb | C | C1 | VI |
AV, atrioventricular; COR, class of recommendation; GOR, grade of recommendation; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter defibrillator; LOE, level of evidence; LVOTO, left ventricular outflow tract obstruction; PTSMA, percutaneous transluminal septal myocardial ablation.
There were reports that DDD pacing was effective for reducing the LV pressure gradient, but its efficacy was not confirmed in either the Pacing In Cardiomyopathy study, a randomized crossover comparative study conducted in Europe and the USA,328 or the Multicenter Study of Pacing Therapy for Hypertrophic Cardiomyopathy.329 Currently, this treatment is considered only when one of the reasons mentioned above is present (see III.6.3.2 Invasive Therapy). In HCM, Because LV diastolic function is impaired, simple RV pacing reduces inflow to the LV by LA contraction. As the AV interval can be set in synchrony with atrial contraction, DDD pacing should be selected. Attention should be paid to complications such as infection, discomfort at the implantation site, and displacement of the pacemaker electrode.330
6.4 Supraventricular Arrhythmias and Thromboembolism (Table 34)
Recommendations | COR | LOE | GOR (MINDS) |
LOE (MINDS) |
---|---|---|---|---|
Oral anticoagulation therapy To prevent thromboembolism in patients with AF |
I | B | A | IVa |
Beta-blockers, verapamil and diltiazem To control heart rate in patients with permanent or persistent AF |
I | C | B | IVa |
Electrical cardioversion or intravenous amiodarone To restore sinus rhythm in patients presenting with recent-onset AF |
IIa | C | B | IVa |
Amiodarone or class I antiarrhythmic drugs To maintain sinus rhythm in patients with recurrent AF |
IIa | C | B | IVa |
Catheter ablation To improve AF symptoms in patients without severe left atrial enlargement, who have drug-refractory symptoms or are unable to take antiarrhythmic drugs |
IIa | C | C1 | IVb |
Atrioventricular node ablation To control heart rate and symptoms when adequate ventricular rate control cannot be achieved with drug therapy |
IIb | C | C1 | VI |
AF, atrial fibrillation; COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
6.4.1 General Remarks
The most commonly encountered arrhythmia in HCM is AF. A meta-analysis of 33 clinical studies showed that the overall prevalence of AF in HCM was 22.5%, and that the overall prevalence of thromboembolism in HCM patients with AF was 27.1%.331 The results also showed that the overall incidence of AF was 3.1 per 100 patients/year, and that the incidence of thromboembolism in HCM patients with AF was 3.8 per 100 patients/year. Increasing age and LA enlargement are risks for the development of AF and thromboembolism.331 AF is associated with an increased risk of HCM-related death, including sudden, HF-related, and stroke-related death (AF: 3%/year; sinus rhythm: 1%/year).246 On the other hand, more than 80% of HCM patients experience some symptoms when AF occurs.246 Symptoms include those associated with HF, such as shortness of breath, dyspnea, and chest pain, and loss of consciousness, such as with syncope. In HCM patients, left atrial and pulmonary capillary pressures increase with decreased diastolic compliance and increased LV end-diastolic pressure due to a shortened diastolic filling time during tachycardia at the occurrence of AF. Under this condition, cardiac output also decreases, and these mechanisms may lead to the development of HCM-related symptoms.
Few data are available on the prevalence and characteristics of atrial flutter or other atrial arrhythmias in HCM patients. Patients with atrial flutter should be treated in the same way as those with AF, as in the AF guidelines.332 In patients with paroxysmal supraventricular tachycardia, catheter ablation is highly effective for WPW syndrome or atrioventricular node reentrant tachycardia.
6.4.2 Prevention of Thromboembolism
In HCM patients, AF is an important risk factor for thromboembolism, including cerebral infarction.246,331 Although no randomized trials assessing the role of anticoagulation among patients with HCM have been conducted, anticoagulation is recommended to prevent thromboembolism in HCM patients who develop AF, unless they have contraindications, because thromboembolism can occur even in younger patients with HCM and AF. Risk stratification based on CHA2DS2-VASc or CHADS2 score is not recommended for HCM patients.6,7
The use of warfarin (prothrombin time/international normalized ratio [PT-INR]: 2.0–3.0; PT-INR 1.6–2.6 for age ≥70 years) is recommended for anticoagulant therapy.246,332,333 Although no clinical trials have been conducted on the effectiveness of direct anticoagulants (DOACs) in reducing thromboembolic risk in patients with HCM and AF, in an observational study DOACs were reported to be useful.334 In addition, the use of anticoagulants before and after cardioversion is recommended in the AF guidelines.332
6.4.3 Rate Control
For the treatment of tachycardic AF, ventricular rate control can improve hemodynamics and symptoms. β-blockers, nondihydropyridine calcium antagonists (verapamil or diltiazem), or their combined use should be considered.6,7 Digoxin is not recommended for HOCM with LVOTO because it increases the degree of obstruction. Digoxin alone or in combination with β-blockers may be useful for patients with moderately or severely reduced LV systolic function (LVEF <50%).6,7
On the other hand, ablation of the atrioventricular node and implantation of a pacemaker are considered to control the rate and symptoms when medication cannot achieve a sufficient ventricular rate.6,7
6.4.4 Restoration of Sinus Rhythm and Prevention of AF Recurrence
Electrical cardioversion of AF is recommended for patients with exacerbation of HF or a severely hemodynamic state, as well as for those with a drug-refractory rapid ventricular rate, which leads to hemodynamic deterioration according to the AF guidelines.332 If the hemodynamic status is stable, electrical or pharmacological cardioversion using amiodarone should be performed after adequate anticoagulation.
No randomized trials have examined the effects of antiarrhythmic drugs or catheter ablation on the prevention of AF in HCM. Amiodarone has been shown to be effective.335,336 On the other hand, Class I antiarrhythmic drugs such as disopyramide and cibenzoline have been used to reduce the pressure gradient in HOCM with LVOTO, but their effects on maintaining sinus rhythm are unknown.
In recent years, the effectiveness of catheter ablation therapy for AF in selected patients with HCM has been reported, and is expected to improve symptoms and quality of life (QOL).337,338 However, antiarrhythmic drugs are often used to maintain sinus rhythm in HCM patients following catheter ablation because the recurrence rate of AF is higher in patients with HCM than in those with the usual nonvalvular AF. In addition, the recurrence rate of AF is higher in HCM patients with a large LA diameter.337,338 The indication of ablation in HCM is considered only in limited cases, in which the LA diameter is not large and the duration from development of AF is relatively short. The usefulness of Maze surgery has been reported.339 In patients with HCM and WPW syndrome, in addition to a history of supraventricular tachycardia, catheter ablation of the accessory pathway is recommended, which also plays a role in the prevention of sudden death in WPW syndrome patients with AF.
6.5 Management of Special Conditions
6.5.1 HCM With Hypertension
One of the diseases morphologically similar to HCM is hypertensive heart disease, in which LVH progresses because of persistent pressure overload by uncontrolled hypertension. This disease is characterized by diastolic dysfunction in the initial phase followed by systolic dysfunction at the advanced phase.340 When a patient with an HCM-like morphology also has hypertension, it is difficult to differentiate whether LVH is due to hypertensive heart disease or HCM,341,342 so it is necessary to make a comprehensive judgment based on clinical background, diagnostic imaging, such as echocardiography, CMR, and 12-lead ECG. On echocardiography, the proportion of patients with a maximum LV wall thickness ≥15 mm or remarkable diastolic dysfunction is more common in HCM.342,343 On CMR, LGE is observed in both hypertensive heart disease and HCM, but in the latter case, it has been reported that LGE is often observed in the region of RV insertion to the ventricular septum or at the most prominent site of LVH.344–347 Other than QRS high voltage, repolarization abnormalities, conduction disturbances, and abnormal Q waves are more frequently observed in patients with HCM on 12-lead ECG.342,348
The points of differential diagnosis between hypertensive heart disease and HCM listed in the 2014 ESC guidelines are shown in Table 35.7
Clinical features favouring hypertension only |
Normal 12 lead ECG or isolated increased voltage without repolarisation abnormality |
Regression of LVH over 6–12 months tight systolic blood pressure control (<130 mmHg) |
Clinical features favouring hypertrophic cardiomyopathy |
Family history of HCM |
Right ventricular hypertrophy |
Late gadolinium enhancement at the RV insertion points or localized to segments of maximum LV thickening on CMR |
Maximum LV wall thickness ≥15 mm (Caucasian); ≥20 mm (black) |
Severe diastolic dysfunction |
Marked repolarisation abnormalities, conduction disease or Q-waves on 12 lead ECG |
CMR, cardiac magnetic resonance imaging; ECG, electrocardiogram; HCM, hypertrophic cardiomyopathy; LV, left ventricle; LVH, left ventricular hypertrophy; RV, right ventricle. (Adapted from Elliott PM, et al. 2014.7) Translated and reproduced by permission of Oxford University Press on behalf of the European Society of Cardiology. Please visit: www.escardio.org/Guidelines/Clinical-Practice-Guidelines/Hypertrophic-Cardiomyopathy. OUP and the ESC are not responsible or in any way liable for the accuracy of the translation. The Japanese Circulation Society is solely responsible for the translation in this publication/reprint.
It is well known that the proportion of apical HCM is higher in Japan than in other countries.31 When LVH is localized at the apex, these patients should be considered as having HCM as opposed to hypertensive heart disease.29,30
Strict blood pressure control is effective for the prevention and regression of LVH in hypertensive heart disease, but usually not in HCM.349–352 Therefore, monitoring the change in LV thickness after strict control of blood pressure with antihypertensive agents also helps in the differential diagnosis of hypertensive heart disease and HCM. However, it is important to remember that the administration of antihypertensive agents such as dihydropyridines, calcium-channel blockers and ACE inhibitors/ARBs may exacerbate the LVOT gradient in HCM.270,271 When choosing antihypertensive agents for patients with hypertension and LVH, it is necessary to assess whether these patients have HOCM, including labile LVOTO.
6.5.2 HCM With Aortic Stenosis
LVH progresses because of continuous pressure overload in patients with aortic stenosis, which may result in a cardiac morphology similar to that of HCM. In patients with aortic stenosis with asymmetrical septal basal hypertrophy mimicking HOCM, it is difficult to distinguish noninvasively whether the pressure gradient is the result of LVOTO or stenosed aortic valve.353,354 Concomitant septal myectomy at the time of aortic valve replacement is widely recommended when a patient with aortic stenosis has asymmetrical septal basal hypertrophy, because (1) the procedure to remove the protruding septal myocardium immediately below the aortic valve leaflets during aortic valve replacement is relatively easy, and (2) the improvement of symptoms may be limited if LVOTO remains or is worsened by reducing the preload after aortic valve replacement354–357 (Table 36). When an aortic stenosis patient with distinct LVOTO undergoes transcatheter aortic valve implantation instead of surgical aortic valve replacement, PTSMA should be considered before or after transcatheter replacement358 (Table 36).
Recommendations | COR | LOE | GOR (MINDS) |
LOE (MINDS) |
---|---|---|---|---|
Concomitant septal myectomy with aortic valve replacement in severe aortic stenosis patients whose LVOTO with septal basal hypertrophy is clearly associated with worsening of clinical condition |
I | B | B | III |
Concomitant septal myectomy with aortic valve replacement in severe aortic stenosis patients with septal basal hypertrophy which may cause LVOTO after surgery |
IIa | C | C1 | IVb |
Preceding or additional PTSMA in severe aortic stenosis patients undergoing transcatheter aortic valve replacement when complicated by severe LVOTO with septal basal hypertrophy |
IIa | C | C1 | V |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence; LVOTO, left ventricular outflow tract obstruction; PTSMA, percutaneous transluminal septal ablation.
6.5.3 Prevention of Infective Endocarditis
Infective endocarditis is caused by bacteria adhering to endocardium damaged by backflow, turbulence, and jet flow of blood in the heart. The risk is high for patients with HOCM and severe valvular disease such as mitral regurgitation.359 When an HCM patient with significant LVOTO is complicated with infective endocarditis causing severe mitral regurgitation and/or aortic regurgitation, surgical replacement is necessary.360 In HOCM patients, the thickened anterior mitral valve leaflet and the surface adjacent to the midventricular septum are the most common sites of infection.360,361
Although the ESC guidelines do not recommend prophylactic antibiotics during dental treatment for patients at high risk of developing infective endocarditis, including HOCM patients, the JCS 2017 “Guidelines for prevention and treatment of infective endocarditis” define HOCM as a high-risk heart disease that should be treated with antibiotics (Table 37).362
Recommendation | COR | LOE | GOR (MINDS) |
LOE (MINDS) |
---|---|---|---|---|
Antibiotic prophylaxis prior to dental procedures in HCM with intra-LV pressure gradient or severe valvular disease |
IIa | C | C1 | VI |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
6.6 HCM in Children
6.6.1 Characteristics and Epidemiology
According to the Japanese Society of Pediatric Cardiology and Cardiac Surgery Rare Disease Surveillance, the incidence of HCM in children is approximately 30–40 cases per year.363 The Pediatric Cardiomyopathy Registry in North America reported that the incidence of HCM was 30.3 in 1 million children under 1 year of age, and 3.2 in 1 million children between 1 and 18 years of age.363 The causes of pediatric HCM are diverse (Table 38), including idiopathic (74%), metabolic disease (9%), syndrome-related (9%), and neuromuscular disease (8%).364 Many cases of HCM due to syndromes (NS, glycogen storage disease, etc.) are often seen in infants. Children with HCM diagnosed when school-aged tend to be asymptomatic or experience syncope or SCD during exercise.
Idiopathic hypertrophic cardiomyopathy |
Sarcomere gene abnormality |
Z-disc gene abnormality |
Calcium-handling gene abnormality, etc. |
Specific cardiomyopathy (secondary cardiomyopathy) |
Genetic/familial |
Syndromic |
Noonan syndrome (PTPN11, KRAS, SOS1, RAF1, etc.) |
LEOPARD syndrome (PTPN11) |
Costello syndrome |
Beckwith-Wiedemann syndrome |
Friedreich ataxia (FXN) |
Congenital myotonic dystrophy |
Glycogen storage disease |
Pompe disease (GAA), Forbes disease, Danon disease (LAMP2) |
PRKAG2 mutation, etc. |
Lysosomal disease |
Fabry disease (GLA), Sandohoff disease, Hurler syndrome, Hunter syndrome |
I-cell disease, etc. |
Mitochondrial disease |
Respiratory chain disorders, fatty acid metabolism disorders |
Metal metabolism disorder |
Wilson disease, hemochromatosis |
Nongenetic/nonfamilial |
Infant of diabetic mother |
Twin-to-twin transfusion syndrome |
Steroid-related cardiac hypertrophy |
Young athlete |
The prognosis depends on the underlying disease, age at onset, and functional phenotype. Prognosis is poor for HCM due to inborn errors of metabolism, mixed HCM/DCM, and mixed HCM/RCM, and the prognosis in patients diagnosed before 1 year of age and with HCM associated with congenital malformation syndrome is also poor.365,366 The best prognosis is for patients with pure idiopathic HCM diagnosed after 1 year of age. The risk factors for a poor prognosis include age at onset, poor weight gain, congestive HF, decreased cardiac contractility, and greater LV wall thickness, and the risk of death or heart transplantation is significantly higher when ≥2 risk factors are present or as the number of risk factors increase.366 In an Australian national registry study, freedom from death or transplantation for HCM diagnosed before the age of 10 years was 86% at 1 year, 80% at 10 years, and 78% at 20 years after presentation, and the reported risk factors included symmetrical LVH, NS, greater LV posterior wall thickness and LV systolic dysfunction.367
6.6.2 Timing and Opportunity for Diagnosis of HCM in Children
a. Fetus
The prevalence of echocardiography in prenatal screening has increased the likelihood of suspected heart disease being detected during fetal life, and fetal echocardiography can identify fetal cardiomyopathy as well as congenital heart disease and fetal arrhythmias. In addition, infants of diabetic mothers, twin-to-twin transfusion syndrome, and Ras/MAPK syndrome are known to be associated with fetal HCM.368
b. Neonate and Infant
Abnormalities may be detected and diagnosed during the regular health checkups in the neonatal and infantile periods. In addition to abnormal heart sounds and murmurs on auscultation, poor weight gain, short stature, physical characteristics (e.g., facial appearance, chest deformities), and hepatomegaly may lead to a diagnosis of HCM, as may chest X-ray performed for other reasons such as bronchitis or pneumonia. HCM diagnosed during this period is often related to systemic disorders (syndromes).369
c. School-Aged Children
In Japan, asymptomatic HCM may be diagnosed by abnormal heart sounds, murmurs, or ECG abnormalities detected during school-based heart health examinations. Medical consultation for syncope or chest pain, ECG recording, chest X-ray for other reasons, or family screening with another proband may lead to a diagnosis of HCM.
During the school heart examination, if the interview table contains a history of chest pain or syncope or a family history of sudden death, even if the ECG is normal, the patient should undergo a secondary examination, and scrutiny is needed in a tertiary examination. ECG assessments should be based on age-specific criteria,370 and if abnormal QRS voltage, left or right atrial load, ST-T wave abnormalities, Q wave abnormalities, or arrhythmias are observed, secondary and tertiary screening should be performed, including a differential diagnosis for HCM. A combined amplitude >23 mm for the R wave on the aVL lead and the S wave on the V2 lead has been reported as a suitable screening for HCM in children.371 Normal ECG findings in Japanese children by age were published in 2017,372 and the ECG criteria for pediatric HCM are planned to be revised in the near future. LGE by CMR, which reflects fibrosis, is observed in about half of pediatric HCM cases and reported to increase over time.373
HCM diagnosed during this period includes Danon disease and Fabry disease. Enzyme-replacement therapy is available for Fabry disease, so early diagnosis is crucial. Danon disease may occur in teenagers, but myopathy is likely to be overlooked because it is mild.
6.6.3 Treatment
The treatment strategy for HCM is to improve cardiac function, reduce symptoms, prevent complications (e.g., sudden death, arrhythmia, embolism, infective endocarditis), and improve the prognosis. Based on the pathophysiology of the underlying disease, the indications for pharmacotherapy and nonpharmacotherapy should be considered, and comprehensive management, including lifestyle guidance, becomes important.7
a. HOCM
i. General Precautions
LVOTO is defined as an instantaneous peak Doppler LVOT pressure gradient ≥30 mmHg at rest. With or without symptoms, all patients with LVOT obstruction should avoid dehydration, vigorous exercise, and obesity. In symptomatic cases (e.g., chest pain, palpitations, shortness of breath, easy fatigue), moderate and vigorous exercise should be prohibited (School Life Management Guidance Criteria B or C) (Figure 21). Vasodilators such as ACE inhibitors and digoxin should be avoided because they worsen the LVOTO. New-onset AF should be managed by prompt restoration of sinus rhythm.
Management of hypertrophic cardiomyopathy in children. (B,C,D) Japanese School Life Management Guidance Criteria. ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; ICD, implantable cardioverter defibrillator; LVOTO, left ventricular outflow tract obstruction; MRA, mineralocorticoid receptor antagonist.
ii. Indications for Pharmacotherapy
In high-risk and symptomatic children, as in adults, pharmacotherapy is essential, and treatment with β-blockers is the mainstay.
a) β-Blockers Nonvasodilating β-blockers are the first choice for significant LVOTO. Nonselective β-blockers such as propranolol are often used,374 and the dosage is generally 2–5 mg/kg/day. However, higher doses (8–24 mg/kg/day) have been reported to improve survival.375,376 Other β-blockers (e.g., atenolol, metoprolol) are also used, but no comparative study of individual β-blockers in children has been reported.
b) Calcium Antagonists Calcium antagonists such as verapamil have been reported to improve symptoms and exercise endurance in adults because of their negative inotropic and heart rate-reducing effects. Although few data are available for children, verapamil can be used when patients are symptomatic and β-blockers are ineffective.377 Verapamil is generally used at a dose of 3–8 mg/kg/day. If severe LVOTO or pulmonary hypertension is present, close monitoring is required because it can provoke pulmonary edema or sudden death.295
c) Antiarrhythmic Drugs Disopyramide and cibenzoline have a negative inotropic effect because of sodium-channel blockade, and can abolish the basal LVOT pressure gradient. Disopyramide and cibenzoline have been reported to be effective in adults, but experience in children is limited, so careful administration is required.378 The ECG (QTc interval) should be monitored and not used in combination with amiodarone or sotalol, both of which prolong the QT interval. Disopyramide and cibenzoline may increase heart rate, so they should be used in combination with β-blockers.
d) Digoxin and ACE Inhibitors Digoxin, other inotropic drugs (positive inotropic drugs), and ACE inhibitors should be avoided in principle because they may worsen the obstruction. ACE inhibitors may be used in D-HCM.
e) Diuretics Diuretics are generally not used, because they cause preload reduction. However, in symptomatic children with HF or severe shortness of breath on exertion, the careful use of small doses of diuretics may improve symptoms.
iii. Indications for Nonpharmacotherapy
a) PTSMA No evidence regarding the long-term prognosis in children treated with PTSMA has been presented; thus, due to the high risk in small children, no recommendations are possible at this time.
b) Septal Myocardial Resection Septal myotomy–myectomy (Morrow procedure) and the modified Konno procedure have been performed, but the experience in children is limited and the long-term results are unknown.379,380
c) Arrhythmia Treatment Although arrhythmias are rare in young children, a cohort study reported that the prevalence of nonsustained VT was 16–18%.381 Treatment with amiodarone or, if indicated, myocardial myectomy or ICD implantation may be considered in children with VT. Despite the limited experience of ICDs in children, implantation should be considered because SCD is more common in school-aged children and adolescents.382
b. Nonobstructive HCM
If neither symptoms nor arrhythmia is present, it remains controversial whether there is an indication for drug treatment in children with nonobstructive HCM. If any risk factors (e.g., family history of sudden death, genetic abnormalities) are present, exercise restriction should be considered. In symptomatic cases, the strategy is to lower the LV diastolic pressure, reduce symptoms, and manage the arrhythmia. As pharmacotherapy, β-blockers or calcium antagonists may be considered if patients have preserved LV systolic function and show shortness of breath or chest pain on exertion. If shortness of breath is apparent, a small dose of diuretics can be carefully added. If patients have impaired LV systolic function (EF <50%) and are symptomatic, ACE inhibitors, ARBs, and small doses of diuretics may be considered in addition to β-blockers.
6.6.4 Prevention of Complications
a. Prevention of SCD
HCM is the most common cause of SCD in the young, especially in relation to exercise.383 The frequency of SCD in children is about twice that in adults, and the most common age is 12–35 years.382 Clinical features associated with an increased risk of SCD in adults have been reported, and these include younger age at diagnosis, nonsustained VT (≥3 consecutive ventricular beats at ≥120 beats/min lasting <30 s), maximum LV wall thickness ≥30 mm, family history of SCD, history of syncope (especially in relation to exercise), history of cardiac arrest or sustained VT, LA enlargement (diameter ≥45 mm), LVOTO, and abnormal exercise blood pressure response (a failure to increase systolic pressure by at least 20 mmHg from rest to peak exercise in patients aged ≤40 years).104,384,385 A predictive probability model (HCM Risk-SCD formula) has been devised, and ICD implantation based on risk stratification has been proposed.7 Recently, a novel risk prediction model for SCD in childhood HCM (HCM Risk-Kids) was reported.386 In general, the severity of LVH (maximum LV wall thickness ≥30 mm or Z-score ≥6), history of syncope, nonsustained VT, family history of SCD, and cardiopulmonary resuscitation are considered to be risk factors for SCD.382
Based on the School Life Management Guidance Table (2011 version) prepared by the Japan School Health Association, almost all exercise and sports are prohibited for high-risk children (School Life Management Guidance Criteria B). Moderate and intense physical activities are prohibited in patients with symptomatic HCM and HOCM (School Life Management Guidance Criteria B or C).387 Recreational exercise does not need to be restricted in asymptomatic cases or by those for whom the risk of sudden death is low, but sports training and competitive sports are prohibited. ICD implantation is the first-line therapy in patients with a history of resuscitation and may be considered if patients have >1 risk factor. If children have only 1 risk factor, the decision on ICD implantation must be made on an individual basis and must balance the benefits against the risks in each case.
In a previous study that investigated SCD in pediatric HCM patients with significant symptoms and high-risk factors (e.g., sum of limb-lead QRS voltage >10 mV, ventricular septal thickness >190% of the upper limit of normal),388 the administration of high-dose β-blockers (e.g., propranolol, metoprolol, bisoprolol) was effective in preventing SCD, and concomitant use of disopyramide reduced the risk of SCD; however, further studies are required. It should be also noted that patients with HCM may have sinus node dysfunction and atrioventricular block, resulting in symptomatic bradycardia.
Children diagnosed at younger than 1 year of age have poor outcomes, including death from congestive HF.389 Even infants with heart murmurs alone have a 1-year survival rate of 50%, and the rate of sudden death increases after a few years.390
b. Prevention of Infective Endocarditis
The preventive use of antimicrobial drugs is required in HOCM patients because the incidence of infective endocarditis is considered to be high,359,362 although no evidence has been established.
c. Prevention of Thromboembolism
Oral anticoagulants are recommended to prevent cardiogenic thromboembolism in patients who develop AF, and antiplatelet drugs may also be used.
6.6.5 Treatment of D-HCM
During the natural course of HCM, patients may develop cardiac dilatation and systolic dysfunction. The evaluation and treatment of D-HCM follow the management of chronic HF, including the use of ACE inhibitors, ARBs, and diuretics, in addition to β-blockers.391
6.6.6 Management and Treatment of Disease-Related HCM
a. Ras/MAPK Syndrome
Noonan syndrome (NS) belongs to the spectrum of Ras/MAPK syndromes (known as RASopathies), and a number of responsible genes (i.e., PTPN11, SOS1, RAF1, BRAF, KRAS, HRAS, and SHOC2) have been reported. Patients present with characteristic patterns of short stature, pterygium, valgus elbow, peculiar facial features, and chest deformities. Cardiac complications include HCM, pulmonary valve dysplasia/stenosis, atrial septal defect, ventricular septal defect, and double-outlet RV. Patients with RAF1 mutations are most often (≈90%) associated with severe HCM.392 The morphological phenotype of HCM in NS is similar to that in idiopathic HCM, such as asymmetrical septal hypertrophy. Children with NS and HCM have been reported to have lower crude survival rates compared with those with idiopathic HCM. Within the NS cohort, a diagnosis of HCM before the age of 6 months with congestive HF suggests a poorer prognosis. Short stature and impaired LV systolic function are also independent risk factors for death.393
LEOPARD syndrome (LS) is also a Ras/MAPK syndrome, and the main features are multiple lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonary artery stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. LS is an autosomal dominant disorder, but many sporadic cases have been reported. HCM is detected in approximately 80% of cases and the severity affects the prognosis. ASH, concentric LVH, and LVOTO are observed in approximately 40% of cases. Mutations in the PTPN11 gene have been suggested to affect disease severity and a Gln510Glu mutation is associated with severe HCM from the neonatal period.394 New therapeutic approaches to modify the Ras/MAPK pathway have been reported.395
b. Metabolic Disorders
Pompe disease (glycogen storage disease type II) is an autosomal recessive disorder in which a large amount of normal glycogen accumulates in cells because of a deficiency or reduction of glycogen-degrading enzyme (acid α-glucosidase) activity, and glycogen accumulation is remarkable in the heart, liver, and skeletal muscles. Patients with infantile-onset Pompe disease (onset of muscle weakness by the age of 2 years) usually present with concentric cardiac hypertrophy, a form of HCM. If enzyme-replacement therapy with alglucosidase α (recombinant) is begun early, cardiac function may be improved.396
In Fabry disease, glycosphingolipids accumulate in lysosomes because of reduced or deficient α-Gal activity, resulting in myocardial hypertrophy. Enzyme-replacement therapy is effective.397
Danon disease is a metabolic disorder with X-linked dominant inheritance in which muscle cells have numerous vacuoles because of abnormal LAMP-2 protein in the lysosomal membrane. In addition to HCM, muscle weakness and neuropsychiatric symptoms are observed, and the prognosis is determined by the cardiac complications (e.g., HCM, arrhythmia). HCM progresses from concentric hypertrophy to D-HCM.398 Males develop this disease earlier and with greater severity, but severe cases have also been reported in females; disease-specific treatments have not yet been developed.
It has been suggested that glycogenosis type III be treated with a ketogenic diet.399,400
c. Mitochondrial Disease
Mitochondrial disease is a highly heterogeneous collection of inherited multisystemic disorders related to genetic abnormalities related to the structure and function of mitochondria. Cardiomyopathy is seen in 20–40% of cases of childhood-onset mitochondrial disease. HCM is the most common cardiomyopathy phenotype, but various types of cardiomyopathies, such as RCM, DCM, and LVNC, are observed. Neonatal/infant-onset patients have an extremely poor prognosis and may be overlooked as having HCM of unknown cause.
d. Maternal Diabetes
Almost one-third of infants born to mothers with diabetes mellitus (types 1 and 2) have pathological cardiac hypertrophy. Maternal hyperglycemia causes fetal hyperglycemia and hyperinsulinemia, resulting in cardiomyocyte hypertrophy. The cardiac phenotype is broad, from mild LVH to severe biventricular hypertrophy, and sometimes has fatal outcomes. In most cases, the cardiac hypertrophy resolves within days to months. Associations between fetal echocardiographic parameters and neonatal outcomes have been reported.401,402
e. Twin-to-Twin Transfusion Syndrome
This is a serious complication that occurs in 10–30% of monochorionic twin pregnancies. An atriovenous anastomosis between the twin placentas results in chronic imbalanced unidirectional blood flow from one placental artery to the other placental vein. The recipient twin shows polycythemia and a high body weight, and the donor twin shows anemia and a low body weight. Cardiac hypertrophy, myocardial disorders, and RVOT stenosis are seen in the recipient twin.403 In some cases, biventricular hypertrophy leads to a fatal outcome, but in others, cardiomyopathy with systolic or diastolic dysfunction improves from 10 days to 2 months after birth.
7. Lifestyle7.1 Lifestyle
(See IV.6.1 Lifestyle)
7.2 Exercise Therapy/Exercise Training (Table 39)
Recommendation | COR | LOE | GOR (MINDS) |
LOE (MINDS) |
---|---|---|---|---|
Patients with HCM To improve exercise capacity |
IIb | C | C1 | III |
HCM patients with advanced deconditioning and those with reduced physical function Resistance training to improve ADL and QOL by increasing muscle strength and endurance |
IIb | C | C1 | V |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
To date, HCM has been known as a causative disease of SCD in athletes and young people404 during physical activity.405 For this reason HCM has been excluded from the indication of exercise thrapy.404,406 Patients with HCM may complain of symptoms associated with physical activity, such as shortness of breath, chest pain, and syncope. These symptoms are related to LVOTO, myocardial ischemia, exacerbation of diastolic dysfunction, and inappropriate dilatation of the vascular bed,407–409 which are thought to limit exercise tolerance.410
Recently, Klempfner et al411 and Saberi et al412 reported the effects of exercise training in patients with HCM. Both studies reported that exercise training was safe and effective for improving physical function and exercise tolerance.
At present, athletic training should be avoided by HCM patients. Exercise therapy for this disease has only just begun. In the future, it will be necessary to increase the number of cases and studies that demonstrate the long-term effects and safety of exercise therapy for HCM patients.
7.3 Pregnancy and Childbirth
7.3.1 Changes in Hemodynamics During Pregnancy and Childbirth
During pregnancy and childbirth, the maternal cardiac function reserve is required because of the dynamic circulatory change. The circulating plasma volume increases about 1.5-fold from nonpregnancy at around 28–32 weeks of gestation. Cardiac output shows a similar increase, but the increase in cardiac output is achieved mainly by an increase in stroke volume in the first half of pregnancy and by an increase in heart rate in the second half of pregnancy.413 For women with organic heart disease, the peak period of increase in circulating plasma volume is at around 30 weeks, which is the time when heart failure is most common414 (Figure 22). Hemoglobin becomes diluted and thus its level decreases. In addition, cardiac output further increases during delivery, and approximately 300–500 mL of uteroplacental blood is transferred to the systemic circulation at each uterine contraction during labor. Maternal bleeding (≈500 mL) can be compensated for by the increase in circulating plasma produced during pregnancy. Compression of the inferior vena cava is released, causing a rapid increase in venous return. It takes about 1–3 months after delivery for hemodynamics to normalize.
Increased percentage of plasma volume in pregnancy and the high incidence period for heart failure in pregnant women with cardiac disease.
It should be noted that pregnancy with HCM always carries a potential risk for such fluctuations. In pregnancies with HOCM, if the LV cavity is enlarged due to an increase in circulating plasma volume during pregnancy, it is possible that the LVOTO may be reduced. However, in severe cases, in addition to LV diastolic dysfunction, an increase in heart rate (i.e., shortened ventricular diastole) increases the pressure gradient in the LVOT. Even in pregnancies with nonobstructive HCM, the severe diastolic dysfunction cannot tolerate an increase in circulating plasma volume, which leads to increased LV end-diastolic pressure and a risk of congestive heart failure. LA enlargement during pregnancy increases the risk of both AF and thrombosis because of hypercoagulability during pregnancy.
7.3.2 Pregnancy and Childbirth Risks
Although most HCM patients can tolerate pregnancy, approximately 20–40% of patients have cardiovascular complications.415–418 Sudden maternal death has been reported, and found to be related to a family history of sudden death and/or a maximum wall thickness ≥30 mm.416 For pregnant women with risk factors for sudden death (see III.6.2 Sudden Death), careful prepregnancy evaluation and counseling, as well as treatment with antiarrhythmic drugs and ICD implantation, if needed, should be considered.
Risk factors for cardiovascular complications include prepregnancy NYHA Class II or higher, LV obstruction, a history of prepregnancy cardiovascular complications,416–419 and medication use before pregnancy. The CARPREG score, which is a scoring system for pregnancy risk assessment, lists LVOTO (pressure gradient >30 mmHg on echocardiography) as one of the predictors of maternal cardiovascular events.420
Although arrhythmias are widely observed from early pregnancy to the postpartum period, heart failure complications occur more frequently during the second and third trimesters and postpartum period, when circulating plasma volume increases.414,417,420 Heart failure tends to appear earlier in pregnancies with HOCM than with nonobstructive HCM.414
According to the JCS guidelines, one of the types of heart disease requiring prepregnancy assessment and strict monitoring during pregnancy is severe LVOT gradient and extreme LVH.421
7.3.3 Pregnancy and Childbirth Management
β-blockers are effective for LVOTO, heart rate control of AF, and ventricular arrhythmias.6,422 If the patient was taking β-blockers before pregnancy, they may be continued during pregnancy. If symptoms appear during pregnancy, treatment may start anew. In patients with severe diastolic dysfunction or LVOTO, increased heart rate plays a significant role in increasing cardiac output during pregnancy, as stroke volume is hardly increased. Be aware that when starting and increasing the dose of β-blockers, a decrease in heart rate may result in an inability to adapt to an increase in circulating plasma volume and subsequent heart failure. Electrical cardioversion can be used while paying attention to the fetus in patients with new-onset AF. If electrical cardioversion is attempted but does not return the sinus rhythm, heart rate control and anticoagulation therapy should be considered. Before pregnancy, PTSMA, septal myectomy, catheter ablation, and/or pacemaker/ICD implantation may be considered, if the patient has those indications. Several reports have been published in which these interventions were carried out during pregnancy or immediately after delivery.423,424
In general, vaginal delivery is the first choice. During delivery, maternal positions and expulsive efforts that reduce venous return should be avoided as much as possible. Careful attention should be paid to maternal and fetal changes in cases involving a large amount of bleeding, the use of vasodilators, including epidural and/or spinal anesthesia, or the use of β-stimulants for tocolysis. Local anesthesia during delivery may reduce venous return and blood pressure because of peripheral vasodilation. In women with severe LV obstruction, therefore, careful consideration should be given to the indications for local anesthesia. When a large amount of bleeding or dehydration due to prolonged delivery occurs, the fluid volume should be adjusted appropriately with fluid replacement or blood transfusion to prevent a decrease in blood pressure. Increased venous return immediately after parturition may cause pulmonary congestion.
DCM is defined as “diseases characterized by diffusely impaired contraction of the LV and dilatation of LV”.8 To confirm the diagnosis, “secondary cardiomyopathy” (referred to as “specific cardiomyopathy” by the WHO/ISFC), which presents similarly to DCM but is secondary to the underlying disease or systemic abnormality, must be excluded.3 As per the ESC, DCM is defined as the presence of LV dilatation and systolic dysfunction in the absence of abnormal loading conditions (e.g., hypertension, valve disease) or CAD sufficient to cause global systolic impairment. RV dilatation and dysfunction may be present, but are not necessary for diagnosis.5
1.1 Secondary Cardiomyopathy to Be Distinguished From DCM
As indicated by the AHA classification, DCM is based on morphological and functional classifications, and etiologically represents a group of mixed genetic and acquired diseases (Figure 1).4 Clinically, many similar diseases cause LV dilatation and systolic dysfunction; therefore, it is necessary to exclude secondary cardiomyopathy, a specific cardiomyopathy with apparent causes (Table 40). DCM needs to be further differentiated from dilated-phase hypertrophic cardiomyopathy (D-HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). In particular, D-HCM is often experienced over a long period of time, and can be particularly difficult to distinguish from DCM at the time of diagnosis.
Myocardial disease | ||
Ischemic heart diseases | Myocardial infarction, stunning, hibernation, microcirculatory disorder | |
Stress | Takotsubo cardiomyopathy | |
Pregnancy | Peripartum cardiomyopathy | |
Immune disorders | Rheumatoid arthritis, SLE, polymyositis, mixed connective tissue disease | |
Cardiotoxic substances | Addictive and abused | Alcohol |
Heavy metals | Copper, iron, lead, cobalt, mercury | |
Drugs | Antitumor drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), anesthetic drugs, antiviral drugs |
|
Inflammatory diseases | Infectious | Myocarditis (viral or non-viral) |
Non-infectious | Sarcoidosis | |
Infiltrative diseases | Amyloidosis, hemochromatosis | |
Endocrine disorders | Hyperthyroidism, Cushing’s disease, pheochromocytoma, adrenal insufficiency, abnormal growth hormone secretion |
|
Metabolic disorders | Diabetes mellitus, obesity | |
Congenital enzyme abnormality | Lysosome | Fabry disease |
Glycogen storage disease | Pompe disease | |
Mucopolysaccharidosis | Hurler syndrome, Hunter syndrome | |
Neuromuscular disorders, other systemic diseases |
Muscular dystrophies, laminopathies, mitochondrial diseases | |
Mechanical overload (pressure overload, volume overload) | ||
Hypertension | Hypertensive heart disease | |
Structural disease | Congenital | Congenital valvular disease, other congenital heart disease |
Acquired | Valvular heart disease | |
Endocardial abnormalities | Eosinophilic endomyocardial diseases, endocardial fibroelastosis | |
High-output heart failure | Severe anemia, hyperthyroidism, Paget’s disease, arteriovenous shunt, beriberi heart |
|
Arrhythmias | ||
Bradyarrhythmias | Sick sinus syndrome, atrioventricular block, etc | |
Tachyarrhythmias | Atrial fibrillation, atrial tachycardia, etc |
2.1 Pathophysiology and Concept
DCM represents a group of “primary” cardiomyopathies characterized by impaired myocardial contraction and dilation of the LV cavity. It is a disease with a poor prognosis that presents with repetitive acute exacerbations due to heart failure. DCM may cause sudden death due to fatal arrhythmias or thromboembolism of the arteries.
It is important to identify gene mutation carriers in the family or early-phase DCM with only arrhythmia, even if systolic function is almost normal. If unexplained structural or functional abnormalities of the myocardium are observed, the preclinical or early stage of DCM should be considered. In such cases, continuous examination, management, and risk assessment are necessary at appropriate time points. Even if typical LV dilation is not observed, cases of LV systolic impairment, so-called hypokinetic nondilated cardiomyopathy, or mildly dilated cardiomyopathy are sometimes clinically serious cases that require caution.425,426 In families with familial DCM, 10–20% of people will progress to DCM within 5 years; therefore, careful follow-up is required, even in asymptomatic cases without LV dilatation.427,428
2.2 Causes of DCM
Although the etiology of DCM has long been unknown, it has been analyzed separately for hereditary (familial) and nonhereditary (nonfamilial) cases, and the notion of a syndrome involving both causes is predominant for DCM among adults.
2.2.1 Hereditary (Familial)
About 20–40% of DCM cases occur because of mutations, and it is expected that many unexplained gene mutations among nonfamilial families are related (for details, see IV.4.11 Genetic Testing (Including Genetic Counseling)).429 Many known causative genes encode for the sarcomere proteins directly related to cardiac contractility, dystrophin-related proteins that play a role in transmitting cardiac contractility, and proteins involved in intracellular calcium regulation. A large-scale, next-generation sequencing (NGS) genomic cohort study of DCM in Europe reported that more than 38% of those analyzed had multiple mutations, and 13% had >2 mutations.430
In recent years, the identification of single-gene abnormalities has been used to develop polygenic risk scores that predict the cumulative effect of multiple susceptibility genes with a mathematical model in genome-wide association studies. Attempts to assess risk based on the concept of genetic predisposition have also begun. Indeed, these technologies could predict the risk of developing cardiomyopathies in combination with lifelong environmental factors.431
2.2.2 Nonhereditary (Nonfamilial)
The cause of nonhereditary DCM is still unclear. Chronic inflammation and autoimmune mechanisms are recognized as involved in the development of DCM. Based on some reports showing the presence of viral genomes in the heart tissue of patients diagnosed with DCM, it is suggested that viral infections trigger a continuous autoimmune mechanism to shift to DCM, even without inflammatory cell infiltration432 or some association with an HLA-DQ/DR/DP polymorphism. In fact, myosin, β1 adrenergic receptor,433,434 M2 muscarinic receptor,435 troponin I,436 Na–K–ATPase pump,437 and laminin438 antibodies have been detected in the serum of patients with DCM, some of which have been shown to have some pathophysiological significance. The detection rate of some autoantibodies is 9–95%, showing remarkable variability and low specificity.439 Therefore, the clinical significance of autoantibody detection in individual cases has not yet been determined.
3. Epidemiology3.1 Prevalence
The exact prevalence of DCM is unknown. Various cohort studies in Japan (Table 41) have reported a prevalence between 1 and 3 per 1,000 people, but these reports included cases of secondary cardiomyopathy.440–447 When considering the number of DCM-specific disease recipient certificates issued for DCM as a designated intractable disease (Ministry of Health, Labour and Welfare Health Administration Report), the prevalence of DCM, including mild illness, is estimated to be 0.5 per person, or approximately 1 in 2,000.
In a registered study of children under the age of 18 years,448 1.13 cases of cardiomyopathy were reported to occur per every 100,000 people per year. It was also reported that 8.34 cases are diagnosed per year and 0.70 cases per 100,000 people aged 1–18 years per year.
3.2 Prognosis
Although no clear investigations regarding the prognosis of DCM have been conducted, the 1-year mortality rate was reported to be 7.3% by the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD),440 and the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-1,441 with reference to the prognosis of patients with general heart failure (HF). The rate of rehospitalization within 3 years for HF patients was reported to be 30% by CHART-1 and 17% by CHART-2. The overall mortality rate was reported as 24% by both CHART-1 and CHART-2. In Japan, the prognosis for HF is expected to be better than previously reported.442 On the other hand, DCM is still the most common cause of severe HF leading to transplantation in Japan, accounting for 66% of the 512 heart transplant cases prior to December 2019.449 Data specific to the recent prognosis of DCM are not available. Although the 5-year survival rate was reported to be 76% in a 1999 survey by the Ministry of Health, Labour and Welfare, it is speculated that prognosis has been improved by appropriate drug treatment, CRT, and VADs.
4. Diagnostic Criteria and Differential Diagnosis4.1 Differentiation of DCM and Secondary Cardiomyopathy
4.1.1 Secondary Cardiomyopathy to Be Differentiated (Specific Cardiomyopathy)
Among the diseases that present with DCM-like manifestation due to various causes, cardiomyopathies that are relatively frequent and require clinical attention for differentiation are described below. It is necessary to exclude these diseases during diagnosis.
a. Ischemic Cardiomyopathy
Severe ischemic heart disease is characterized by dilated LV and reduced systolic function similar to DCM, but caused by chronic ischemia. Many cases have a history of old myocardial infarction, but it is also caused by severe myocardial ischemia due to repeated onset of angina, or myocardial hypoxia due to anemia and sleep apnea syndrome. Because ischemic heart disease is one of the most common causes of hospitalization due to exacerbation of HF, it must be first excluded in patients suspected of DCM. Distinct wall motion is characteristic, but may be diffuse, and idiopathic DCM may also show asynergy, making it difficult to distinguish between DCM and ischemic cardiomyopathy.
b. Hypertensive Heart Disease
Hypertensive heart disease is a DCM-like pathology that presents with cardiac dysfunction and histological abnormalities such as LVH, cardiomyocyte hypertrophy, and interstitial and perivascular fibrosis. It is characterized by efferent hypertrophy and LV enlargement.
Various forms of LVH are known, especially in the early stage of hypertensive heart disease.450 In the late stage of the disease, LV hypertrophy (LVH) is not observed and the LV ejection fraction (LVEF) may decrease. The development of HF can be attributed to histological and functional disorders of the heart, as well as other organs such as blood vessels and kidneys, because of hypertension.
c. Cardiac Sarcoidosis
Cardiac sarcoidosis is a systemic granulomatous disease of unknown etiology that occurs frequently in the lungs, hilar lymph nodes, eyes, and skin. The prevalence of cardiac involvement is said to be approximately 5% among sarcoidosis cases; however, this is higher when autopsy findings are included.451,452 In Japan, it occurs most commonly in middle-aged women and older men, but is also found in younger people, and men have no typical age of onset.453
Diagnosis can be difficult in cases of isolated cardiac sarcoidosis that develops only in the heart, and the condition may only be evident after an autopsy or heart transplantation in patients treated for cardiomyopathy.454 Ventricular wall thickening consistent with the site of granulomatous inflammation and stromal edema are commonly observed, and because the inflammation gradually disappears and fibrosis of the lesion progresses, the base of the ventricular septum can be characteristic of cardiac sarcoidosis. Local wall motion abnormalities and ventricular aneurysms in the left and right ventricles are observed, but if the lesion spreads extensively, it presents with a DCM-like pathology.455 Histopathologically, epithelioid cell granuloma without case necrosis, lymphocyte infiltration with interstitial edema, fibrosis, and microvascular lesions are characteristic findings. Differentiation by fluorodeoxyglucose-positron emission tomography (FDG-PET), cardiac magnetic resonance imaging (CMR), and histopathology is important.
d. Amyloidosis
Systemic amyloidosis is classified into AL amyloidosis, AA amyloidosis, hereditary ATTR amyloidosis, wild-type ATTR amyloidosis, and dialysis-related amyloidosis (see III.2.2.2 for description of types of amyloidosis).
Cardiac amyloidosis results from amyloid deposition in the myocardium, causing an infiltrative/restrictive cardiomyopathy.57 The main pathological condition is diastolic dysfunction associated with thickening of the ventricular wall. As it progresses, systolic insufficiency, progressive and refractory HF, and impaired cardiac conduction system with various arrhythmias develop. LV and RV wall thickening, intramyocardial granular sparkling sign, valve thickening, bilateral atrial enlargement, atrial wall thickening, pericardial effusion, and atrial thrombus may be observed on echocardiography.456–458 Coronary amyloid deposition may cause ischemia.459 Histopathological evidence of amyloid deposits leads to a definitive diagnosis. When hereditary amyloidosis is suspected, genetic analysis is necessary.460
e. Myocarditis
Most cases of myocarditis are caused by infection with viruses, bacteria, rickettsia, chlamydia, fungi, or parasites. Coxsackie B virus is the most common virus causing viral myocarditis. Patients such as fulminant myocarditis can take a rapid course. After rapid and widespread inflammation of the myocardium, LV dysfunction is often prolonged, with extensive fibrosis. Immediate diagnosis by endomyocardial biopsy and acute management for circulatory maintenance are important. Furthermore, myocarditis, including noninfectious myocarditis, may be related to autoantibodies. In either case, if cardiomyocyte necrosis occurs because of sustained inflammation, the subsequent release of self-antigens triggers persistent inflammation as a chronic myocarditis, and eventually progresses to DCM.461–463 (Figure 23). ESC defines DCM that is associated with persistent inflammation as inflammatory DCM (iDCM).58 However, at present, the etiology and diagnosis of iDCM have not yet been determined.
Persistent inflammation and progression of DCM.
f. Myocardial Disease Associated With Muscular Dystrophy
Muscular dystrophy consists of a group of hereditary and progressive disorders of muscular weakness that are classified as Duchenne, Becker, Emery–Dreifuss, limb–girdle muscular dystrophy, facial scapulohumeral, or myotonic. It is caused by mutations in the dystrophin protein that structurally links the muscle cytoskeleton to the extracellular matrix.
i. Duchenne Muscular Dystrophy (DMD)
Many DMD patients have reduced LV systolic function in their teenage years. Because the HF symptoms are seldom accompanied by limited activity, regular cardiac checks are performed regardless of the symptoms. Echocardiographic evaluation is often difficult because of the effects of thoracic deformities and scoliosis. Even if LV wall motion is normal, extensive perfusion defects seen on 201Tl myocardial scintigraphy are useful for prognosis. The characteristic feature of DMD is cardiomyocyte degeneration and consequent substitution by fat and fibrous tissue that gradually spreads from the base of the posterior wall to the free wall of the LV. DCM-like cardiomyopathy is more common than HCM-like cardiomyopathy, but some cases have been reported in which HCM-like shifts to a DCM-like phenotype. Mitral valve prolapse is observed in almost all cases, but the underlying mechanism remains unknown. Dystrophin protein is deficient, but cardiac dysfunction does not correlate with the degree of skeletal muscle weakness, and may be complicated if motor function is maintained.464
ii. Becker Muscular Dystrophy
Becker muscular dystrophy shows a clinical picture similar to that of DMD, but its progression is somewhat slower. The frequency of cardiomyopathy in Becker muscular dystrophy is 60–75%,465 and the time of onset varies greatly between individuals. Cardiac function may decline even when the patients start to walk, and regulary evaluations are required after junior high school. Unlike in DMD, fibrosis of the LV posterior wall is not typically observed. The HCM- or DCM-like phenotype, regional LV wall dyskinesia, apical thrombosis, or mitral regurgitation may be observed. The typical course involves RV enlargement in the early stages, followed by LV enlargement and LV systolic dysfunction.466 Although DMD and Becker muscular dystrophy inherit an X-linked recessive trait, approximately 11% of carriers are reported to have progressive LV dysfunction; hence, follow-up is important.467
iii. Emery–Dreifuss Muscular Dystrophy and Other Types
Emery–Dreifuss has X-linked latent or autosomal dominant inheritance and is characterized by frequent conduction disturbances such as complete atrioventricular block and sinus node dysfunction despite poor skeletal muscle symptoms. Initially, diastolic dysfunction and LVH are observed. With progression, the LV enlarges, LV wall thickness decreases or becomes normal, and similar conditions to those of DCM are observed. Myotonic dystrophy, in which the right and left atria are also enlarged, may cause conduction impairment of the cardiac stimulus, but rarely presents in typical DCM. In muscular dystrophy, the frequency of atrial arrhythmias is high, but the phenotype of cardiomyopathy is minimal.
g. Alcoholic Cardiomyopathy
Alcoholic cardiomyopathy is a toxic cardiomyopathy induced by long-term and heavy drinking, which is generally considered to be 80–90 g/day of pure ethanol (equivalent to 4–5 gou of sake [180 mL] or 4–5 bottles of beer) for more than 5 years. Histologically, changes in the structure of the intracellular organelles, and especially changes in mitochondrial size and lipid droplets in the myocardium, are observed. Prohibition of drinking is necessary, and even small doses are exacerbated by drinking.
h. Mitochondrial Cardiomyopathy
Mitochondrial cardiomyopathy is a myocardial disorder associated with mitochondrial diseases. It often appears as a cardiac manifestation of mitochondrial diseases that affect multiple organs, but cardiomyopathy sometimes occurs in the foreground. More than 20 mutations (point mutations or deletions) in the mitochondrial genes associated with mitochondrial cardiomyopathy have been reported, many of which result in typical mitochondrial diseases such as MELAS, myoclonic epilepsy with ragged-red fibers (MERRF), chronic progressive external ophthalmoplegia syndrome (CPEO), or Kearns–Sayre syndrome (KSS). Typical cardiac manifestations of mitochondrial disease are hypertrophy; however, mitochondrial cardiomyopathy may also present as DCM or RCM. Initially, contractile capacity is maintained in comparison with the degree of hypertrophy. However, as the disease progresses, LV systolic function rapidly decreases and the patient may present as a DCM-like condition.
i. Abnormalities in Mitochondrial DNA Genes
Cardiomyopathy caused by mitochondrial gene abnormalities, such as MELAS, occurring as a result of a 3243A>G mutation, develops when the mutant mitochondria exceed a certain heteroplasmy ratio (the mixture of mutant and normal genes). Genetic diagnosis by cardiac muscle biopsy and evaluation by electron microscopy are important. Affected organs other than the heart include the skeletal muscles, central nervous system, endocrine glands, gastrointestinal tract, and peripheral nerves. As cardiac involvement can be life-threatening and cause Adams–Stokes syndrome and sudden death, cardiac assessment at the time of diagnosis is necessary and patients need to be monitored over time, even if asymptomatic.468
ii. Nuclear DNA Gene Abnormalities
Mitochondrial respiratory chain and related molecules encoded by nuclear DNA can also cause mitochondrial disease. In many cases, it is difficult to identify the causative gene of the pathological condition, so it is often necessary to evaluate mitochondrial dysfunction in the myocardium together with mitochondrial assessment in other organs such as the skeletal muscles.
i. Drug-Induced Cardiomyopathy
This cardiomyopathy exhibits cardiac dysfunction caused by drugs. Many anticancer drugs such as anthracycline doxorubicin (adriamycin) and idarubicin, alkylating agents such as cyclophosphamide and ifosfamide, antimetabolic drugs such as clofarabine, and antimicrotubule inhibitors such as docetaxel have long been known to cause cardiotoxicity.
Interest in the field of cardio-oncology has grown because of the increased survival of patients with cancer using classic anticancer drugs and other recent molecular-targeted therapies. Patients with cardiotoxicity may have a reduced quality of life (QOL) and prognosis, so guidelines have been published and task forces have been assembled by several academic societies.469–472
i. Anthracycline-Based Anticancer Drugs
Doxorubicin (Adriamycin) is a widely used representative cardiotoxic drug. It causes severe damage to the myocardium and chronic toxicity involves cumulative cardiotoxicity that occurs in proportion to the total dose. Although this condition may occur even 10 years after the last dose, it usually has a median onset of 3 months after administration (Table 42).472
Risk factors |
• Cumulative dose |
• Female sex |
• Age |
- >65 years old |
- Paediatric population (<18 years) |
• Renal failure |
• Concomitant or previous radiation therapy involving the heart |
• Concomitant chemotherapy |
- Alkylating or antimicrotubule agents |
- Immuno- and targeted therapies |
• Pre-existing conditions |
- Cardiac diseases associating increased wall stress |
- Arterial hypertension |
- Genetic factors |
aAnthracyclines (daunorubicin, doxorubicin, epirubicin, idarubicin) or anthracenedione (mitoxantrone). (Source: Prepared based on Zamorano JL, et al. 2016472)
ii. Trastuzumab
Trastuzumab (Herceptin), a humanized monoclonal antibody to the human epidermal growth factor receptor 2 (HER2) receptor, significantly improves the prognosis of HER2-expressing breast cancer patients. However, it increases the frequency of cardiomyopathy. To minimize the risk of cardiotoxicity, careful monitoring of the LVEF during treatment with trastuzumab is required. Cardiomyopathy is more likely to be induced by trastuzumab and anthracycline-based combination regimens than with trastuzumab alone.
iii. Immune Checkpoint Inhibitors
Activation of the immune system by immune checkpoint inhibitors can induce myocarditis and cardiomyopathy as side effects. The frequency is 0.06% for nivolumab, and 0.27% for nivolumab and ipilimumab in combination. However, attention should be paid to the fact that even if the initial symptoms are slight, they may rapidly become fulminant and fatal.473
Other anticancer drugs that can cause cardiomyopathy are shown in Table 43.472
Chemotherapy agents | Incidence (%) |
---|---|
Anthracyclines (dose dependent) | |
Doxorubicin (Adriamycin) | |
400 mg/m2 | 3–5 |
550 mg/m2 | 7–26 |
700 mg/m2 | 18–48 |
Idarubicin (>90 mg/m2) | 5–18 |
Epirubicin (>900 mg/m2) | 0.9–11.4 |
Mitoxanthone >120 mg/m2 | 2.6 |
Liposomal anthracyclines (>900 mg/m2) | 2 |
Alkylating agents | |
Cyclophosphamide | 7–28 |
Ifosfamide | |
<10 g/m2 | 0.5 |
12.5–16 g/m2 | 17 |
Antimetabolites | |
Clofarabine | 27 |
Antimicrotubule agents | |
Docetaxel | 2.3–13 |
Paclitaxel | <1 |
Monoclonal antibodies | |
Trastuzumab | 1.7–20.1a |
Bevacizumab | 1.6–4b |
Pertuzumab | 0.7–1.2 |
Small molecule tyrosine kinase inhibitors | |
Sunitinib | 2.7–19 |
Pazopanib | 7–11 |
Sorafenib | 4–8 |
Dasatinib | 2–4 |
Imatinib mesylate | 0.2–2.7 |
Lapatinib | 0.2–1.5 |
Nilotinib | 1 |
Proteasome inhibitors | |
Carfilzomib | 11–25 |
Bortezomib | 2–5 |
Miscellanous | |
Everolimus | <1 |
Temsirolimus | <1 |
aWhen used in combination with anthracyclines and cyclophosphamide. bIn patients receiving concurrent anthracyclines. (Source: Prepared based on Zamorano JL, et al. 2016472)
j. Fabry Disease
The cardiac lesions of Fabry disease mainly present as LVH. As the disease stage progresses, LV systolic dysfunction is accompanied by regression of hypertrophy and thinning localized at the base of the posterior wall of the LV, resulting in a DCM-like condition.
k. Peripartum Cardiomyopathy
Peripartum cardiomyopathy presents in late pregnancy or the early postpartum period in women who have no history of heart disease and no other known causes of HF. More than half of such patients recover their cardiac function, but in approximately 40% of cases, dysfunction is ongoing and severe cases are fatal. Pregnancy and delivery are thought to be involved in the onset and progression of this disease. Gestational hypertension, multiple pregnancies, and the use of uterine contraction inhibitors are related to this condition. The incidence of recurrence is high with subsequent pregnancies.425,474
4.1.2 Other Cardiomyopathies
Several other primary cardiomyopathies exhibit structural and functional features similar to those of DCM. D-HCM and ARVC are differentiated from DCM. Although LVNC is not classified as a cardiomyopathy, it is an overlap disorder that should be noted.
a. D-HCM
In some cases of HCM, the thickened myocardial wall gradually thins over time, resulting in decreased LV contractility and a dilated LV lumen, and eventually presents as a condition similar to DCM. The proportion of those with a family history is high and sudden death due to fatal arrhythmias and exacerbation of HF are common, so the prognosis is poor.
b. ARVC
ARVC is a heart muscle disease characterized by a severe ventricular arrhythmia originating from the RV, and may occur as manifestation of RV-predominant cardiac enlargement and cardiac dysfunction with fatty degeneration and fibrosis.475 The LV remains normal or is mildly abnormal. Conduction delay is characterized by an ε-wave in the right precordial lead (leads V1–3) or localized QRS width extension (>110 ms). Frequent ventricular premature contractions and VT of the left bundle block from the RV are commonly observed. Desmosomal gene mutations are considered to be a major cause of ARVC. Complications of VT and HF have a poor prognosis.476
c. LVNC
LVNC is defined as an unclassified cardiomyopathy by the WHO,3 and as hereditary cardiomyopathy by AHA. The formation process is impaired, and while spongy fetal myocardium remains, cardiac function is likely to decrease because of hypoplasia of the myocardial dense layer. Echocardiography reveals a 2-layer structure in which the myocardial wall has a thick layer with densification disorder on the endocardial side, and a densified thin layer on the epicardial side. LVNC has been recognized as a congenital heart disease, but adult cases have been increasing with the development of diagnostic imaging tools such as echocardiography and MRI. Genetic abnormalities such as Z-band alternatively spliced PDZ-motif and tafazzin proteins have been reported. Although LVNC is recognized genetically, sporadic cases are not rare, and can occur in both children and adults. Thrombosis is frequent because of the complex trabecular structure, and LVNC may also be accompanied by arrhythmias and LV dilatation/dysfunction. It clinically presents as a DCM-like condition.477,478
4.2 Symptoms/Physical Findings
4.2.1 Subjective Symptoms
No subjective symptoms are characteristic of DCM, and in some cases patients are asymptomatic. Subjective symptoms include those associated with organ congestion or decreased cardiac output due to HF. Patients may complain of symptoms such as dyspnea, edema, fatigue, and appetite loss, as well as arrhythmia and embolism. VT or bradyarrhythmia can cause dizziness and syncope, and sudden death is not uncommon. For symptoms, refer to the “Guidelines for acute and chronic heart failure” (revised in 2017).11
4.3 Electrocardiography (ECG)
4.3.1 Standard ECG
There are no specific ECG findings for DCM, but there are changes in waveforms and arrhythmias due to causes such as fibrosis of the myocardium, dilation of the atria and ventricles, an impaired conduction system, and HF. High voltage suggestive of LVH (enlargement), an R-wave reduction (especially poor R progression from leads V1–3), abnormal Q waves, prolonged QRS duration, prolonged ventricular activation time in the left chest lead, bundle branch block, intraventricular conduction delays, and ST-T changes are observed. As the LV dilation progresses, the QRS width exceeds 0.12 s, and left bundle branch block is observed. According to RV enlargement and the increase in pressure overload, the T wave is inverted in the right precordial leads and spreads to leads V4 and V5.
Atrial expansion and fibrosis also occur with atrioventricular valve regurgitation and increased LV end-diastolic pressure, which causes prolonged P-wave width and LA load, premature atrial contraction, and atrial fibrillation (AF). Premature ventricular contractions also become more frequent with the decline in cardiac function, and sporadic and multifocal extrasystoles also appear.
Tachycardia generally develops in HF. If tachycardia of ectopic atrial origin or sinus tachycardia of more than 100 beats/min during sleep is present, tachycardia-induced cardiomyopathy due to atrial tachycardia or inappropriate sinus tachycardia may be suspected.479 If the conduction system is impaired because of myocardial degeneration, 1st–3rd-degree atrioventricular block occurs.
b. Holter ECG
Atrial and ventricular arrhythmias increase with impaired LV function. DCM involves premature ventricular contraction, multifocal premature contraction, and nonsustained VT. Holter monitoring is indispensable to determine an indication for ICD or CRT-defibrillator (CRT-D) and for heart rate control in supraventricular tachycardia.
c. Signal-Averaged ECG
The use of signal-averaged ECG to predict the prognosis of DCM remains limited.480 If a late potential is recorded clearly beyond the end of the QRS, then changes are already present in the myocardium from the underlying VT.
d. Exercise Testing
Exercise testing is mainly used in DCM to evaluate ventricular arrhythmias and exercise tolerance. The former is mainly performed using a treadmill, and the latter using cardiopulmonary exercise or the 6-min walking test.
Exercise testing can determine the induction of arrhythmia and changes in blood pressure during exercise. If severe arrhythmia is induced, sudden death may occur, and an appropriate treatment, such as ICD implantation, should be considered. In particular, when ventricular arrhythmias of Lown grades 2–4 exhibiting right bundle branch block-type are induced by exercise, the prognosis is significantly worse compared with that of left bundle branch block-type arrhythmia-induced and non-induced cases.481,482
Peak oxygen uptake and anaerobic metabolism thresholds are indicators of exercise tolerance that are more objective than NYHA class and can be used to evaluate treatment effects and prognosis.
The 6-min walking test estimates exercise capacity.483 It may be useful for prognostic evaluation in severe cases, but the findings may not be consistent with the clinical physical condition.484
e. Electrophysiological Study (EPS)
There has been a negative view of the significance of predicting the prognosis of HF cases such as DCM by EPS.485 Based on the American College of Cardiology/ American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guidelines for device treatment,486 if persistent VT/VF is induced during the EPS in unexplained syncope, it is considered a Class I indication for ICD implantation. Therefore, it is meaningful to perform an EPS in cases of DCM with syncope.
4.4 Biomarkers
Although no specific biomarkers are known for DCM, many have been reported for HF, among which BNP and NT-proBNP are important. The severity of their levels is determined by screening, and they are widely used to predict prognosis (Figure 24).487 For more details on biomarkers, see the JCS 2017/JHFS 2017 “Guidelines for diagnosis and treatment of acute and chronic heart failure”.11 The recommended classes and levels of evidence for biomarkers in heart failure are shown in Table 44.11
Cut-off levels of plasma BNP and NT-proBNP for the diagnosis of heart failure. BNP, brain (B-type) natriuretic peptide; HF, heart failure; NT-proBNP, N-terminal pro-brain (B-type) natriuretic peptide. (Adapted from Japanese Heart Failure Society487)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Plasma BNP and serum NT-proBNP | ||||
Diagnosis | I | A | A | I |
Severity | I | A | A | I |
Prognosis assessment | I | A | A | I |
Efficacy evaluation | IIa | B | B | II |
Screening | IIa | C | B | II |
Plasma atrial (A-type) natriuretic peptide (ANP) | ||||
Diagnosis | I | A | A | I |
Severity | IIa | B | B | II |
Prognosis assessment | IIa | B | B | II |
Efficacy evaluation | IIb | C | C1 | III |
Screening | IIb | C | C1 | III |
Myocardial troponins (T, I)* and plasma noradrenaline# | ||||
Diagnosis | – | – | – | – |
Severity | IIa | B | B | II |
Prognosis assessment | IIa | B | B | II |
Efficacy evaluation | – | – | – | – |
Screening | – | – | – | – |
Aldosterone# and plasma renin activity# | ||||
Diagnosis | – | – | – | – |
Severity | IIa | C | B | III |
Prognosis assessment | IIa | C | B | III |
Efficacy evaluation | – | – | – | – |
Screening | – | – | – | – |
Neurohumoral factors (other than above)# | ||||
Diagnosis | – | – | – | – |
Severity | IIb | C | C1 | V |
Prognosis assessment | IIb | C | C1 | V |
Efficacy evaluation | – | – | – | – |
Screening | – | – | – | – |
*The use of cardiac troponins as biomarkers for heart failure is not covered by the National Health Insurance (NHI) in Japan. However, the guidelines for the management of heart failure proposed by the American College of Cardiology (ACC), the American Heart Association (AHA), and the Heart Failure Society of America (HFSA) suggest the measurement of cardiac troponins as a Class I recommendation with level of evidence A. The guidelines proposed by the European Society of Cardiology (ECS) suggest as a Class I recommendation with level of evidence C. #The use as a biomarker is not covered by the NHI in Japan. COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence. (Adapted from JCS Guideline 2018.11)
4.5 Echocardiography
Transthoracic 2D echocardiography and Doppler echocardiography can be used to diagnose DCM and specific cardiomyopathies because DCM, defined as “decreased contractility and an enlarged ventricle”, can be diagnosed easily at the bedside. If echocardiography shows LV enlargement and systolic dysfunction, DCM or secondary cardiomyopathy is suspected. However, there is no clear indicator of how much LV enlargement or decreased wall motion results in DCM.
4.5.1 Differentiation of Secondary Cardiomyopathy From Cardiac Morphology
DCM is characterized by dilatation of the ventricular cavity and systolic dysfunction. Observation of the cardiac morphology by echocardiography may help differentiate secondary cardiomyopathy. However, ultimately, it is difficult to differentiate by echocardiography alone, and therefore must be combined with other diagnostic tools such as CMR, radionuclide myocardial scintigraphy, and myocardial biopsy.
4.5.2 Evaluation of Cardiac Function, Hemodynamics, and Complications
The evaluation of cardiac function, hemodynamics, and complications follows the JCS 2017/JHFS 2017 “Guidelines for diagnosis and treatment of acute and chronic heart failure”.11
a. Functional Mitral Regurgitation
LV dysfunction, LV enlargement, and annulus enlargement inhibit closure of the leaflets of the mitral valve, causing mitral regurgitation in some cases. Severity is a factor affecting cardiac dysfunction and prognosis, and its evaluation is important.488,489
b. LV Dyssynchrony
LV intraventricular dyssynchrony with delayed LV contraction timing is thought to occur and affect the prognosis of patients with HF with a wide QRS width, such as a conduction block in the left bundle block. Although CRT can be used, echocardiographic indices do not predict effectiveness;490 however, apical shuffle and septal flash are recognized as simple and effective visual methods.491
Echocardiography recommendations and levels of evidence for DCM are shown in Table 45.
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Echocardiography to assess cardiac function, LV wall motion, valvular disease, right ventricular function, and pulmonary hypertension in patients with suspected DCM |
I | C | B | IVb |
Echocardiography in patients with DCM 1) Assessment of cardiac function, LV wall motion, valvular disease, right ventricular function, and pulmonary hypertension in patients with a change in clinical status 2) Reevaluation of patients who need echocardiographic information to determine or modify treatment 3) Echocardiography for detection of cardiac thrombus in patients with severe LV systolic dysfunction, atrial fibrillation, or thromboembolic events *Transesophageal echocardiography should be considered if necessary |
I | C | B | IVb |
Echocardiography to assess differential diagnosis of DCM | I | C | B | IVb |
Echocardiography as a follow-up procedure for patients with DCM without any change in clinical status | IIa | C | C1 | IVb |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
4.6 CMR
The roles of CMR are in DCM evaluation are: (1) evaluation of cardiac function by cine MRI; (2) differential diagnosis of cardiomyopathy and tissue characterization of the myocardium, mainly by delayed-enhanced MRI; and (3) the evaluation of severity and prognosis.
Recommendations for clinical evaluation by CMR and levels of evidence are shown in Table 46.
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Cine MRI to assess cardiac anatomy and function | I | A | A | I |
Delayed-enhanced MRI to differentiate between ischemic and nonischemic cardiomyopathy and to identify underlying heart disease in patients with nonischemic myocardiopathy |
IIa | B | B | IVb |
Delayed-enhanced MRI to predict incidence of arrhythmic events, mortality, and probability of improvement of cardiac function |
IIa | C | B | IVa |
T1 mapping to estimate quantity of myocardial fibrosis | IIa | C | B | IVb |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
4.6.1 Evaluation of Cardiac Function by Cine MRI
Cine MRI can evaluate: (1) LVEF and RVEF; (2) cardiac output; (3) LV and RV end-diastolic and end-systolic volumes; and (4) cardiac mass. Cine MRI can also accurately evaluate RV/LV function and local wall motion and with high reproducibility using 3D images.492
4.6.2 Evaluation of Myocardial Tissue Characterization by CMR
a. Delayed-Enhanced MRI
Delayed-enhanced MRI involves T1-weighted imaging using the inversion–recovery method to visualize the infarcted region with a high signal in the equilibrium phase at 10–15 min after administration of the MR contrast agent gadolinium (Gd). Gd is distributed in the extracellular fluid, but in the normal myocardium, the extracellular fluid space is small and blood flow is maintained. When blood flow decreases because of an old infarction and fibrosis, and the extracellular fluid space increases, Gd flows in slowly and outflow is delayed, so that the disordered area is depicted as a high-signal area. Delayed-enhanced MRI takes advantage of this property, and as such, is useful for (1) quantifying the size of the myocardial infarction,493 (2) identifying subendocardial infarctions,494,495 and (3) evaluating the presence of myocardial viability necessary for revascularization.496,497
b. T2-Weighted Images
Myocardium with inflammatory edema in acute myocardial infarction,498 acute myocarditis,499 or cardiac sarcoidosis500 has a prolonged T2 relaxation time and increased myocardial signal intensity on T2-weighted images. Generally, DCM does not exhibit a high T2 signal.
4.6.3 Identification of Cardiomyopathy by LGE Pattern
In differentiating ischemic from nonischemic cardiomyopathy, and DCM from secondary cardiomyopathy, both the distribution pattern and morphological evaluation of LGE are useful.496,501–503 In the case of ischemic cardiomyopathy, LGE extends from the subendocardium in the territory of the coronary artery. However, it is often difficult to distinguish a specific nonischemic cardiomyopathy by LGE alone because of the large overlap in the LGE patterns.504
In DCM, there are various LGE patterns, including no LGE, LGE extending from the subendocardium, similar to ischemic cardiomyopathy, and solitary patchy LGE that does not match the coronary artery territory. Although a variety of LGE patterns can be present, one of the most characteristic features is a delayed linear contrast pattern that runs vertically in the middle layer of the LV wall.503,505–508 The presence or absence and extension of LGE have been reported as predictors of arrhythmic events, death, and future cardiac function.509,510
Diffuse and mild myocardial fibrosis in DCM may be difficult to evaluate using LGE. A new method for evaluating myocardial properties is the absolute value of the T1 value without using a contrast agent. A correlation has been reported between the myocardial T1 value and histological myocardial fibrosis.511
4.6.4 Other Associated Cardiomyopathies (Table 47)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Myocardial infarction: delayed-enhanced MRI to assess myocardial infarct size, subendocardial infarction, myocardial viability |
IIa | A | B | II |
Cardiac amyloidosis: cardiac MRI including phase-sensitive inversion–recovery method to classify condition, to select appropriate therapy, and to predict prognosis |
IIb | C | C1 | IVa |
Muscular dystrophy: cardiac MRI to assess myocardial damage and to predict prognosis | IIa | C | B | IVa |
Peripartum cardiomyopathy: delayed-enhanced MRI to predict prognosis | IIb | C | C1 | V |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
a. Left Ventricular Noncompaction
The distinctive morphology of the myocardial trabeculae and the formation of deep gaps are considered to be characteristic of LVNC, and morphological evaluation by cine MRI (ratio of noncompacted to compacted myocardium of ≥2 : 3) is useful for diagnosis;512 however, its significance as a prognostic indicator has not been established.513,514
b. Hypertensive Heart Disease
Few reports have been published on the CMR findings in hypertensive heart disease. Delayed contrast enhancement of the middle layer of the myocardium is observed in 50% of cases, but both the location and pattern are nonspecific.155 Thus, diagnosis of hypertensive heart disease by CMR alone is difficult.
c. Cardiac Amyloidosis
Ordinary delayed-enhanced MRI is performed with an inversion time (TI) set so that the signal intensity of the normal myocardium becomes null, and thus contrast between the injured and normal myocardia is obtained. Therefore, it is difficult to depict diffuse amyloid deposition clearly by delayed-enhanced MRI. The phase-sensitive inversion–recovery method of MRI provides optimal contrast between the signals of the normal myocardium and the delayed-enhanced area without complicated TI settings, and thus may be useful for visualizing delayed-enhanced areas more clearly and predicting prognosis in cardiac amyloidosis.515 Because amyloid deposition increases the T1 values, T1 mapping is reported to be useful for the diagnosis of cardiac amyloidosis.516 In addition, asymmetric hypertrophy of the LV myocardium, transmural delayed-imaging, and delayed enhancement of the RV in variant ATTR caused by a mutation in the TTR gene, are more frequent than in primary AL amyloidosis.164,517 CMR may be useful for the classification of cardiac amyloidosis and treatment options.
d. ARVC
The following new diagnostic criteria for ARVC were announced in 2010: (1) RVEF ≤40% and (2) RV end-diastolic volume/body surface area ratio ≥110 mL/m2 (males) or ≥100 mL/m2 (females), in addition to local RV wall motion loss, paradoxical motion, or RV systolic dyssynchrony on cine MRI.518
The rate of ARVC diagnosed with CMR has been reported to be lower using these new criteria compared with the previous diagnostic criteria (1994).519,520 On the other hand, T1-weighted MRI images can identify myocardial steatosis, but the sensitivity and specificity are not high, so this is not included in diagnostic criteria.
e. Myocardial Disease Associated With Muscular Dystrophy
LGE is distributed on the inferolateral wall of the base of the heart and mainly occurs on the epicardial side or in the middle layer of the LV wall. The frequency of LGE is 32–75%.521–523 LV systolic dysfunction and LGE (myocardial fibrosis) on CMR are useful for diagnosing myocardial damage associated with muscular dystrophy, and both are independent predictors of prognosis.524,525
f. Drug-Induced Cardiomyopathy
No delayed-enhancement findings specific to the cardiotoxicity of the anthracycline anticancer drug doxorubicin (Adriamycin) have been reported. In a study examining LGE in trastuzumab-induced cardiomyopathy, a distribution pattern in the middle layer of the lateral LV wall was typical.526,527
g. Fabry Disease
LGE is distributed on the inferolateral wall of the base of the heart, and varies from the transmural to the epicardial and subendocardial sides. The frequency of LGE may vary depending on disease stage. It has been reported that T1 mapping is useful for the diagnosis of this disease because lipid accumulation in the myocardium shortens the T1 value.158
h. Peripartum Cardiomyopathy
In a report of 10 cases, LGE was observed in 4 and in these cases, rehospitalization due to exacerbation of HF was common and impaired contraction of the LV was prolonged.528 The presence of LGE may be associated with the prognosis of perinatal cardiomyopathy.
4.7 Nuclear Imaging/Computed Tomography (Table 48)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
SPECT using thallium chloride or technetium-labeled tracers to assess myocardial viability | IIa | B | B | IVa |
ECG-gated SPECT to assess left ventricular volume and LVEF | IIa | B | B | IVa |
I-123-BMIPP scintigraphy to predict prognosis | IIb | C | C1 | IVb |
I-123-MIBG scintigraphy to predict prognosis | IIb | C | C1 | IVb |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence; LVEF, left ventricular ejection fraction.
Although no specific findings have been reported for the diagnosis of DCM in nuclear imaging or CT examinations, they are considered to be useful for the auxiliary diagnosis of etiology and pathological conditions and the evaluation of therapeutic effects.
4.7.1 Myocardial Perfusion Imaging
201Tl and 99 mTc are used for myocardial perfusion imaging. They are distributed in the viable myocardium in a blood flow-dependent manner, and the fibrotic region is depicted as abnormal accumulation. Both agents are useful for discriminating DCM from ischemic cardiomyopathy.529,530 It has been reported that abnormal uptake at rest in DCM correlates with cardiac function indicators, pathological findings (degree of fibrosis), and prognosis.531,532 In addition, ECG-gated single-photon emission CT can be used to calculate LV volume and LVEF.
4.7.2 Myocardial Fatty Acid Metabolism Imaging
Approximately 60% of the total energy-producing substrates of cardiomyocytes depend on aerobic β-oxidation of fatty acids, and their metabolism can be evaluated by imaging with 123I-BMIPP, a long-chain fatty acid of the side chain type. It has been reported to be an indicator of the therapeutic effect of β-blockers.533 It has also been reported that abnormal 123I-BMIPP accumulation at rest in DCM is a predictor of poor prognosis.534
4.7.3 Myocardial Sympathetic Function Imaging
123I-MIBG has a structure similar to the neurotransmitter norepinephrine and is used for imaging of myocardial sympathetic nerve function. The use of 123I-MIBG makes it possible to evaluate functional abnormalities of the sympathetic nervous system. Planer images are obtained as early images 15 min after administration and as late images 3–4 h after administration, and the heart/mediastinum ratio (H/M) and washout rate are determined. As the severity of HF increases, the late-stage H/M decreases and the rate of washout increases.535 These parameters are also predictive of prognosis.536
4.7.4 Myocardial Glucose Metabolism Imaging (FDG-PET)
FDG is a glucose analog that is taken into cells via glucose transporters that appear on the cell membrane, as well as being a PET tracer that depicts tissues with active glucose metabolism. FDG-PET is covered by the national insurance system of Japan as a myocardial viability test for ischemic heart disease, and has been expanded for use as a diagnostic method for inflammatory sites in cardiac sarcoidosis since 2012.
Approximately 90% of the fasting energy substrate in the normal myocardium is composed of free fatty acids, but in ischemic or failing myocardium, a transition from fatty acid to glucose metabolism is observed, as is the physiological accumulation of FDG in normal myocardium. In studies using PET, a decrease in fatty acid metabolism and an increase in glucose metabolism (change in the metabolic state from aerobic to anaerobic) in DCM have been reported.537 When glucose metabolism is maintained, the response to β-blockers is favorable, and maintaining glucose metabolism in the heart is important for predicting the therapeutic effect.538
FDG-PET can detect areas of active inflammation with high sensitivity, and its characteristics can be used to detect cardiac lesions in sarcoidosis.539–542 Compared with DCM, cardiac sarcoidosis shows strong heterogeneity of FDG accumulation in the heart; thus, FDG-PET is useful for the differential diagnosis of cardiac sarcoidosis and DCM.541
4.7.5 CT
CT shows poorer contrast between normal and abnormal myocardia than CMR, and only plays a small role in the diagnosis of cardiomyopathies. The utility of CT is limited in differentiating ischemic cardiomyopathy by coronary CT angiography,543,544 and evaluating LV enlargement and LV thrombus.
4.8 Exercise Tolerance
Heart failure is a major condition of DCM. Exercise capacity is defined by the activity capacity of patients with HF, and reflects its severity. The assessment of exercise tolerance is useful for not only estimating the severity and prognosis of HF,545 but also assessing the tolerance of daily activities, providing guidance in selecting occupations and work content, and assessing risks during surgery in patients with DCM.546
4.8.1 NYHA Functional Class
The NYHA functional class is used to assess the severity of HF based on the level of activities of daily living (ADLs); however, it is not a quantitative or objective scaling system, especially for patients with a long history of HF, who restrict their ADLs.
4.8.2 Specific Activity Scale (SAS)
The SAS describes the amount of exercise required to perform a given ADL with metabolic equivalents (METs) (Table 49).547,548 This index is very useful for understanding the patient’s behavior in detail, especially for the evaluation of exercise capacity in moderate to severe HF in which subjective symptoms appear in daily life.549
In the Specific Activity Scale (SAS), patients are asked to answer the following questions with “yes,” “hard to do” or “I don’t know”. The amount of exercise (in METs) described in the first question to which the patient answered “hard to do” indicates the minimum amount of physical activity to provoke symptoms, and is recorded as the SAS score. |
1. Can you have a comfortable sleep at night? (≤1 MET) |
2. Do you feel comfortable in the lying position? (≤1 MET) |
3. Can you take meals or wash your face by yourself? (1.6 METs) |
4. Can you go to the bathroom by yourself? (2 METs) |
5. Can you change your clothes by yourself? (2 METs) |
6. Can you do kitchen work or sweep the room with a broom? (2 to 3 METs) |
7. Can you make your bed by yourself? (2 to 3 METs) |
8. Can you swab the floor? (3 to 4 METs) |
9. Can you have a shower without trouble? (3 to 4 METs) |
10. Can you practice radio gymnastic exercises without any trouble? (3 to 4 METs) |
11. Can you walk 100–200 m of level ground at the same speed as healthy persons do (4 km/hr) without any trouble? (3 to 4 METs) |
12. Can you garden (weeding for a brief time, etc.) without any trouble? (4 METs) |
13. Can you take a bath by yourself? (4 to 5 METs) |
14. Can you go upstairs at the same speed as healthy persons do without any trouble? (5 to 6 METs) |
15. Can you do light farming (digging the garden, etc.)? (5 to 7 METs) |
16. Can you walk 200 m of level ground at a quick pace without any trouble? (6 to 7 METs) |
17. Can you remove snow? (6 to 7 METs) |
18. Can you practice tennis (or ping pong) without any trouble? (6 to 7 METs) |
19. Can you practice jogging (at about 8 km/hr) over a distance of 300 to 400 meters without any trouble? (7 to 8 METs) |
20. Can you practice swimming without any trouble? (7 to 8 METs) |
21. Can you practice rope skipping without any trouble? (≥8 METs) |
Minimum amount of physical activity to provoke symptoms: METs |
4.8.3 6-min Walking Test
The 6-min walking test is a maximal exercise test to measure the maximal distance an individual is able to walk in 6 min. It is a simple test that does not require special equipment. The reference value for the Japanese population is calculated by multiplying [454 − 0.87 × age (years) − 0.66 × body weight (kg)] ± 2 standard deviations (82 m/m) by height (m).550 It has been reported that the 6-min walking distance correlates well with the NYHA functional class and peak oxygen uptake,551 and is useful in predicting the prognosis of patients with HF.552
4.8.4 Cardiopulmonary Exercise Test
The most objective index of exercise tolerance is oxygen uptake during maximal exercise. The peak oxygen uptake (peak V̇O2) is measured during cardiopulmonary exercise testing (CPET) using a treadmill or bicycle ergometer. Oxygen uptake is an index that integrates systemic functions (cardiac, respiratory, and peripheral functions, and pulmonary and systemic circulation).553 and is a suitable parameter for assessing prognosis,545,554–556 determining candidates for heart transplantation,545,556–558 and classifying the severity of HF.559 Patients with a peak V̇O2 <14 mL/kg/min have a poor prognosis,555 and those with <10 mL/kg/min have an extremely poor prognosis. When peak V̇O2 is expressed as a percentage of age-predicted peak V̇O2 (% peak V̇O2), patients with a % peak V̇O2 <50% are considered to have a poor prognosis.545 A comparison of NYHA functional class, the SAS, and % maximal oxygen uptake is shown in Table 50.548 CPET is useful for discriminating whether exercise restriction is due to HF in patients whose exercise is restricted by shortness of breath during exertion.553
NYHA classification |
Specific Activity Scale (SAS) |
Percent peak oxygen uptake (% peak V̇O2) |
---|---|---|
I | 6 METs or more | 80% or more of the reference level |
II | 3.5 to 5.9 METs | 60 to 80% of the reference level |
III | 2 to 3.4 METs | 40 to 60% of the reference level |
IV | 1 to 1.9 METs or less | Impossible to determine or <40% of the reference level |
There is no established formula indicating exact correspondence between NYHA functional classes and SAS. In this table, according to a consensus among experts, the following assumption was used: the amount of exercise is 2 METs for walking inside a room, 3.5 METs for usual walking, 4 METs for light exercise or stretching exercise, 5 to 6 METs for fast walking, and 6 to 7 METs for walking upstairs.
METs, metabolic equivalents; NYHA, New York Heart Association. (Excerpted from The Japanese Intractable Diseases Information Center548)
The anaerobic threshold, which is defined as the point during exercise when anaerobic metabolism occurs in addition to aerobic metabolism, is also a good index of the severity of HF.559 Moreover, the anaerobic threshold is used as an index of daily activity levels, which determines the allowable exercise level and exercise prescriptions.560,561
The slope of increase of ventilation relative to carbon dioxide production (V̇E/V̇CO2 slope), which can be obtained without performing the maximum load, has been attracting increasing attention. This index indicates the tidal volume needed to eliminate the carbon dioxide produced during exercise, and is also called ventilation efficiency. Patients with a V̇E/V̇CO2 slope >35 are considered to have a poor prognosis.562 Recommendations for the evaluation of exercise tolerance in HF and the evidence levels are summarized in Table 51.
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Medical interview To survey the patient’s exercise capacity, mental status, cognitive function, and social environment |
I | B | B | IVa |
Cardiopulmonary exercise testing To consider the indication of heart transplantation and other advanced treatment |
I | B | B | II |
Cardiopulmonary exercise testing To specify the cause in patients in whom dyspnea on exertion or easy fatigability limits their physical activities |
I | B | B | IVb |
Measurement of peak oxygen uptake To assess prognosis |
I | B | B | II |
Cardiopulmonary exercise testing To develop an exercise prescription |
IIa | B | B | II |
Cardiopulmonary exercise testing In patients with atrial fibrillation or pacing, to assess heart rate response, to determine optimal exercise programs, to evaluate blood pressure, arrhythmia, strength of physical activities during exercise, to assess change in exercise capacity over time, and to assess treatment efficacy |
IIa | B | B | II |
Cardiopulmonary exercise testing As a routine test procedure |
III | C | C2 | VI |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
4.9 Cardiac Catheterization
The main objectives of cardiac catheterization for the treatment of DCM are as follows: (1) differentiation from ischemic cardiomyopathy by coronary angiography and evaluation of coronary artery lesions when CAD is suspected; (2) evaluation of LV volume and LVEF, wall motion abnormalities, and complicated valvular diseases such as mitral regurgitation by LV angiography; (3) hemodynamic evaluation by intracardiac pressure measurement and cardiac output measurement; (4) evaluation of secondary cardiomyopathy by subendocardial myocardial biopsy; and (5) electrophysiological examination of arrhythmia and other evaluations of comorbid heart disease.
Although cardiac catheterization can be performed safely in many cases, it is an invasive procedure. First, noninvasive imaging and physiological examinations are performed. For (1) and (2) above, useful information can often be obtained from coronary CT, nuclear medicine, and other imaging examinations such as CMR (see IV.4.6). Please refer to the next section for (5).
4.9.1 Right Heart Catheterization (Table 52)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Patients who meet both of the following criteria 1. In patients with symptomatic heart failure, those who are complicated with ARDS or circulation failure 2. In patients who cannot be assessed for cardiac output, left ventricular end-diastolic pressure, and intravascular volume with noninvasive cardiac imaging appropriately |
I | C | B | IVa |
In patients who meet either of the following criteria with symptomatic heart failure that does not respond to standard treatment based on noninvasive data 1. In patients who cannot have fluid retention, cardiac output, total systemic vascular resistance, and pulmonary vascular resistance measured accurately 2. In patients with low systolic blood pressure not responding to initial management 3. Exacerbation of renal function 4. Dependent on intravenous inotropes 5. In patients being considered for heart transplantation or mechanical circulatory support |
IIa | C | B | IVa |
Invasive pulmonary artery pressure monitoring as routine in normotensive patients with symptomatic acute heart failure who respond well to diuretics and vasodilators |
III | B | D | II |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
The usefulness of monitoring with pulmonary artery catheters to measure pulmonary arterial pressure, intracardiac pressure, and cardiac output for evaluation of the pathology of HF has not been proven.563 In DCM, the principle is to manage the disease based on noninvasive data such as physical findings, urine output, X-ray findings, echocardiography, and blood chemistry. However, invasive hemodynamic monitoring is recommended in cases such as patients with acute respiratory distress syndrome or circulatory insufficiency due to recurrent HF.563–565 In addition, in patients whose HF symptoms do not improve even with standard treatment based on noninvasive data, and (1) fluid retention, cardiac output, total vascular resistance, and pulmonary vascular resistance are uncertain, (2) systolic blood pressure is low and does not respond to initial treatment, (3) renal function worsens, (4) parenteral vasoactive agents are required, and (5) mechanical assisted circulation or heart transplantation needs to be considered, hemodynamic management by invasive pulmonary artery pressure monitoring is recommended.563–565 Routine invasive hemodynamic monitoring is not recommended in patients with responsive normotensive acute decompensated HF.563–565
The Fick and thermodilution methods are widely used to measure cardiac output using a pulmonary artery catheter. It should be noted that the reliability of the thermodilution method is reduced in the presence of moderate or severe tricuspid regurgitation or intracardiac shunts.566,567
Mixed venous oxygen saturation, which can be measured with a pulmonary artery catheter, is an important indicator of systemic tissue perfusion and reflects conditions such as cardiac output, ventilatory capacity, hemoglobin quantity and quality, and tissue metabolism. A decrease indicates systemic circulatory insufficiency. Therefore, it is highly useful in assessing the severity of cardiac insufficiency and in treating and assessing the effects of treatment.568
4.9.2 Left Heart Catheterization
LV end-diastolic pressure (LVEDP) rises with LV dysfunction. In management, the pulmonary artery wedge pressure measured by right heart catheterization is often used as a substitute; however, LVEDP is a direct measurement and therefore more reliable.
LV angiography can evaluate not only LV wall motion, but also LV end-diastolic volume, LV end-systolic volume, LVEF, and the degree of mitral regurgitation. In patients with reduced systolic function despite no LV dilatation, hypertensive cardiomyopathy, D-HCM, and stage myocardial diseases such as cardiac amyloidosis and Fabry disease should be excluded. If regional wall movement abnormalities are observed, they must be differentiated from those of sarcoidosis and chronic myocarditis, in addition to ischemic heart disease.
The purpose of coronary angiography is to exclude ischemic conditions. In patients with low to moderate pretest probability, exclusion diagnosis by coronary CT may be used.569
4.10 Endomyocardial Biopsy and Pathology
4.10.1 Indications (See Also III.4.7)
As in other primary cardiomyopathies, there is no specific histopathological finding in DCM, and the relationship between histological degenerative findings and cardiac function or prognosis is not clear. However, it is useful for differential diagnosis when the possibility of secondary cardiomyopathies cannot be excluded (Table 53).
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
In patients showing dilated heart failure in whom secondary cardiomyopathy is suspected and it cannot be defined by other clinical examinations |
IIa | C | C1 | V |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
4.10.2 Pathology of DCM and Related Primary and Secondary Cardiomyopathies
a. Gross Pathological Findings
The definition of DCM is not coincident among proposed guidelines such as the 2006 AHA4 and 2008 ESC guidelines.5 However, the 1995 WHO/ISFC proposal,3 which emphasizes the distinction between primary DCM and secondary cardiomyopathy, is useful for the interpretation of endomyocardial biopsy.
The typical gross findings of DCM are a large, spherical outline of the heart, flexible walls, and increased weight (mean, 500–600 g). Although all 4 chambers are enlarged, the LV or biventricular chambers are enlarged more remarkably than the atria, and the mitral and/or tricuspid valve orifice diameter is increased (Figure 25A). Mural thrombus is often observed in the heart chamber, and patchy fibrosis in the myocardium and thickened endocardium can be seen.222 Thickening of reticulated trabecula with thinning of the ventricular wall develops an LVNC-like morphology.570 Besides typical cases showing marked enlargement of the heart, mildly dilated cardiomyopathy is a form that potentially worsens rapidly irrespective of the modest LV dilation.426
Dilated cardiomyopathy (autopsy case). (A) Gross pathological finding (heart weight: 525 g). (B) Histology (H&E, bar=100 μm).
Regarding differentiation from the other primary cardiomyopathies, in the case of D-HCM, the asymmetric septal thickening is gradually lost and approaches a DCM-like morphology (Figure 26A).571,572 An increase in adipose tissue in the ventricular wall is often observed nonspecifically, especially in middle-aged to elderly women, but in the advanced stage of ARVC, the epicardial surface is extensively replaced by adipose tissue and the RV cavity dilates markedly. The degeneration of the RV begins with the tricuspid annulus, RV outflow track, and apex, which is known as the triangle of dysplasia.573
Dilated-phase hypertrophic cardiomyopathy (autopsy case). (A) Gross pathological finding (heart weight: 460 g). (B) Histology (H&E, bar=100 μm).
As a secondary cardiomyopathy that should be distinguished from DCM, ischemic cardiomyopathy usually presents as circumferential fibrosis dominantly seen in the endocardial side. Advanced atherosclerosis is usually observed in the coronary arteries running on the epicardial surface (Figure 27A).574 In addition, drug-induced cardiomyopathy due to anthracycline,575 peripartum cardiomyopathy,576 and alcoholic cardiomyopathy577 also show chamber dilatation similar to DCM, and macroscopic differentiation is usually difficult (Figure 28A). Wet beriberi (beriberi heart) due to vitamin B1 deficiency may coexist with alcoholic cardiomyopathy and exhibit a DCM-like morphology. However, wet beriberi potentially shows RV-dominant enlargement.578 In many cases of acute myocarditis, especially in fulminant cases, the cardiac chambers are enlarged with thickening of the ventricular wall due to inflammation (Figure 29A). Chronic myocarditis (Figure 30A) is often difficult to distinguish from DCM without histological findings.579,580 In addition, cardiomyopathy associated with collagen vascular diseases such as systemic lupus erythematosus, scleroderma, and rheumatoid arthritis can possibly show a DCM-like morphology.581 Even in cardiac sarcoidosis (Figure 31A), a differential diagnosis from DCM is often difficult, but granulomatous lesions and scars may be seen as yellowish-white or grayish-white plaques in the myocardium, typically with marked thinning of the anterior septum.454 Hemochromatosis also shows a DCM-like morphology, but the myocardium becomes brownish because of iron deposition (Figure 32A).582
Ischemic cardiomyopathy (autopsy case). (A) Gross pathological finding (heart weight: 525 g). (B) Histology (H&E, bar=250 μm).
Alcoholic cardiomyopathy (autopsy case). (A) Gross pathological finding (heart weight: 580 g). (B) Histology (H&E, bar=100 μm). *Mural thrombus.
Acute (fulminant) myocarditis (autopsy case). (A) Gross pathological finding (heart weight: 720 g). (B) Histology (H&E, bar=100 μm).
Chronic myocarditis (autopsy case). (A) Gross pathological finding (heart weight: 460 g). (B) Histology (H&E, bar=100 μm).
Cardiac sarcoidosis (autopsy case). (A) Gross pathological finding (heart weight: 330 g). (B) Histology (H&E, bar=100 μm).
Hemochromatosis (autopsy case). (A) Gross pathological finding (heart weight: 440 g). (B) Histology (H&E, bar=50 μm).
Many cases of cardiac amyloidosis or Fabry disease present as concentric hypertrophy; however, these disorders potentially show a DCM-like morphology in the advanced stage.583 Diabetic cardiomyopathy584 and uremic cardiomyopathy585 may present a DCM-like morphology, even though they have LVH at an early stage because of the influence of coexisting hypertension. Cardiomyopathy associated with neuromuscular diseases such as Duchenne muscular dystrophy or Becker-type muscular dystrophy also shows a DCM-like morphology, with an increase in heart weight and expansion of the heart chamber, which is characterized by severe fibrosis and scarring on the posterior and lateral wall of the LV.586
b. Histopathological Findings
The histological findings for DCM are nonspecific, but various degrees of myocardial degeneration are observed in each case. Compensative hypertrophy of cardiomyocytes appears with nuclear degeneration (e.g., nuclear swelling, irregularity, chromatin concentration), myofibrillar loss, and vacuolar degeneration in the cytoplasm (Figure 25B).5,222 A highly degenerative myocardium with bizarre nuclei is exhibited commonly in end-stage cardiomyopathies.587 If severe vacuolation is noted in the cardiomyocytes, differentiation of storage diseases such as Fabry disease583 and mitochondrial cardiomyopathy230 is required. Screening by electron microscopy, and enzymatic or genetic analyses is recommended for suspected cases. Lipofuscin usually increases with age, but it should be differentiated from iron deposition in hemochromatosis (Figure 32B). Perivascular and interstitial fibrosis (intercellular and/or interfascicular fibrosis) are recognized as reactive fibrosis, and replacement fibrosis occurs in the area of cardiomyocyte loss. Fibrosis is often associated with thickening of the endocardium and/or fat infiltration.222 A well-defined ischemic scar is caused by not only ischemic cardiomyopathy, but also microvascular disease associated with cardiomyopathies.588 Focal and/or replacement fibrosis may also occur in post-myocarditis and cardiac sarcoidosis (Figure 31B). In patients with suspected sarcoidosis, dense fibrosis may be a possible scar of granulomatous inflammation.454 A large amount of amyloid deposition can be easily detected as amorphous and eosinophilic material around cardiomyocytes and vessels, even in conventional H&E sections. However, in cases of small amounts of amyloid deposition, it may be difficult to detect, even with special staining such as Congo red or direct fast scarlet. Transmission electron microscopy is useful in such cases.583 It is necessary to pay attention to false-positive staining of elastic fibers by amyloid staining, which is occasionally found in the thickened endocardium and vascular wall.
In DCM, varying degrees of lymphocytic infiltration may be observed in the interstitial space, but if active/continuous inflammation is recognized, chronic myocarditis is raised as a differential diagnosis (Figure 30B).579,580 Recently, iDCM has been proposed by ESC, which is defined by the number of inflammatory cells in the myocardium: total number ≥4 cells/mm2 (the sum of CD3-positive T-cells and CD68-positive macrophages).58,589 However, chronic myocarditis as defined in the Japanese guidelines580 does not fully correspond with iDCM as proposed in the ESC guidelines;58,589 thus, further investigations are needed to clarify the clinical significance of inflammatory cells in the myocardium. It has been pointed out that immunostaining with Tenascin-C could possibly indicate preexisting interstitial inflammation.590 Peripartum cardiomyopathy may be associated with myocarditis.576,591 Focal infiltration of inflammatory cells can also be seen in takotsubo and catecholamine-induced cardiomyopathies.592 Because ischemic scars are often accompanied by mononuclear cell infiltration, it is important to refer to the clinicopathological correlations. The appearance of multinucleate giant cells is an important finding for identifying granulomatous inflammation, especially sarcoidosis. Fat infiltration of the myocardium is often associated with obesity, diabetes, and alcoholic cardiomyopathy,222,577 but fibro-fatty change is a characteristic finding in ARVC. Although myofibrillar disarrangement is nonspecific for various conditions, marked myofibrillar disarrangement with disarray may indicate D-HCM, which is usually associated with severe fibrosis (Figure 26B).571,572 The major histopathological findings for differentiating DCM from other related forms of cardiomyopathies are listed in Table 54.
Dilated cardiomyopathy |
Dilated phase of hypertrophic cardiomyopathy |
Ischemic cardiomyopathy |
Myocarditis | Cardiac Sarcoidosis |
ARVC/D | Other secondary cardiomyopathies |
|
---|---|---|---|---|---|---|---|
Macroscopic findings |
Eccentric hypertrophy with dilated cardiac chambers. Frequent mural thrombus. Circumferential enlargement of atrioventricular valve. Development of obvious trabeculation may be seen (Figure 25A). |
Dilated cardiac chambers similar to dilated cardiomyopathy are often observed. Asymmetric septal hypertrophy (ASH) is gradually disappeared in the advanced stage (Figure 26A). |
Dilated cardiac chambers similar to dilated cardiomyopathy are often observed. Severe coronary atherosclerosis and fibrotic scar are occured in the territory of responsible coronary artery or circumferentually. Ventricular aneurysm may be associated (Figure 27A). |
In the acute phase, ventricular swelling is associated with congestion, edema and inflammatory change. Occasionally mural thrombus is observed (Figure 29A). On the other hand, it is ususally diffucult to differentiate chronic myocarditis from dilated cardiomyopathy without histology (Figure 30A). |
Dilated cardiac chambers similar to dilated cardiomyopathy are often observed. Thinning of the anterior ventricular septum is characteristic (Figure 31A), although lesions can potentially exist anywhere in the heart. |
Dilated right ventricle and replacement by adipose tissue are charactaristics. Right ventricular outflow track, infundibulum and apex show initially more obvious changes. In advanced stage, fibro-fatty degeneration may develop into the left ventricle and heart represents DCM-like morphology. |
Alcoholic (Figure 28A), drug- induced, peripartum cardiomyopathies may represent dilated cardiac chambers similar to dilated cardiomyopathy. Hypertensive heart, diabetes and/or uremic cardiomyopathies, amyloidosis, Fabry disease, etc. can be shifted from hypertrophic heart to DCM-like morphology. In hemochromatosis (Figure 32A), myocardium is shown reddish brown. |
Microscopic findings |
In a typical (advanced) DCM case, compensative hypertrophy of the cardiomyocytes are usually seen with severe myofiber loss and interstitial and/or replacemental fibrosis (Figure 25B). Fibrosis may occur circumferentially in the left ventricle and spetum. |
Similar histology with DCM is usually seen but disarray of hypertrophic cardiomyocytes may be observed. Many cases show the histological features of the end-stage cardiomyopathy having prominant degeneration such as severe fibrosis (Figure 26B). |
Ischemic scar formation is usually observed, predominantly in subendcardium. Scar lesion usually has clear border with preexisting viable myocardium. Microscopically, several myocardial layers just under the endocardium are possibly preserved without infraction (Figure 27B). |
In acute myocarditis, myocytolysis (necrosis) adjecent to inflammatory cells (usually lymphocytes or eosinophils, dominant) are recognized as typical evidence of active inflammation (Figure 29B). In chronic myocarditis, active myocardial inflammation is found in the myocardium showing DCM-like histology (Figure 30B). Focal fibrosis may be a clue for post-myocarditic change. |
Noncaseous epithelioid granuloma and multinucleated giant cells are crucial for suggesting cardiac sarcoidosis (Figure 31B). If granulomatous inflammation is not revealed, additional observation with deep cut section may be helpful. Scar-like fibrosis and lymphocyte infiltration may be as reference. CD4+ T cells are dominant in the center of the granuloma and CD8+ T cells are peripherally, of which findings are useful for defferentiating from giant cell myocarditis. |
In addition to characteristic fibro-fatty replacement of the myocardium, various degree of lymphocyte infiltration or disarrangement of hypertrophic cardiomyocytes may be observed. Histopathological findings are often diverse, which reflects heterogenous genesis. |
Perivascular fibrosis is seen in hypertensive heart and also in diabetic and uremic cardiomyopathies. Electron microscopy is useful for screening of storage diseases (e.g., Fabry disease) and mitochondrial cardiomyopathy, if vacuolation is noted in light microscopy. Iron stain is helpful for definition of hemochromatosis (Figure 32B). Congo red stain for amyloidosis should be comfirmed with yellow- green birefringence. Alcoholic and drug-induced cardiomyopathies do not show specific findings (Figure 28B). Some cases of peripartum cardiomypathy may be associated with myocarditis. |
Supplementary notes |
Since pathological findings are nonspecific, definitive diagnosis should be made comprehensively by careful exclusion including clinical information. Prediction of the prognosis from pathological changes are not established, since discrepancies between cardiac function and morphological abnormalities. |
In the case without clinical history of hypertrophic cardiomyopathy, it is diffucult to differenciate from dilated cardiomyopathy. Histological findings may be limited in supportive information. |
To confirm the diagnosis, clinical findings related ischemia and presence or absence of coronary lesions are emphasized. |
Mild lymphocytic infiltration in myocardial tissue is generally not specific for myocarditis. Peripartum cardiomyopathy, Takotsubo cardiomyopathy, catecholamine cardiomyopathy, etc. may represent infiltration of mononuclear cells. Although a part of inflammatory dilated cardimyopathy (ESC guideline) is overlapped with chronic myocarditis (JCS guideline), clinical implication of chronic inflammation in the myocardium is remained to be elucidated. |
In cases showing characteristic clinical findings, histologically recognized glanulomatous inflammation is highly suggestive of cardiac sarcoidosis. When granulomatous inflammation is found unexpectedly in the heart, it is necessary to differenciate the other causes of granulomatous inflammation such as foreign body reaction. |
Fat infiltration in the myocardial tissue can be seen as a nonspecific finding, especially in middle-aged to elderly women, diabetetic or obese patients, etc. Although ARVC/D is rare condition, it should be considered when characteristic patterns of arrhythmias and fibro-fatty replacement mainly in right ventricle are clinically suggested. |
When ultrastructual abnormalities are observed under electron microscopy and strage diseases such as Fabry disease or mitochondiral disease are suspected, enzymatic or genetic analysis is needed for the definition. Discrimination of amyloid precursor protein sometimes requires amino acids or genetic analysis in addition to immunostaining. To gather clinical information such as history of alcohol intake or anticancer drug administration, is important to improve diagnostic accuracy. |
4.11 Genetic Testing (Including Genetic Counseling)
Approximately 20–30% of DCM cases have a familial etiology. Mutations in the genes for lamin (LMNA), titin (TTN), β-myosin heavy chain (MYH7), cardiac muscle sodium channel (SCN5A), transcription factor Eya4 (EYA4), and RNA-binding motif protein 20 (RBM20) have been identified by linkage analysis using pedigrees. However, in DCM, large families sufficient for linkage analysis are few, and many other mutations have been identified as pathogenic variants (i.e., genetic abnormalities likely to cause DCM) by candidate gene approaches. Damage to any of the pathways involved in cardiac function may lead to the pathology of DCM (e.g., cardiomyocyte damage, cell death, fibrous replacement), and pathogenic variants have been reported in approximately 40 genes (Table 55).593 Each variant ultimately impairs cardiac function through decreased contractility, calcium sensitivity, power transmission, and calcium reuptake into sarcoplasmic reticulum. It is likely that DCM will not necessarily develop in relatives who have the same genetic abnormality as the patient (i.e., low penetrance), and in some families, each relative with the same variant has a different disease state. Therefore, the clinical use of genetic testing for the definitive diagnosis of DCM requires more knowledge.
Gene | Locus | Pattern of inheritance |
---|---|---|
Sarcomere | ||
cardiac actin (ACTC) | 15q14 | AD |
cardiac β-myosin heavy chain (MYH7) | 14q11 | AD |
cardiac troponin T (TNNT2) | 1q32 | AD |
cardiac troponin I (TNNI3) | 19q13 | AR |
cardiac troponin C (TNNC1) | 3p21 | AD |
α-tropomyosin (TPM1) | 15q22 | AD |
titin (TTN) | 2q31 | AD |
cardiac myosin binding protein C (MYBPC3) | 11p11 | AD |
cardiac α-myosin heavy chain (MYH6) | 14q12 | AD |
myosin light chain kinase 3 (MYLK3) | 16q11 | AD |
Z-band and related molecules | ||
αB-crystallin (CRYAB) | 11q22 | AD |
four and a half LIM protein 2 (FHL2) | 2q12 | AD |
muscle LIM protein (CSRP3) | 11p15 | AD |
T-cap (telethonin) (TCAP) | 17q12 | AD |
cypher/ZASP (LDB3) | 10q22-q23 | AD |
α-actinin-2 (ACTN2) | 1q42-q43 | AD |
BCL2-associated athanogene 3 (BAG3) | 10q25-q26 | AD |
nexilin (NEXN) | 1p31 | AD |
myopalladin (MYPN) | 10q21 | AD |
CARP (ANKRD1) | 10q23 | AD |
Cytoskeleton | ||
δ-sarcoglycan (SGCD) | 5q33 | AD |
β-sarcoglycan (SGCB) | 4q12 | AD |
dystrophin (DMD) | Xp21 | X-linked |
desmin (DES) | 2q35 | AD |
fukutin (FKTN) | 9q31 | AD |
metavinculin (VCL) | 10q22-q23 | AD |
laminin-α4 (LAMA4) | 6q21 | AD |
integrin-linked kinase (ILK) | 11p15 | AD |
lamin A/C (LMNA) | 1q21 | AD |
emerin (EMD) | Xq28 | X-linked |
Ion channel/calcium handling | ||
phospholamban (PLN) | 6q22 | AD |
KATP channel (ABCC9) | 12p12 | AD |
cardiac sodium channel (SCN5A) | 3p21 | AD |
Transcription factor | ||
Eya4 (EYA4) | 6q23 | AD |
Other | ||
presenilin 1 (PSEN1) | 14q24 | AD |
presenilin 2 (PSEN2) | 1q31 | AD |
RNA binding motif protein 20 (RBM20) | 10q25 | AD |
Mitochondria | ||
mitochondrial DNA | Mitochondria | Maternal |
AD, autosomal dominant; AR, autosomal recessive. (Adapted from Morita H, 2014.593)
TTN is a giant elastic protein that connects the Z-band to the M-band in sarcomeres, but the use of next generation sequencing (NGS) has made it possible to perform global comprehensive genetic analysis, and the importance of TTN in the pathophysiology of DCM has attracted increasing attention. Truncating variants that cause the production of short, truncated TTN proteins are found in 25% of familial and 18% of sporadic DCM cases.594 A truncating variant may be considered a cause of DCM because it affects protein structure and function, but its penetrance is low and may not always be linked to the development of DCM.595 In addition, considering that a truncating variant is seen in 3% of healthy individuals,594 even when a truncating variant is detected in a DCM patient, it cannot necessarily be regarded as a variant causing DCM. The prognosis of DCM patients with the truncating variant of TTN is relatively good, showing a good response to initial treatment followed by reverse remodeling.596
4.11.1 Detection of Truncating Variants of TTN
Detection of the truncating variant of TTN is useful for diagnosing DCM and predicting the prognosis to a certain extent if the genetic variant corresponds to a previously reported mutation or is found to be a causative mutation in pedigree analysis.
4.11.2 Lamin A/C Gene (LMNA) Mutation
Lamin is a component of the inner nuclear membrane, and DCM caused by a mutation of LMNA is typically accompanied by atrioventricular block. Therefore, a search for LMNA is recommended in patients with DCM associated with conduction disturbance. Nonsustained VT, LVEF <45%, male sex, and an LMNA non-missense mutation have been shown to be predictive of lethal arrhythmia.597 Based on this evidence, identification of LMNA mutation is considered to be effective as a basis for judging early ICD implantation. A genetic study in Japanese DCM patients revealed that the patients with a LMNA mutation had a poor prognosis.596 Taken together, the detection of a variant of LMNA is useful for the diagnosis of DCM as well as prediction of the prognosis if it matches a previously reported mutation or if it is found to be the causative mutation in pedigree analysis (Table 56).
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Detection of truncating variant in titin gene | IIa | C | B | V |
Detection of lamin A/C gene variant | I | C | A | V |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
The use of NGS has enabled us to identify many rare variants in patients with DCM. Practically, however, it is difficult to determine whether these rare variants are genetic mutations that really cause DCM. In light of the current situation, if the rare variant was previously reported as a causative mutation in a database or similar repository (if it matches a so-called “reported mutation”), or if it is found to be a causal mutation in any pedigree analysis, it is considered a diagnostically significant variant.
4.11.3 Genetic Counseling (Table 57)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Genetic counseling for all patients with DCM regardless of family screening | I | B | A | IVa |
Genetic counseling when receiving a genetic testing | I | B | A | IVa |
Genetic counseling by professionals trained in genetics | IIa | C | C1 | IVa |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
Genetic counseling to explain the significance and potential risks of genetic diagnosis is recommended for patients with DCM (with or without family screening) undergoing genetic testing (Class I). Genetic counseling should be performed by professionals trained in genetics (Class IIa).
5. Evaluation and Treatment by Disease State5.1 Heart Failure (Including VADs and Heart Transplantation)
Refer to the “Guidelines for diagnosis and treatment of acute and chronic heart failure” (JCS 2017/JHFS 2017) for details on the conditions and treatments (Tables 58–66).11 For the acute treatment of the most severe cases with mechanical assistance, see Table 59.
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Diuretics | ||||
Loop diuretics | ||||
Intravenous and oral administration to alleviate fluid retention in patients with acute heart failure | I | C | B | II |
Continuous intravenous infusion to patients not responding to bolus injections | IIa | B | B | IVb |
Vasopressin V2 receptor antagonists (tolvaptan) | ||||
Use for the treatment of fluid retention in patients not responding well to other diuretics including loop diuretics (Excluding patients with hypernatremia) |
IIa | A | B | II |
Use for the treatment of fluid retention in patients with hyponatremia | IIa | C | C1 | II |
MRAs | ||||
Use in combination with loop diuretics in patients in whom loop diuretics become less effective | IIb | C | C1 | III |
Use in patients with hypokalemia and normal renal function | IIa | B | B | II |
Use in patients with renal dysfunction and hyperkalemia | III | C | D | VI |
Thiazide diuretics | ||||
Use in combination with furosemide in patients in whom furosemide becomes less effective | IIb | C | C1 | III |
Vasodilators | ||||
Nitrates | ||||
Use for the treatment of pulmonary congestion in patients with acute heart failure or acute worsening chronic heart failure |
I | B | A | II |
Nicorandil | ||||
Use for the treatment of pulmonary congestion in patients with acute heart failure or acute worsening chronic heart failure |
IIb | C | C1 | II |
Carperitide | ||||
Use for the treatment of pulmonary congestion in patients with decompensated heart failure | IIa | B | B | II |
Use in combination with inotropes in patients with intractable heart failure | IIa | B | C1 | II |
Use in patients with serious hypotension, cardiogenic shock, acute right ventricular infarction, or dehydration |
III | C | C2 | VI |
Calcium channel blockers | ||||
Sublingual administration of nifedipine to patients with hypertensive emergency | III | C | D | IVb |
Inotropes/vasopressors | ||||
Dobutamine | ||||
Use in patients with pump dysfunction and pulmonary congestion | IIa | C | B | II |
Dopamine | ||||
Use in expectation of increase in urine volume and renal protective effect | IIb | A | C2 | II |
Norepinephrine | ||||
Use in combination with catecholamines in patients with pulmonary congestion and hypotension | IIa | B | B | III |
PDE III inhibitors | ||||
Use in patients with non-ischemic pump dysfunction and pulmonary congestion | IIa | A | B | II |
Use in patients with ischemic pump dysfunction and pulmonary congestion | IIb | A | B | II |
Use in combination with dobutamine in patients with a severe reduction in cardiac output | IIb | C | C1 | IVb |
Rate controllers | ||||
Digitalis | ||||
Use for rate control of atrial fibrillation in patients with tachycardia-induced heart failure | I | A | B | II |
Landiolol | ||||
Use for rate control of atrial fibrillation in patients with tachycardia-induced heart failure | I | C | B | II |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence; MRA, mineralocorticoid receptor antagonist; PDE, phosphodiesterase. (Adapted from JCS Guideline 2018.11)
Profile | INTERMACS | Status | Options of device therapy |
---|---|---|---|
J-MACS | |||
1 | Critical cardiogenic shock “Crash and burn” |
Patients with compromised hemodynamics and peripheral hypoperfusion despite rapid escalation of intravenous inotropes and/or introduction of mechanical circulatory support |
IABP, peripheral VA-ECMO, percutaneous VAD, centrifugal pumps for extracorporeal circulation, and paracorporeal VADs |
2 | Progressive decline despite inotropic support “Sliding on inotropes” |
Patients with declining renal function, nutritional status, and signs of congestion despite intravenous inotropes and required incremental doses of them |
IABP, peripheral VA-ECMO, percutaneous VAD, centrifugal pumps for extracorporeal circulation, paracorporeal VADs, implantable LVADs |
3 | Stable but inotrope- dependent “Dependent stability” |
Patients with stable hemodynamics on intravenous inotropes at relatively low doses, but physicians are not able to discontinue the intravenous treatment because of the risk of hypotension, worsening symptoms of heart failure, or worsening renal function |
Implantable LVADs |
4 | Resting symptoms “Frequent flyer” |
Patients who can be weaned from intravenous inotropic support temporarily and be discharged from hospital, but may soon repeat hospitalizations for worsening heart failure |
Consider implantable LVADs (especially patients with modifier A*) |
5 | Exertion intolerant “House-bound” |
Patients who can do daily routines in the house, but have significant limitations in activities of daily livings, and hardly go out |
Consider implantable LVADs for patients with modifier A* |
6 | Exertion limited “Walking wounded” |
Patients who can go out, but are difficult in doing anything other than light activities, and have symptoms during walk less than 100-meter |
Consider implantable LVADs for patients with modifier A* |
7 | Advanced NYHA III “Placeholder” |
Patients can walk more than 100 meters without fatigue, and have had no hospitalizations in the recent 6 months |
Consider implantable LVADs for patients with modifier A* |
*Recurrent appropriate ICD shocks due to life-threatening ventricular arrhythmias. IABP, intra-aortic balloon pump; LVAD, left ventricular assist device; PCPS, percutaneous cardiopulmonary support; VAD, ventricular assist device; VA-ECMO, veno-arterial extracorporeal membrane oxygenation. (Adapted from JCS Guideline 2018.11)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
ACE inhibitors | ||||
Use in all patients (including asymptomatic patients) unless contraindicated | I | A | A | I |
ARBs | ||||
Use in patients intolerable ACE inhibitors | I | A | A | I |
Concomitant use with ACE inhibitors | IIb | B | C2 | II |
β-blockers | ||||
Use in symptomatic patients to improve prognosis | I | A | A | I |
Use in asymptomatic patients with left ventricular systolic dysfunction | IIa | B | A | II |
Use for rate control in patients with atrial fibrillation with a rapid ventricular response |
IIa | B | B | II |
MRAs | ||||
Use in patients with NYHA Class II-IV, LVEF <35% who are receiving loop diuretics and ACE inhibitors |
I | A | A | I |
Loop diuretics, thiazide diuretics | ||||
Use in patients with symptoms of congestion | I | C | C1 | III |
Vasopressin V2 receptor antagonists | ||||
Start treatment during hospitalization to relieve symptoms of fluid retention due to heart failure in patients who do not respond well to other types of diuretics including loop diuretics |
IIa | B | B | II |
Other diuretics such as carbonate dehydratase inhibitors and osmotic diuretics | ||||
Diuretics other than loop diuretics, thiazide diuretics, and MRAs | IIb | C | C2 | III |
Digitalis | ||||
Patients in sinus rhythm (maintain digoxin concentration in blood at ≤0.8 ng/mL) |
IIa | B | C1 | II |
Use for rate control in patients with atrial fibrillation with a rapid ventricular response |
IIa | B | B | II |
Oral inotropic drugs | ||||
Use short-term to improve QOL and discontinue intravenous inotropic drugs | IIa | B | C1 | II |
Use when initiating β-blockers | IIb | B | C1 | II |
Long-term use in asymptomatic patients | III | C | D | III |
Amiodarone | ||||
Use in patients with a history of serious ventricular arrhythmia leading to cardiac arrest |
IIa | B | C1 | II |
Concomitant use of isosorbide dinitrate and hydralazine | ||||
Use as an alternative to ACE inhibitors or ARBs | IIb | B | C2 | II |
Others | ||||
Treatment with calcium channel blockers in patients without angina pectoris or hypertension |
III | B | C2 | II |
Long-term oral treatment with Vaughan Williams Class I antiarrhythmic agents |
III | B | D | III |
Use of α-blockers | III | B | D | II |
ARB, angiotensin II receptor blocker; ACE, angiotensin converting enzyme; COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; QOL, quality of life; SGLT, sodium glucose cotransporter. (Adapted from JCS Guideline 2018.11)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
NYHA Class III/IV | ||||
Patients who meet all the following criteria: (1) Receiving optimal medical therapy (2) LVEF ≤35% (3) Left bundle branch block (LBBB) with QRS interval ≥120 msec (4) Sinus rhythm |
I | A | A | I |
Patients who meet all the following criteria: (1) Receiving optimal medical therapy (2) LVEF ≤35% (3) Non-LBBB with QRS interval ≥150 msec (4) Sinus rhythm |
IIa | B | B | II |
Patients who meet all the following criteria: (1) Receiving optimal medical therapy (2) LVEF ≤35% (3) Non-LBBB with QRS interval 120 to 149 msec (4) Sinus rhythm |
IIb | B | C1 | III |
Patients who meet all the following criteria: (1) Receiving optimal medical therapy (2) LVEF <50% (3) Indicated for pacing or ICD (4) Expected to require ventricular pacing frequently |
IIa | B | B | II |
Patients who meet all the following criteria: (1) Receiving optimal medical therapy (2) LVEF ≤35% (3) LBBB with QRS ≥120 msec, or non-LBBB with QRS interval ≥150 msec (4) Have atrial fibrillation and can undergo biventricular pacing at a high pacing percentage |
IIa | B | B | II |
NYHA Class II | ||||
Patients who meet all the following criteria: (1) Receiving optimal medical therapy (2) LVEF ≤30% (3) LBBB with QRS interval ≥150 msec (4) Sinus rhythm |
I | B | B | II |
Patients who meet all the following criteria: (1) Receiving optimal medical therapy (2) LVEF ≤30% (3) Non-LBBB with QRS interval ≥150 msec (4) Sinus rhythm |
IIa | B | B | II |
Patients who meet all the following criteria: (1) Receiving optimal medical therapy (2) LVEF ≤30% (3) QRS interval 120 to 149 msec (4) Sinus rhythm |
IIb | B | C1 | III |
Patients who meet all the following criteria: (1) Receiving optimal medical therapy (2) LVEF <50% (3) Indicated for pacing or ICD (4) Expected to require ventricular pacing frequently |
IIa | B | B | II |
NYHA Class I | ||||
Patients who meet all the following criteria: (1) Receiving optimal medical therapy (2) LVEF <50% (3) Indicated for pacing or ICD (4) Expected to require ventricular pacing frequently |
IIb | B | B | II |
NYHA Class I to IV | ||||
Patients who meet either of the following criteria: (1) Have limited physical activity due to chronic diseases (2) Can neither express consent nor cooperate with treatment due to mental disorder or other reasons. (3) Suspected with a life expectancy of 1 year or less |
III | C | C2 | VI |
Different criteria are set for NYHA Class III/IV and II patients in sinus rhythm:
1) LVEF cutoff value is ≤35% for NYHA Class III/IV patients and, ≤30% for NYHA Class II patients.
2) In patients with a QRS interval of 120 to 149 msec, the use of CRT is a Class I and IIb recommendation for NYHA Class III/IV patients with LBBB and non-LBBB, respectively, and is a Class IIb recommendation for NYHA Class II patients regardless of whether LBBB or non-LBBB is present.
COR, class of recommendation; CRT, cardiac resynchronization therapy; GOR, grade of recommendation; ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block; LOE, level of evidence; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association. (Adapted from JCS Guideline 2018.11)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
MitraClip for patients who have symptomatic severe function mitral regurgitation regardless of guideline-directed medical therapy, are considered to carry high risk in open heart surgery but have mitral valve anatomy suitable for edge-to-edge repair by discussion within a multidisciplinary team |
IIa | B | B | II |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
Selection criteria | Patient status | Patient has advanced heart failure with progressive symptoms (generally NYHA class IV) despite standard therapy recommended in the relevant guidelines (stage D), who is listed or being listed for heart transplantation |
Age | <65 years | |
Body surface area | Refer to the criterion specified for each device | |
Severity | Patient depending on intravenous inotropes (INTERMACS profile 2 or 3), IABP or paracorporeal LVAD, or with modifier A (especially for patients with INTERMACS profile 4) |
|
Social indications | Patient and his/her caregivers understand the characteristics of VAD therapy in Japan as a long-term home-based treatment, and the patient is highly expected to return to society |
|
Exclusion criteria | Systemic diseases | Patient has malignancy, collagen disease or other refractory systemic diseases that have poor prognosis |
Respiratory diseases | Severe respiratory failure, irreversible pulmonary hypertension | |
End-organ dysfunction | Irreversible hepatic or renal dysfunction, insulin-dependent diabetes mellitus |
|
Cardiovascular disorders | Difficult-to-treat aortic aneurysm, untreatable moderate or severe aortic valve insufficiency, mechanical aortic valve that cannot be replaced by a bioprosthetic valve, severe peripheral vascular disease |
|
Pregnancy | Women being pregnant or planning to become pregnant | |
Others | Severe obesity |
IABP, intra-aortic balloon pump; LVAD, left ventricular assist device; NYHA, New York Heart Association. (Adapted from JCS Guideline 2018.11)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Treatment with implantable LVADs in patients with stage D HFrEF who are eligible for heart transplantation in order to reduce the risk of death and hospitalizations for heart failure and improve QOL |
IIa | C | B | IVa |
COR, class of recommendation; GOR, grade of recommendation; HFrEF, heart failure with reduced ejection fraction; LVAD, left ventricular assist device; LOE, level of evidence; QOL, quality of life. (Adapted from JCS Guideline 2018.11)
1. Indications |
Heart transplantation is indicated for patients with the following severe heart diseases in whom conventional treatment is not expected to save or prolong life: 1) Dilated cardiomyopathy, and dilated phase hypertrophic cardiomyopathy 2) Ischemic myocardial disease 3) Others (Conditions approved by the Heart Transplantation Indication Review Committee of the Japanese Circulation Society and the Japanese Society of Pediatric Cardiology and Cardiac Surgery) |
2. Eligibility Criteria |
1) Patients with an intractable end-stage heart disease that meet at least one of the following conditions: a) Heart failure requiring long-term or repeated hospitalization b) Patients with heart failure that remains in NYHA Class III or IV despite conventional treatment including β-blockers and ACE inhibitors c) Patients with life-threatening severe arrythmias not responding to any currently available treatments 2) It is desirable that patients be <65 years of age 3) Patients and their family members should fully understand heart transplantation and can cooperate to the treatment |
3. Exclusion criteria |
A) Absolute exclusion criteria 1) Irreversible renal or hepatic dysfunction 2) Active infection (including cytomegalovirus infection) 3) Pulmonary hypertension (with pulmonary vascular resistance of ≥6 Wood units despite treatment with vasodilators) 4) Drug and substance abuse (including alcoholic myocardial disease) 5) Malignant tumor 6) Human immunodeficiency virus (HIV) antibody positive B) Relative exclusion criteria 1) Renal or hepatic dysfunction 2) Active peptic ulcer 3) Insulin-dependent diabetes mellitus 4) Mental disorders/neurosis (may be listed as exclusion criterion if no improvement is seen despite efforts to eliminate anxiety about the patient’s own disease or condition) 5) History of pulmonary infarction, pulmonary vascular obstructive disease 6) Collagen disorder or other systemic diseases |
4. Determination of eligibility for heart transplantation |
• For the time being, the institutional review committee and the Heart Transplantation Indication Review Subcommittee of the Japanese Circulation Society will review patients in two stages to determine who are indicated for heart transplantation. After the selection of patients indicated for heart transplantation, the patients and family members provide informed consent and are included in the waiting list. Transplantation is conducted for patients on the list. • The indications and the eligibility criteria listed above will be revised according to the advancement of medical/surgical treatment. • Other organ disorders should be considered carefully to determine medical urgency. |
ACE, angiotensin converting enzyme; IABP, intra-aortic balloon pump; LVAD, left ventricular assist device; NYHA, New York Heart Association. (Adapted from JCS Guideline 2018.11)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Heart transplantation for patients with severe HFrEF resistant to appropriate drug therapies and device treatments |
IIa | C | B | IVa |
COR, class of recommendation; GOR, grade of recommendation; HFrEF, heart failure with reduced ejection fraction; LOE, level of evidence. (Adapted from JCS Guideline 2018.11)
5.1.1 Standard Treatment for Heart Failure
a. Acute Heart Failure
Acute HF associated with DCM can be either initial or acute onset during treatment. There are 2 types of acute exacerbations in the chronic phase that occur during treatment. Most cases are left HF, usually in the form of acute cardiogenic pulmonary edema, systemic fluid retention, or low perfusion due to low cardiac output. Initial treatment is performed based on clinical scenarios, which are categorized from CS1 to CS3 according to systolic blood pressure at the time of visit. To provide better treatment, the presence or absence of congestion (wet or dry) and low perfusion (cold or warm) should be evaluated. The disease state is clarified by referring to the Nohria–Stevenson classification, which has 4 categories (Figure 33).11
Basic treatment strategies from initial to acute phase management of acute heart failure. ACS, acute coronary syndrome; BP, blood pressure; SBP, systolic blood pressure. (Adapted from JCS Guideline 201811)
b. Chronic Heart Failure
DCM usually involves LV systolic dysfunction (LVEF <40%) and HFrEF. For details on the treatment of HFrEF in stage C, please refer to the guidelines (Tables 60,61).11 Recently, a randomized controlled trial reported that it was undesirable to discontinue drug treatment in patients with DCM who showed improvements in LVEF to ≥50% and achieved reverse remodeling (HF with recovered EF) because about half of such patients developed significant remodeling deterioration within 6 months.598
Stage D is cases in which the standard treatment as described above does not improve the symptoms of NYHA Class III or higher. For such patients, heart transplantation and implantable VADs are considered to improve the prognosis. For more details, please see the guidelines (Tables 59,63–66).11
5.1.2 Surgical Ventricular Restoration (SVR), Mitral Valve Surgery, and Myocardial Sheets
a. SVR
Originally, SVR was started as an operation for LV aneurysm. In a randomized trial, no significant difference was seen between a coronary artery bypass grafting alone group and an SVR add-on group in ischemic cardiomyopathy.599 The effectiveness of SVR including Batista surgery for DCM is uncertain, and is currently not recommended in the European and US guidelines for the treatment of HF.565,600
b. Mitral Valvuloplasty/Replacement
During LV remodeling, cardiac enlargement causes tethering of the leaflets, often leading to functional mitral regurgitation. Therefore, valvuloplasty or replacement may be performed on the mitral valve either simultaneously with or independently of SVR.
Reports on the effect of sole mitral valve surgery on DCM are limited. The 2017 US guidelines state that valve surgery is Class IIb in severe functional mitral regurgitation, although the data for ischemic cardiomyopathy are controversial. In a randomized trial, mitral valvuloplasty (annular plasty) and valve replacement were compared, and the results showed no significant difference in survival. However, there are many recurrent cases involving valvuloplasty. Tendon-preserving valve replacement is probably better than annuloplasty.601,602 Several techniques, such as adding an approach to the papillary muscles, have been attempted.603
Percutaneous mitral valve repair using the MitraClip system began in Europe in 2003 and in Japan in April 2018. The Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) study showed that a combination of the MitraClip system and pharmacotherapy reduced the number of HF hospitalizations and deaths over a 2-year period compared with pharmacotherapy alone.604 Thus, treatment options using the MitraClip system might be expanded in advanced HF patients with functional mitral regurgitation (Table 62).
c. Myocardial Sheets
Myocardial sheets are a type of regenerative medicine for advanced HF. In this treatment, sheets (usually 5) consisting of 6×107 myoblasts are transplanted to the epicardium by left thoracotomy. The transplanted myoblasts then become ischemic and the HIF-1 gene is expressed, which secretes cytokines such as hepatocyte growth factor, vascular endothelial growth factor, and basic fibroblast growth factor, thereby leading to angiogenesis and stem cell induction. In addition, improvement of cardiac function is expected because suppression of fibrosis is promoted.605,606 Currently, myocardial sheets are approved for ischemic cardiomyopathy in Japan, but not for DCM.
5.2 Supraventricular Arrhythmia (Table 67)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Heart failure with atrial fibrillation | ||||
Rate control | I | C | C1 | VI |
Rhythm control if hemodynamics cannot be maintained | I | C | C1 | VI |
Rate control for atrial fibrillation | ||||
β-blockers | I | A | A | I |
Digitalis (combination with β-blockers or β-blockers is contraindicated) | IIa | B | A | I |
Amiodarone (in case of insufficient with β-blockers and digitalis) | IIb | C | C1 | VI |
Ablation of the AV node for atrial tachycardia and atrial fibrillation (if pacemaker therapy is allowed) |
IIb | C | B | II |
Nondihydropyridine calcium antagonists (verapamil, diltiazem) | III | C | D | II |
Rhythm control for atrial fibrillation | ||||
Amiodarone (for a short period of time) | IIb | B | B | II |
Catheter ablation | IIa | B | B | II |
Sodium-channel blockers (strong negative inotropic effect) | III | A | D | II |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
In DCM, ventricular arrhythmias such as VT and supraventricular arrhythmias such as AF, atrial flutter, and atrial tachycardia occur. AF is observed in 20% of patients with HF, and the frequency increases as the cardiac function class increases with age.607 AF reduces atrial contraction, and tachycardia can easily lead to HF in patients with low cardiac function and worsen the prognosis for life.608,609 In the Atrial Fibrillation in Congestive Heart Failure (AF-CHF) study,610 no significant difference was found between the rhythm and rate control treatment groups. The most important thing to be aware of in terms of AF complications is the occurrence of cardiogenic cerebral infarction. The importance of anticoagulant therapy is also emphasized in the Japanese guidelines.332
In recent years, catheter ablation, which has been widely performed for paroxysmal AF, has been shown to be slightly superior to antiarrhythmic drug treatment for maintaining sinus rhythm. However, no clear evidence that it improves the prognosis in patients with HF has been presented. The Japanese guidelines recommend ablation for AF, which is indicated at the same level with or without HF (LV dysfunction) (Class IIa).611
5.2.1 Rate Control
The optimal resting heart rate in patients with HF and AF is considered to be 60–100 beats/min.612,613 Although a previous report indicated that control at a resting heart rate of 110 beats/min is sufficient,614 the European guidelines for HF recommend a lower heart rate of 60–100 beats/min.600 The Japanese guidelines recommend digitalis, landiolol, carvedilol, and bisoprolol for heart rate control in patients with no accessory pathways and reduced cardiac function.332 The ESC guidelines recommend β-blockers, and digitalis, or a combination, for heart rate regulation.600 β-blockers reduce the heart rate during activity, and digitalis decreases the heart rate at night.615 A resting heart rate <70 beats/min is a rather poor prognosis,616 which may be related to the fact that a large amount of β-blockers does not improve prognosis in patients with AF,617 and that the use of digitalis is a poor prognostic factor.618,619 However, because of their safety, β-blockers are considered first-line drugs. Amiodarone and nondihydropyridine Ca antagonists (verapamil and diltiazem) decrease the heart rate, but have side effects and negative inotropic effects, so generally they should be avoided.
5.2.2 Rhythm Control
For patients with chronic HF, the prognosis is the same as for rate control, even if rhythm control is performed by drugs and cardioversion.610 Urgent cardioversion should be done only when it is more lethal, and heart rate control should be prioritized. According to the Japanese and European guidelines, amiodarone, which is less effective for production, is recommended for pharmacodefibrillation and sinus rhythm maintenance.332,600,620 The use of amiodarone may be associated with extracardiac side effects, such as severe pulmonary complications or thyroid dysfunction, or with other drugs such as digitalis or oral anticoagulants,332 and should be limited to short-term use, usually within 6 months.600 Sodium-channel blockers with negative inotropic effects are contraindicated in organic heart disease because of increased mortality rates.621
5.2.3 Catheter Ablation
Except for tachycardia-induced cardiomyopathy, the safety and efficacy of catheter ablation as a rhythm control method for AF has not been established in patients with HF.620 In a meta-analysis of 1,838 AF patients with LV systolic dysfunction,622 the average rate of maintaining sinus rhythm during a 23-month observation period was 60%, and the incidence of complications was 4.2%. Ablation improved LVEF and NT-proBNP. At present, large-scale clinical trials regarding the usefulness of ablation for AF in patients with LV dysfunction are underway. The Catheter Ablation for Atrial Fibrillation with Heart Failure (CASTLE-AF) trial showed for the first time that catheter ablation significantly reduces all-cause death and rehospitalization for worsening HF in patients with HFrEF compared with medical therapy.623
Ablation of the atrioventricular node is sometimes performed in patients with difficult to treat atrial tachycardia or AF. However, atrioventricular node ablation is irreversible and requires permanent pacemaker implantation and the continued use of anticoagulants. RV pacing may lead to ventricular dyssynchrony and can further impair cardiac function in patients with LV systolic dysfunction. In the PABA-CHF study, the pulmonary vein isolation group had a longer 6-min walking distance, better LVEF, and improved QOL compared with the biventricular pacing group.624
Table 67 shows recommendations and levels of evidence for the treatment of supraventricular arrhythmias.
5.3 Sudden Cardiac Death (SCD) and Ventricular Arrhythmias
5.3.1 Prevention of SCD With an ICD (Table 68)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Patients with ventricular fibrillation without reversible factors | I | A | A | I |
Patients with sustained ventricular tachycardia without reversible factors such as electrolyte abnormality and who meet one or more of the following conditions: (1) Syncope in association with ventricular tachycardia (2) A blood pressure of 80 mmHg or less, symptoms of cerebral ischemia or chest pain in association with ventricular tachycardia (3) Polymorphic ventricular tachycardia (4) Hemodynamically stable monomorphic ventricular tachycardia in whom pharmacotherapy is ineffective or cannot be continued due to adverse drug effect, or cannot be assessed for drug efficacy, or catheter ablation is ineffective or impossible |
I | C | A | VI |
Patients in whom sustained ventricular tachycardia becomes no longer inducible after catheter ablation |
IIa | B | B | III |
Patients with sustained ventricular tachycardia for whom effective pharmacotherapy was established by detailed follow-up and drug efficacy evaluation |
IIa | B | B | VI |
Patients who are more likely to develop ventricular tachycardia or ventricular fibrillation triggered by an acute reversible disorder (e.g., acute myocardial ischemia, electrolyte abnormality, and drugs) and are at high risk for exposure to the disorder again despite sufficient treatment |
IIa | C | C1 | VI |
Patients who meet all of the following conditions: (1) After ≥3 months of optimal medical therapy (2) Symptomatic HF (NYHA class II–III) (3) LVEF ≤35% (4) Non sustained VT or unexplained syncope |
I | A | B | II |
Patients who meet all of the following conditions: (1) After ≥3 months of optimal medical therapy (2) Symptomatic HF (NYHA class II–III) (3) LVEF ≤35% |
IIa | B | B | II |
Patients unexplained syncope and an ejection fraction ≤35% | IIa | C | C1 | VI |
An indication of WCD for patients who meet all of the following conditions: (1) Received new medical therapy for heart failure (within 90 days) (2) An increased risk of sudden cardiac death (who meet above primary prevention conditions of ICD in principle) (3) Having possibility to recover LV systolic function |
IIa | C | B | III |
Patients who meet one or more of the following conditions: (1) Impossibility to express consent or cooperate with treatment due to mental disorder or other reasons (2) Physical restriction for chronic diseases (3) Life prognosis is less than 12 months (4) Ventricular tachycardia/fibrillation with a known acute reversible disorder (e.g., acute ischemia, electrolyte abnormality, and drugs) which can be eliminated (5) Frequent ventricular tachycardia/fibrillation which cannot be controlled with antiarrhythmic drugs and/or catheter ablation (6) Severe drug-resistant congestive heart failure and NYHA Class IV symptoms who are not indicated for heart transplantation, CRT, or left ventricular assist device |
III | C | C2 | IVb |
COR, class of recommendation; CRT, cardiac resynchronization therapy; GOR, grade of recommendation; HF, heart failure; ICD, implantable cardioverter defibrillator; LOE, level of evidence; LVEF, left ventricular ejection fraction; VT, ventricular tachycardia.
In patients with DCM, fibrosis of the LV causes intraventricular conduction disturbances and heterogeneity of ventricular conduction, which forms a reentry circuit that is the substrate of ventricular arrhythmia. SCD accounts for 30–40% of all-cause deaths in patients with DCM, mainly because of ventricular arrhythmias.625 ICDs play a pivotal role in preventing SCD. Antiarrhythmic drugs, HF therapy, and catheter ablation are combined with ICD therapy to improve prognosis (Figure 34).
The flowchart for the prevention for sudden cardiac death in patients with DCM. Solid arrows and borders indicate indications of class IIa or higher, and dashed arrows and borders indicate the conditions indicated for class IIb or no classification. Positive Lamin A/C mutation do not depend on this flowchart. (1) Non-sustained VT, (2) LVEF <45%, (3) Male, (4) Non-missense mutation. Careful consideration should be given to ICD indications in patients with above some risk factors (especially two or more). *Evaluate ICD indications depend on LVEF and heart failure symptoms after adequate heart failure treatment (90 days or more). Consider wearable defibrillator within 90 days. **In patients with dilated cardiomyopathy and syncope, the prognosis is poor regardless of the cause. When the etiology is uncertain as a result of noninvasive examinations, consider electrophysiological study or ICD implantation. CRT/CRT-D, cardiac resynchronization therapy / cardiac resynchronization therapy-defibrillator; ECG, electrocardiography; HF, heart failure; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; PM, pacemaker; VF, ventricular fibrillation; VT, ventricular tachycardia; WCD, wearable cardioverter defibrillator.
a. Secondary Prevention
In patients with DCM, resuscitation from sustained VT/VF and cardiac arrest is considered to be a risk factor for SCD, with a 2-year recurrence rate of 10–20%.25 A meta-analysis of 256 DCM cases from Antiarrhythmics vs. Implantable Defibrillators (AVID)626 and Canadian Implantable defibrillator Study (CIDS)627 reported that ICD implantation was associated with a 31% nonsignificant reduction in all-cause death relative to medical therapy (P=0.22).628 Although this report was underpowered, the observed mortality reduction was consistent with the observed benefit in the entire study population; therefore, ICD implantation is indicated as Class I or IIa.
b. Primary Prevention
The risk factors for SCD other than previous ventricular arrhythmias are decreased LV systolic function and severe HF. Several randomized control trials and meta-analyses have revealed that patients with severely reduced LVEF (≤35%) and NYHA Class II–III HF are at high risk of SCD. In Defibrillations in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE),629 ICDs reduced the risk of SCD, with a trend towards a 35% reduction in all-cause death compared with amiodarone (P=0.08) in patients with LVEF ≤35% and premature ventricular contractions (≥10 beats/h) or nonsustained VT. The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)630 included 792 (48%) nonischemic cardiomyopathy patients with LVEF ≤35% (NYHA Class II–III), and demonstrated that total mortality at 5 years was 21% in the ICD and 27% in the placebo groups (P=0.06). A meta-analysis of 5 clinical trials (n=1,854)628 showed that ICDs significantly reduced total mortality by 31%. The Defibrillator implantation in patients with Non-Ischemic Systolic Heart failure (DANISH) trial included patients with LVEF ≤35%, NYHA Class II–IV (if CRT was planned), and NT-proBNP >200 pg/mL.631 During a median follow-up of 68 months, ICDs significantly reduced SCD (secondary endpoint) (hazard ratio [HR], 0.50, P=0.005), with a trend towards reduced all-cause death (primary endpoint; HR, 0.87; 95% confidence interval [CI], 0.68–1.12). Thus, after appropriate HF therapy (guideline-directed and >90 days), ICD implantation for the primary prevention of SCD in patients with LVEF ≤35% and NYHA Class II–III is recommended. In addition to these parameters, patients with nonsustained VT are recommended for ICD implantation as a Class I indication because of a higher risk of SCD. If HF therapy has not been performed for 90 days, a wearable defibrillator is effective,632–634 and considered a bridge therapy until an indication for an ICD.
c. Syncope
Unexplained syncope is a risk factor for SCD in patients with DCM.635 According to the ESC guidelines on syncope, an ICD is considered as a Class IIa indication, even in patients with mild to moderate reduced LVEF (36–50%).636 Ventricular arrhythmia, supraventricular arrhythmia, bradycardia, and neuroreflex are the known causes of syncopal attack,635,637 and syncope is a risk factor for SCD regardless of cause in patients with DCM.638 An external event recorder is considered if syncope is observed within 4 weeks.639 If the cause of syncope cannot be detected, an implantable loop recorder is also considered. The usefulness of an electrophysiologic study in patients with DCM is controversial.485,640–644 ICDs are considered in patients with unexplained syncope with nonsustained VT, low cardiac function (LVEF ≤35%) and NYHA Class I (Table 69), and considered in patients with unexplained syncope with mild to moderate reduced LVEF.
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
EPS for the evaluation of sudden cardiac death risk in patients with syncope of unknown origin |
IIb | B | C1 | IVa |
COR, class of recommendation; GOR, grade of recommendation; LOE, level of evidence.
d. Gene Mutations and SCD
Genetic counseling and screening are considered in juvenile cases (<40 years), patients with a family history of SCD (see IV.4.11 Genetic Testing (Including Genetic Counseling)). Laminopathies are diseases caused by mutations in the LMNA gene that result in DCM. Nonsustained VT, LVEF <45% at first evaluation, male sex, and non-missense mutations are independent risk factors for lethal ventricular arrhythmias.645–649 In patients with LMNA mutations and 1–2 of these risk factors, ICD implantation is considered a Class IIa indication in the ACC/AHA/HRS and ESC guidelines.650,651
5.3.2 Management of Ventricular Arrhythmias Associated With Cardiomyopathy
a. Pharmacotherapy (Table 70)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Use of oral or intravenous amiodaron, intravenous nifekalant for frequent ICD shock |
I | B | B | IVa |
Removal of causes for recurrence of arrhythmias (hypokalemia, hypomagnesemia, proarrhythmic drugs, thyroid dysfunction) |
I | A | B | IVa |
Use of oral amiodaron to avoid shock of ICD in patients who have the experience of appropriate ICD shocks |
IIa | C | B | IVa |
Use of oral amiodarone in patients with LVEF ≤35%, NYHA class II or III as primary prevention of ventricular arrhythmias |
IIa | C | B | IVa |
Use of oral amiodarone in patients with symptomatic frequent premature ventricular contraction or nonsustained ventricular tachycardia |
IIa | B | B | IVa |
Use of oral antiarrhythmic drugs in patients with asymptomatic nonsustained ventricular tachycardi or premature ventricular contraction but without above condition |
III | A | D | II |
Use of Na channel blocker in patients with ventricular arrhythmias | III | A | D | II |
COR, class of recommendation; GOR, grade of recommendation; ICD, implantable cardioverter defibrillator; LOE, level of evidence; LVEF, left ventricular ejection fraction.
Premature ventricular contractions in patients with cardiomyopathy not only trigger malignant ventricular arrhythmias, but also cause both appropriate and inappropriate ICD shocks. The roles of medical therapy for ventricular arrhythmias include the suppression of malignant arrhythmias and the reduction of ICD shock delivery. Intravenous injection of amiodarone or nifekalant is recommended because of their immediate and strong preventive effects.322,652,653 In electrical storm cases, in addition to medical therapy, correction of hypokalemia and/or hypomagnesemia as well as sedation are also considered. The use of oral amiodarone is recommended for symptomatic ventricular arrhythmias in patients with low cardiac function (LVEF ≤35%) and HF symptoms.332 By contrast, neither sodium- nor calcium-channel blockers are recommended for any ventricular arrhythmias in patients with low cardiac function.
b. Catheter Ablation and Surgery (Table 71)
COR | LOE | GOR (MINDS) |
LOE (MINDS) |
|
---|---|---|---|---|
Catheter ablation for ventricular tachycardia (bundle reentry, bundle branch reentry) | I | C | A | V |
Emergent catheter ablation for frequent ICD shocks (electrical storm) that cannot be controlled with medical therapy |
I | C | C1 | IVb |
Catheter ablation for frequent premature ventricular contraction (≥10% of total heart rate per day) that is considered to relate to reduced left ventricular systolic function when medications are ineffective or cannot be used due to side effects or the patient wishes no medical therapy |
I | B | B | II |
Catheter ablation for premature ventricular contraction or nonsustained ventricular tachycardia that reduces pacing frequency of cardiac resynchronization therapy leading to its insufficient effects when medications are ineffective or cannot be used due to side effects |
IIa | B | B | IVa |
Catheter ablation for frequent premature ventricular contraction in patients who wish catheter therapy even if medications are effective or not used |
IIa | B | B | IVb |
Catheter ablation for asymptomatic sustained ventricular tachycardia (except bundle or bundle branch reentry) that cannot be controlled with medications |
IIa | B | B | IVa |
Catheter ablation for repetitive polymorphic ventricular tachycardia or ventricular fibrillation triggered by premature ventricular contraction originated from right ventricular outflow tract or peripheral Purkinje fibers, when medications are ineffective or cannot be used due to side effects |
IIb | C | C1 | V |
COR, class of recommendation; GOR, grade of recommendation; ICD, implantable cardioverter defibrillator; LOE, level of evidence.
For more information, see the relevant section of the JCS/JHRS “Guideline of nonpharmacotherapy for cardiac arrhythmias”.611 Catheter ablation or surgery may be recommended in patients with frequent premature ventricular contractions. Routine catheter ablation for ventricular arrhythmias is not recommended because it has been shown to be less effective in patients with cardiomyopathy than in those with ischemic cardiomyopathy.654 Catheter and surgical ablation are recommended only in the case of an electrical storm.655 In addition, catheter ablation is considered for restoring LVEF in patients with frequent premature ventricular contractions, nonsustained VT, and symptomatic ventricular arrhythmias.656–658
5.4 Thromboembolism
5.4.1 Pathogenesis
In HF patients with reduced LVEF, such as DCM, decreased blood flow velocity due to decreased cardiac function, an abnormal platelet–coagulation–fibrinolysis system, and changes in vascular wall properties are thought to induce an environment where thrombosis is likely to occur.659 Thrombus, which forms in the heart chamber, causes cerebral infarction and systemic embolism in the left heart system, and pulmonary and paradoxical embolism in the right heart system. In addition to low blood flow, venous thrombus is likely to form due to decreased physical function and systemic edema. In general, the frequency of stroke in HF patients is reported to be 1.2–1.8% per year.660 However, it has been reported that the frequency of stroke in patients with reduced LVEF who were in sinus rhythm is 1% per year.661
5.4.2 Risk Factors
Obviously, AF is a risk factor for thromboembolism, but the relationship between thromboembolism and systolic dysfunction661,662 or LV thrombus663,664 on echocardiography remains controversial.
5.4.3 Treatment
Regarding anticoagulant and/or antiplatelet therapies to prevent thromboembolism, cardiologists need to consider carefully whether their treatments should be initiated after taking into account the balance between the benefits of treatment and the risk of bleeding complications.
a. Anticoagulation Therapy
i. Prevention of Deep Vein Thrombosis During Acute Heart Failure
During the acute phase of HF, when patients require prolonged bed rest, the use of low-dose unfractionated heparin is recommended to prevent deep venous thrombosis and pulmonary thromboembolism. Elastic stockings and intermittent pneumatic compression need to be used with caution because increased venous return can aggravate HF.665
ii. Heart Failure With AF
Anticoagulant therapy is indicated in HF patients with AF. The use of heparin is recommended for rapid anticoagulation. A meta-analysis of DOACs vs. warfarin in AF patients (e.g., RELY, ARISOTLE, ROCKET-AF, ENGAGE AF-TIMI) reported that the use of DOACs reduced the incidence of stroke, systemic embolism, and bleeding complications, regardless of the presence of HF.666 However, evidence regarding the superiority of DOACs in HF with reduced LVEF remains insufficient.
iii. Sinus Rhythm Heart Failure With a History of Thromboembolism
The use of warfarin in patients with a history of systemic or pulmonary embolism is recommended, as the evidence supporting DOACs remains insufficient.
iv. Sinus Rhythm HF Without a History of Thromboembolism
No evidence has been presented that anticoagulants are effective in patients with sinus rhythm and no history of thromboembolism. Warfarin should be used to prevent thromboembolism in patients with acute intracardiac thrombosis. In a randomized trial evaluating the preventive effect of anticoagulants on thromboembolism and sinus rhythm in HF patients, warfarin did not show clinical utility compared with the control.667–670 The HELAS study, in which patients with DCM (LVEF <35%) were eligible, demonstrated that warfarin did not prevent thromboembolism during an approximate 2-year observation period.669 The WARCEF trial demonstrated that, among patients with HF with reduced systolic function (LVEF <35%), warfarin prevented ischemic stroke compared with aspirin, but significantly increased major bleeding. There was no significant difference between warfarin and aspirin therapies in preventing the composite outcome of death, ischemic stroke, and intracerebral hemorrhage.670 The COMMANDER HF, a randomized controlled trial of patients with HFrEF and CAD, demonstrated that low-dose rivaroxaban was not associated with a lower rate of the composite outcome of all-cause death, myocardial infarction, or stroke compared with placebo.671
b. Antiplatelet Drugs
No clinical trials have found a preventive effect of antiplatelet drugs on thromboembolism.667–669 In patients with CAD, antiplatelet drugs are recommended based on the treatment for CAD.
6. Management of Daily Life6.1 Lifestyle
Section 6.1.1 mainly refers to HCM.
Regarding DCM, please refer also to the HF guidelines.11
6.1.1 Activity and Sports
In patients with HCM, regardless of symptoms and the presence or absence of a LVOT pressure gradient, except for some light sports (e.g., billiards, bowling, golf), participation in competitive sports should be stopped, especially among those who are at high risk of syncope or sudden death.374,672 If there are no symptoms or risk of sudden death, it is desirable to perform moderate exercise to maintain a healthy lifestyle.7 In patients with chronic HF, safe and effective exercise based on the results of CPET is recommended.11 For more details, please see IV.6.2 Exercise Training/Exercise Therapy.
6.1.2 Diet
Patients should be instructed to follow a balanced diet to maintain an appropriate body mass index.673 Excessive salt intake should be avoided, regardless of the severity of symptoms and history of HF.11 In particular, for patients with coronary risk factors, it is necessary to review not only salt intake, but also dietary habits, to correct coronary risk factors, as well as dehydration due to reduced preload and increased contractility in patients with HCM.673
6.1.3 Alcohol
For patients with HCM, the ingestion of a small amount of alcohol (50 mL of 40% ethanol) decreases systolic blood pressure, enhances systolic anterior motion, and increases the LVOT pressure gradient.674 Therefore, alcohol consumption is not advised for patients with HCM, especially those with LVOT obstruction. Such patients should avoid excessive alcohol consumption and dehydration.7
6.1.4 Smoking
No clear evidence has been presented regarding the effects of smoking on HCM or DCM; however, it has been reported that smoking triggers coronary spasms in HCM.80 For more information on specific methods to support smoking cessation, please see the “Guidelines for smoking cessation” (revised in 2010).675
6.1.5 Sexual Activity
Sexual activity in terms of exercise intensity is 2–3 METs during early climax and 3–4 METs during climax, accompanied by increases in both heart rate and blood pressure.11 The risk of sexual symptoms and sudden death is high for patients and partners. For patients with HOCM, in particular, it is assumed that drugs are tolerated well and in a stable state.676,677
6.1.6 Pregnancy and Birth
Please refer to Chapter IV.
6.1.7 Infection Prevention
It is important to instruct patients and their families in regard to infection prevention. Influenza and pneumococcal vaccines should be given, especially to patients with HOCM. As the incidence of infective endocarditis is high,362 adequate guidance on infection prevention is needed.
6.1.8 Employment
Most patients with HCM and DCM are able to continue their normal working life. Appropriate counseling that enables such patients to continue working should be considered, taking the social and economic effects of the diagnosis into account. However, if physical illness is reduced as the disease progresses, consultation with a specialist should be arranged for work that involves intense activity. Some specialized occupations require strict eligibility criteria and are described in more detail in the “Guidelines for exercise conditions in schools, occupations, and sports for patients with heart disease”.561
6.1.9 Leisure and Travel
Air travel is safe for patients with asymptomatic or mild asymptomatic HCM and DCM. However, lengthy and high altitude air travel, as well as travel to hot and humid areas, requires caution. For specific management, please see the “Guidelines for the management of acute and chronic heart failure” (revised in 2017).11
6.1.10 Psychological Support
Depression and anxiety are frequent psychological symptoms in all patients with cardiovascular disease, and their relationship with a worse prognosis has been reported.11 In particular, patients express remorse for their risk of inheritance.7 When announcing the diagnosis, it is necessary to take the social background of the patient and his or her family into account. It is advisable to discuss how to give the name of the diagnosis, including to multidisciplinary healthcare professionals, and to carry out regular mental screening, taking the burden of disease management throughout life and the fear of sudden death into account. These patients should also be given assistance acquiring counseling as needed.
6.2 Exercise Training/Exercise Therapy
Although many reports have been published on the favorable effects of exercise therapy for chronic HF, the main cause of the disease among such patients is ischemic cardiomyopathy. It is difficult to study the effects of exercise training focusing only on DCM. As there is no difference in exercise training for HFrEF patients in daily clinical practice, the following information is for HFrEF including DCM. The Japanese Circulation Society has already published guidelines for the management of acute and chronic heart failure (revised in 2017).11
6.2.1 Effect of Exercise Therapy11 (Table 72)
COR | LOE | |
---|---|---|
Patients with HFrEF Combination with drug therapy to relieve symptoms and improve exercise capacity |
I | A |
Patients with HFrEF To improve QOL, reduce cardiac accidents, and improve life expectancy |
IIa | B |
Patients with advanced deconditioning and patients with reduced physical function Resistance training to improve ADL and QOL by increasing muscle strength and endurance |
IIa | C |
ADL, activities of daily living; COR, class of recommendation; GOR, grade of recommendation; HFrEF, heart failure with reduced ejection fraction; LOE, level of evidence; QOL, quality of life.
Regarding HCM, please refer to Chapter III.7.2.
Exercise training based on aerobic exercise for chronic HF is a nonspecific intervention, and several systemic or local effects are considered: (1) vascular endothelial function; (2) cardiac hemodynamics; (3) neurohumoral factors; (4) respiratory system; and (5) skeletal muscle metabolism and function.678
In an ExTraMATCH (Exercise training meta-analysis of trials in patients with chronic heart failure) meta-analysis of 801 patients with chronic HF,679 mortality was significantly reduced by 35% (hazard ration [HR], 0.65, 95% CI, 0.46–0.92, P=0.015), and the secondary endpoint of death or admission to hospital was significantly reduced by 28% (HR, 0.72, 95% CI, 0.56–0.93, P=0.011). Subsequently, HF-ACTION (Heart failure: a controlled trial investigating outcomes of exercise training),680 a multicenter, prospective, randomized controlled trial, was conducted. In that study, the exercise training group did not show significant differences in mortality and hospitalization compared with the usual care group. After adjusting for key prognostic factors, the HR revealed significant improvement for cardiovascular death and HF hospitalization. Other adverse events were similar between groups.
In addition, another meta-analysis showed that exercise therapy for HF did not significantly reduce overall mortality, but did significantly reduced any hospitalization and HF hospitalization.681
6.2.2 How to Proceed With Exercise Therapy
Exercise training is recommended for patients with stable chronic HF, so it is important to exclude contraindicated diseases (Table 73).11,682 It should be noted that there are no limitations, considering the minimum adaptation criteria for LVEF. It is desirable to perform an exercise test (preferably CPET) and to prescribe exercise therapy based on the results. See the guidelines and Table 74 for more information on exercise training.11,682
I. Absolute contraindications |
1) Exacerbation of heart failure symptoms (e.g., dyspnea, easy fatigability) during the last 3 days |
2) Unstable angina or low-threshold myocardial ischemia that is induced by slow walking on a flat surface (2 METs) |
3) Severe valvular disease indicated for surgery, especially aortic stenosis |
4) Severe left ventricular outflow tract stenosis (hypertrophic obstructive cardiomyopathy) |
5) Untreated severe exercise-induced arrhythmia (ventricular fibrillation, sustained ventricular tachycardia) |
6) Active myocarditis/pericarditis |
7) Acute systemic disease or fever |
8) Other diseases in which exercise therapy is contraindicated (moderate or severe aortic aneurysm, severe hypertension, thrombophlebitis, embolism within past 2 weeks, and serious organ diseases) |
II. Relative contraindications |
1) NYHA Class IV or hemodynamically unstable heart failure |
2) Heart failure with an increase in body weight by ≥2 kg during the last week |
3) Exercise-induced decrease in systolic blood pressure |
4) Moderate left ventricular outflow tract stenosis |
5) Exercise-induced moderate arrhythmia (e.g., nonsustained ventricular tachycardia, tachycardiac atrial fibrillation) |
6) Advanced atrioventricular block, exercise-induced Mobitz type II atrioventricular block |
7) Occurrence or exacerbation of exercise-induced symptoms (e.g., fatigue, dizziness, excessive sweating, dyspnea) |
III. Not contraindicated |
1) Elderly patients |
2) Decreased LVEF |
3) Use of ventricular assist devices (LVADs) |
4) Use of implantable cardiac devices (e.g., ICDs, CRT-D) |
CRT-D, cardiac resynchronization therapy defibrillator; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; LVAD, left ventricular assist device; METs, metabolic equivalents; NYHA, New York Heart Association. (Adapted from The Japanese Circulation Society.11)
Type of exercise | • Walking (begin with supervised indoor walking), cycle ergometer, light aerobics, low-intensity resistance training (for patients with muscle weakness) • Jogging, swimming, and vigorous aerobics are not recommended |
Exercise intensity | [Early phase] • Indoor walking at 50 to 80 m/min for 5 to 10 min or a cycle ergometer at 10 to 20 W for 5 to 10 min • The duration and intensity of exercise should be increased gradually over 1 month as guided by signs/symptoms during exercise |
[Goal in the stable phase] • The target heart rate (HR) is set at 40 to 60% of the peak V̇O2 or at anaerobic threshold level • The target HR is set at 30 to 50% of HR reserve, or 50 to 70% of the maximum HR • Target rating of perceived exertion (RPE) is set at Borg scale 11 (fairly light) to 13 (somewhat hard) |
|
Duration | • Start with 5 to 10 min/session, 2 sessions a day, and then increase gradually from 30 to 60 min/day |
Frequency | • 3 to 5 days/week (3 days/week for patients with severe heart failure, and may be increased up to 5 days/week for those with stable condition) • Low-intensity resistance training may be added at a frequency of 2 to 3 days/week |
Precautions | • Exercise during the first month should be light in intensity and careful monitoring for worsening heart failure should be made • Start with supervised training and then combine with non-supervised (home-based) exercise training during the stable phase • Changes in subjective symptoms, physical findings, body weight, and blood BNP or NT-proBNP levels should be observed carefully |
BNP, brain (B-type) natriuretic peptide; NT-proBNP, N-terminal pro-brain (B-type) natriuretic peptide. (Adapted from The Japanese Circulation Society.11)
6.2.3 Disease Management Programs
Cardiac rehabilitation is comprehensive treatment and care that includes a disease management program. It is designed for all patients with HF and aims to recover their condition, prevent exacerbation, improve their psychological status, and help them return to the community. Many programs consisting of education/consultation for drugs, diet and water restrictions, and self-care support for patients and their families are provided. Outpatient support, telephone support, and home-visit nursing/rehabilitation are also delivered to HF patients. It has been confirmed that such programs suppress the exacerbation of HF and improve prognosis,683 and the effectiveness of adding outpatient cardiac rehabilitation to HF management programs has been reported.684,685
6.3 Pregnancy and Birth
6.3.1 Changes in Hemodynamics During Pregnancy and Childbirth
During pregnancy and childbirth, circulation changes dynamically (see III.6.3 Pregnancy and Childbirth). In pregnancies complicated by DCM, the risk of complications, such as further deterioration of cardiac function, HF, ventricular arrhythmia, and thromboembolism, increases because of increases in circulating plasma volume, heart rate, and coagulation ability due to pregnancy.
6.3.2 Pregnancy and Childbirth Risks
DCM patients with only mild cardiac dysfunction without symptoms often have a good pregnancy course. However, the risk of progressed cardiac dysfunction during pregnancy and childbirth should be fully explained before pregnancy.422
Few cohort studies of pregnancy with DCM have been reported, but the incidence of maternal cardiovascular complications is approximately 10–40%. The risk factors for maternal cardiovascular complications are LVEF <45%, NYHA Class III–IV, and a history of cardiovascular events before pregnancy.686,687 In another study on pregnancy with heart disease, including DCM, LVEF <40% was found to be a predictor of cardiovascular complications.420 In pregnancy with DCM, HF is mostly diagnosed from the latter half of pregnancy to 2 months after delivery (median, 35 weeks of pregnancy,421 whereas arrhythmias and strokes can occur throughout the pregnancy.686
According to the JCS guidelines, HF (NYHA Class III–IV, LVEF <35–40%) requires strict monitoring during pregnancy or a strong recommendation to avoid pregnancy.421 In the modified WHO classification, which is widely used for risk assessment in pregnancies with cardiovascular disease, LVEF <30% and NYHA Class III–IV indicate WHO Class IV, which is defined as “extremely high maternal mortality or severe morbidity risk”. In the event of pregnancy that is contraindicated, termination should be discussed. If the pregnancy continues, intensive specialist cardiac and obstetric monitoring are needed throughout pregnancy, childbirth, and the puerperium. If an LVEF <20% is observed during pregnancy, the pregnancy should be terminated because the risk of maternal death is very high.422 The same criteria are considered for cardiomyopathies clinically similar to DCM, such as drug-induced and ischemic cardiomyopathies.
6.3.3 Pregnancy and Childbirth Management
In high-risk patients, frequent echocardiography is needed to evaluate cardiac function and pulmonary hypertension. As angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) have been reported to cause insufficient amounts of amniotic fluid and renal damage to the fetus, their use during pregnancy is contraindicated. ACE inhibitors and ARBs should be stopped for women desiring pregnancy, and they should be carefully monitored whether or not HF worsens. Aldosterone antagonists are considered safe in normal doses. β-blockers are not teratogenic and can be used during pregnancy; however, they require careful monitoring of the fetus and newborn because they may cause intrauterine growth restriction and neonatal hypoglycemia. In addition, diuretics, carperitide, and catecholamine can be used for acute exacerbation of HF during pregnancy. Delivery by cesarean section should be considered in patients with poorly controlled HF. In patients with deteriorated cardiac function, vaginal delivery with epidural anesthesia is recommended to reduce the cardiac load.
Chairs
• Hiroaki Kitaoka, Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
• Hiroyuki Tsutsui, Department of Cardiovascular Medicine, Kyushu University
Members
• Taishiro Chikamori, Department of Cardiology, Tokyo Medical University Hospital
• Noboru Fujino, Department of Cardiovascular and Internal Medicine, Kanazawa University, Graduate School of Medical Science
• Keiichi Fukuda, Department of Cardiology, Keio University School of Medicine
• Nobuhisa Hagiwara, Department of Cardiology, Tokyo Women’s Medical University
• Taiki Higo, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences
• Tomomi Ide, Department of Cardiovascular Medicine, Kyushu University
• Hatsue Ishibashi-Ueda, Department of Pathology, National Cerebral and Cardiovascular Center
• Mitsuaki Isobe, Sakakibara Heart Institute
• Chizuko Kamiya, Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center
• Seiya Kato, Division of Pathology, Saiseikai Fukuoka General Hospital
• Yasuki Kihara, Kobe City Medical Center General Hospital
• Koichiro Kinugawa, Second Department of Internal Medicine, University of Toyama
• Shintaro Kinugawa, Department of Cardiovascular Medicine, Kyushu University
• Shigetoyo Kogaki, Department of Pediatrics and Neonatology, Osaka General Medical Center
• Issei Komuro, Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo
• Toru Kubo, Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
• Yuichiro Maekawa, Division of Cardiology, Internal Medicine III, Hamamatsu University School of Medicine
• Shigeru Makita, Department of Cardiac Rehabilitation, Saitama International Medical Center, Saitama Medical University
• Yoshiro Matsui, Department of Cardiac Surgery, Hanaoka Seishu Memorial Hospital
• Shouji Matsushima, Department of Cardiovascular Medicine, Kyushu University
• Minoru Ono, Department of Cardiac Surgery, The University of Tokyo Hospital
• Yasushi Sakata, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
• Yoshiki Sawa, Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine
• Wataru Shimizu, Department of Cardiovascular Medicine, Nippon Medical School
• Kunihiko Teraoka, Department of Cardiology, Sakakibara Heart Institute
• Miyuki Tsuchihashi-Makaya, School of Nursing, Kitasato University
• Masafumi Watanabe, Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine
• Michihiro Yoshimura, Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine
Collaborators
• Arata Fukusima, Asabu Heart & Gastrointestinal Clinic
• Satoshi Hida, Department of Cardiovascular Medicine, Tokyo Medical University
• Shungo Hikoso, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
• Teruhiko Imamura, Second Department of Internal Medicine, University of Toyama
• Hiroko Ishida, Nippon Medical School, Musashikosugi Hospital
• Makoto Kawai, Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine
• Toshiro Kitagawa, Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences
• Takashi Kohno, Department of Cardiovascular Medicine, Kyorin University School of Medicine
• Satoshi Kurisu, Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences
• Hiroyuki Morita, Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo
• Yoji Nagata, Division of Cardiology, Fukui CardioVascular Center
• Makiko Nakamura, Second Department of Internal Medicine, University of Toyama
• Tsuyoshi Shiga, Department of Clinical Pharmacology and Therapeutics, The Jikei University School of Medicine
• Hitoshi Takano, Department of Cardiovascular Medicine, Nippon Medical School Hospital
• Yasuyoshi Takei, Department of Cardiology, Tokyo Medical University Hospital
• Tetsu Watanabe, Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine
• Teppei Yamamoto, Department of Cardiovascular Medicine, Nippon Medical School
• Shinsuke Yuasa, Department of Cardiology, Keio University School of Medicine
Independent Assessment Committee
• Takashi Akasaka, Department of Cardiovascular Medicine, Wakayama Medical University
• Yoshinori Doi, Department of Medicine, Chikamori Hospital
• Takeshi Kimura, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
• Masafumi Kitakaze, Department of Cardiology, Hanwa Daini Senboku Hospital
• Masami Kosuge, Division of Cardiology, Yokohama City University Medical Center
• Morimasa Takayama, Department of Cardiology, Sakakibara Heart Institute
• Hitonobu Tomoike, Sakakibara Heart Institute
(Listed in alphabetical order; affiliations as of March 2021)
Author | Potential COI of the participant | Potential COI of the marital partner, first-degree family members, or those who share income and property |
Declaration about the head of your affiliated rganization/department (if the participant is conducting joint research with the head of the organization/department) |
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Employer / leadership position (private company) |
Stock or stock options |
Intellectual property / royalties |
Speakers’ bureau | Payment for manuscripts |
Research grant | Scholarship (educational) grant |
Endowed chair | Other rewards |
Employer / leadership position (private company) |
Stock or stock options |
Intellectual property / royalties |
Research grant |
Scholarship (educational) grant |
|
Chair: Hiroaki Kitaoka |
Bayer Yakuhin, Ltd. Daiichi Sankyo Company, Limited Mitsubishi Tanabe Pharma Corporation |
Astellas Pharma Inc. Bayer Yakuhin, Ltd. Daiichi Sankyo Company, Limited |
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Chair: Hiroyuki Tsutsui |
MSD K.K. Astellas Pharma Inc. Novartis Pharma K.K. Bayer Yakuhin, Ltd. Pfizer Japan Inc. Bristol-Myers Squibb Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Mitsubishi Tanabe Pharma Corporation Nippon Boehringer Ingelheim Co., Ltd. Takeda Pharmaceutical Company Limited |
nippon rinsho Co.,Ltd. Medical Review Co.,Ltd |
IQVIA Services Japan K.K. Actelion Pharmaceuticals Japan Ltd. Daiichi Sankyo Company, Limited Mitsubishi Tanabe Pharma Corporation Japan Tobacco Inc. Nippon Boehringer Ingelheim Co., Ltd. |
MSD K.K. Astellas Pharma Inc. Novartis Pharma K.K. Daiichi Sankyo Company, Limited Teijin Pharma Limited Mitsubishi Tanabe Pharma Corporation Takeda Pharmaceutical Company Limited |
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Member: Taishiro Chikamori |
Mitsubishi Tanabe Pharma Corporation |
Ono Pharmaceutical Co., Ltd. Medtronic Japan Co., Ltd. |
MSD K.K. Bayer Yakuhin, Ltd. Sumitomo Dainippon Pharma Co., Ltd. Daiichi Sankyo Company, Limited Mitsubishi Tanabe Pharma Corporation FUJIFILM RI Pharma Co., Ltd. Takeda Pharmaceutical Company Limited |
St. Jude Medical Japan Co., Ltd. |
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Member: Keiichi Fukuda |
GlaxoSmithKline K.K. Actelion Pharmaceuticals Japan Ltd. Bayer Yakuhin, Ltd. Pfizer Japan Inc. Mochida Pharmaceutical Co.,Ltd. |
Bayer Yakuhin, Ltd. |
Bayer Yakuhin, Ltd. | Actelion Pharmaceuticals Japan Ltd. Nippon Shinyaku Co., Ltd. |
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Member: Nobuhisa Hagiwara |
Bayer Yakuhin, Ltd. Bristol-Myers Squibb Nippon Boehringer Ingelheim Co., Ltd. |
Aegerion Pharmaceuticals, Inc. Astellas Pharma Inc. Bayer Yakuhin, Ltd. Pfizer Japan Inc. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited TORAY INDUSTRIES, INC. Nippon Boehringer Ingelheim Co., Ltd. Takeda Pharmaceutical Company Limited |
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Member: Mitsuaki Isobe |
Chugai Pharmaceutical Co.,Ltd. Daiichi Sankyo Company, Limited Otsuka Pharmaceutical Co., Ltd. |
Teijin Pharma Limited Daiichi Sankyo Company, Limited Mitsubishi Tanabe Pharma Corporation Ono Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd. |
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Member: Yasuki Kihara |
Actelion Pharmaceuticals Japan Ltd. Bayer Yakuhin, Ltd. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited TEIJIN HOME HEALTHCARE LIMITED Nippon Boehringer Ingelheim Co., Ltd. Takeda Pharmaceutical Company Limited |
Teijin Pharma Limited EP-CRSU Co., Ltd. |
MSD K.K. Astellas Pharma Inc. Sanofi K.K. BIOTRONIK Japan, Inc. Pfizer Japan Inc. Boston Scientific Corporation Akane-kai Tsuchiya Hospital Federation of National Public Services and Affiliated Personnel Mutual Aid Associations Kure Kyosai Hospital Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Nippon Boehringer Ingelheim Co., Ltd. Takeda Pharmaceutical Company Limited Senoo Hospital |
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Member: Koichiro Kinugawa |
AstraZeneca K.K. Nipro Corporation Boehringer Ingelheim International GmbH Ono Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Mitsubishi Tanabe Pharma Corporation |
Otsuka Pharmaceutical Co., Ltd. |
SECOM MEDICAL SYSTEM CO.,LTD. |
Otsuka Pharmaceutical Co., Ltd. Ono Pharmaceutical Co., Ltd. Actelion Pharmaceuticals Japan Ltd. |
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Member: Issei Komuro |
MSD K.K. Actelion Pharmaceuticals Japan Ltd. Amgen Astellas BioPharma K.K. Astellas Pharma Inc. AstraZeneca K.K. TOA EIYO LTD. Bayer Yakuhin, Ltd. Shionogi & Co., Ltd. Ono Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Mitsubishi Tanabe Pharma Corporation Nippon Boehringer Ingelheim Co., Ltd. Takeda Pharmaceutical Company Limited |
Quintiles Transnational Japan k.k. Ono Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Meiji Co., Ltd. |
Astellas Pharma Inc. Edwards Lifesciences Corporation TERUMO CORPORATION TOA EIYO LTD. Nipro Corporation Bayer Yakuhin, Ltd. Kowa Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Sumitomo Dainippon Pharma Co., Ltd. Daiichi Sankyo Company, Limited Teijin Pharma Limited Mitsubishi Tanabe Pharma Corporation Takeda Pharmaceutical Company Limited |
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Member: Toru Kubo |
Sumitomo Dainippon Pharma Co., Ltd. |
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Member: Yuichiro Maekawa |
Bristol-Myers Squibb Daiichi Sankyo Company, Limited |
Abbott Vascular Japan Co., Ltd. St. Jude Medical Japan Co., Ltd. TERUMO CORPORATION Boston Scientific Corporation Takeda Pharmaceutical Company Limited |
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Member: Shigeru Makita |
Otsuka Pharmaceutical Co., Ltd. |
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Member: Yoshiro Matsui |
Abbott Japan LLC Edwards Lifesciences Corporation Sanofi K.K. St. Jude Medical Japan Co., Ltd. SENKO MEDICAL INSTRUMENT Mfg. Co., Ltd. Japan Lifeline Co.,Ltd. |
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Member: Minoru Ono |
Sun Medical Technology Research Corp. Nipro Corporation |
Kono Seisakusho Co., Ltd. |
Astellas Pharma Inc. Edwards Lifesciences Corporation Eisai Co., Ltd. Sun Medical Technology Research Corp. St. Jude Medical Japan Co., Ltd. TERUMO CORPORATION |
Kono Seisakusho Co., Ltd. |
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Member: Yasushi Sakata |
Actelion Pharmaceuticals Japan Ltd. Otsuka Pharmaceutical Co., Ltd. Ono Pharmaceutical Co., Ltd. Kowa Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Bristol-Myers Squibb Nippon Boehringer Ingelheim Co., Ltd. Medtronic Japan Co., Ltd. Mitsubishi Tanabe Pharma Corporation St. Jude Medical Japan Co., Ltd. Novartis Pharma K.K. BIOTRONIK Japan, Inc. Boston Scientific Corporation |
Roche Diagnostics K.K. Astellas Pharma Inc. FUJIFILM RI Pharma Co., Ltd. Edwards Lifesciences Corporation REGiMMUNE Co., Ltd. Shionogi & Co., Ltd. JIMRO Co., Ltd. Abbott Vascular Japan Co., Ltd. |
Astellas Pharma Inc. Abbott Vascular Japan Co., Ltd. Eisai Co., Ltd. Edwards Lifesciences Corporation Otsuka Pharmaceutical Co., Ltd. Johnson & Johnson K.K. Daiichi Sankyo Company, Limited Sumitomo Dainippon Pharma Co., Ltd. Takeda Pharmaceutical Company Limited BIOTRONIK Japan, Inc. St. Jude Medical Japan Co., Ltd. Mitsubishi Tanabe Pharma Corporation Teijin Pharma Limited Nippon Boehringer Ingelheim Co., Ltd. Bayer Yakuhin, Ltd. Boston Scientific Corporation Lister CO., LTD Medtronic Japan Co., Ltd. |
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Member: Yoshiki Sawa |
TERUMO CORPORATION |
TERUMO CORPORATION (industry-university joint research) TERUMO CORPORATION (clinical trial) Nipro Corporation |
TERUMO CORPORATION Nipro Corporation |
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Member: Wataru Shimizu |
Bayer Yakuhin, Ltd. Pfizer Japan Inc. Bristol-Myers Squibb Ono Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Nippon Boehringer Ingelheim Co., Ltd. |
Astellas Pharma Inc. Eisai Co., Ltd. St. Jude Medical Japan Co., Ltd. Novartis Pharma K.K. Bayer Yakuhin, Ltd. Pfizer Japan Inc. Bristol-Myers Squibb Ono Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Mitsubishi Tanabe Pharma Corporation Nippon Boehringer Ingelheim Co., Ltd. |
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Member: Kunihiko Teraoka |
IKAROS PUBLICATIONS LTD. |
IKAROS PUBLICATIONS LTD. |
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Member: Masafumi Watanabe |
Bayer Yakuhin, Ltd. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Nippon Boehringer Ingelheim Co., Ltd. |
Astellas Pharma Inc. Bayer Yakuhin, Ltd. Ono Pharmaceutical Co., Ltd. Chugai Pharmaceutical Co.,Ltd. Medtronic Japan Co., Ltd. |
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Member: Michihiro Yoshimura |
AstraZeneca K.K. Pfizer Japan Inc. Kowa Pharmaceutical Co., Ltd. Mochida Pharmaceutical Co.,Ltd. Taisho Toyama Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Mitsubishi Tanabe Pharma Corporation FUJI YAKUHIN CO., LTD. |
Astellas Pharma Inc. Shionogi & Co., Ltd. Teijin Pharma Limited Mitsubishi Tanabe Pharma Corporation |
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Collaborator: Satoshi Hida |
Nihon Medi-Physics Co.,Ltd. FUJIFILM RI Pharma Co., Ltd. |
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Collaborator: Shungo Hikoso |
Roche Diagnostics K.K. FUJIFILM RI Pharma Co., Ltd. |
Actelion Pharmaceuticals Japan Ltd. |
Roche Diagnostics K.K. REGiMMUNE Co., Ltd. |
Astellas Pharma Inc. Abbott Vascular Japan Co., Ltd. Johnson & Johnson K.K. St. Jude Medical Japan Co., Ltd. Bayer Yakuhin, Ltd. BIOTRONIK Japan, Inc. Boston Scientific Corporation Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Teijin Pharma Limited Mitsubishi Tanabe Pharma Corporation Nippon Boehringer Ingelheim Co., Ltd. Medtronic Japan Co., Ltd. FUJIFILM RI Pharma Co., Ltd. Takeda Pharmaceutical Company Limited |
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Collaborator: Teruhiko Imamura |
TEIJIN LIMITED |
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Collaborator: Hiroko Ishida |
Calbee, Inc. | |||||||||||||
Collaborator: Makoto Kawai |
Daiichi Sankyo Company, Limited |
Daiichi Sankyo Company, Limited |
Teijin Pharma Limited Shionogi & Co., Ltd. |
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Collaborator: Takashi Kohno |
MSD K.K. Chugai Pharmaceutical Co.,Ltd. Nippon Boehringer Ingelheim Co., Ltd. Shionogi & Co., Ltd. TOA EIYO LTD. |
Bayer Yakuhin, Ltd. |
Astellas Pharma Inc. Pfizer Japan Inc. Bristol-Myers Squibb Otsuka Pharmaceutical Co., Ltd. Mitsubishi Tanabe Pharma Corporation Takeda Pharmaceutical Company Limited |
|||||||||||
Collaborator: Tsuyoshi Shiga |
TOA EIYO LTD. Bayer Yakuhin, Ltd. Bristol-Myers Squibb Daiichi Sankyo Company, Limited Nippon Boehringer Ingelheim Co., Ltd. |
Bayer Yakuhin, Ltd. Ono Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited |
Eisai Co., Ltd. | |||||||||||
Collaborator: Hitoshi Takano |
Takeda Pharmaceutical Company Limited |
St. Jude Medical Japan Co., Ltd. Daiichi Sankyo Company, Limited Nippon Boehringer Ingelheim Co., Ltd. |
||||||||||||
Collaborator: Tetsu Watanabe |
Daiichi Sankyo Company, Limited |
Pfizer Japan Inc. Astellas Pharma Inc. |
||||||||||||
Collaborator: Teppei Yamamoto |
Astellas Pharma Inc. St. Jude Medical Japan Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Nippon Boehringer Ingelheim Co., Ltd. |
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Collaborator: Shinsuke Yuasa |
Daiichi Sankyo Company, Limited |
Bayer Yakuhin, Ltd. |
Astellas Pharma Inc. Pfizer Japan Inc. Bristol-Myers Squibb Otsuka Pharmaceutical Co., Ltd. Mitsubishi Tanabe Pharma Corporation Takeda Pharmaceutical Company Limited |
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Independent Assessment Committee: Takashi Akasaka |
Amgen Astellas BioPharma K.K. Abbott Vascular Japan Co., Ltd. St. Jude Medical Japan Co., Ltd. Daiichi Sankyo Company, Limited Nippon Boehringer Ingelheim Co., Ltd. |
Daiichi Sankyo Company, Limited Infraredx |
ACIST Japan Inc. Astellas Pharma Inc. St. Jude Medical Japan Co., Ltd. Novartis Pharma K.K. eartFlow Japan G.K. Bayer Yakuhin, Ltd. Pfizer Japan Inc. Daiichi Sankyo Company, Limited |
Abbott Vascular Japan Co., Ltd. TERUMO CORPORATION Goodman Co.,LTD. St. Jude Medical Japan Co., Ltd. Boston Scientific Corporation |
||||||||||
Independent Assessment Committee: Yoshinori Doi |
Pfizer Japan Inc. Sumitomo Dainippon Pharma Co., Ltd. Daiichi Sankyo Company, Limited |
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Independent Assessment Committee: Takeshi Kimura |
Abbott Vascular Japan Co., Ltd. Sanofi K.K. Bristol-Myers Squibb Kowa Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Nippon Boehringer Ingelheim Co., Ltd. |
EP-CRSU Co., Ltd. IQVIA Services Japan K.K. Otsuka Pharmaceutical Co., Ltd. EPS Corporation |
Astellas Pharma Inc. Boston Scientific Corporation MID,Inc. Otsuka Pharmaceutical Co., Ltd. Sumitomo Dainippon Pharma Co., Ltd. Daiichi Sankyo Company, Limited Mitsubishi Tanabe Pharma Corporation Nippon Boehringer Ingelheim Co., Ltd. Takeda Pharmaceutical Company Limited |
|||||||||||
Independent Assessment Committee: Masafumi Kitakaze |
AstraZeneca K.K. Novartis Pharma K.K. Pfizer Japan Inc. Ono Pharmaceutical Co., Ltd. Mitsubishi Tanabe Pharma Corporation Takeda Pharmaceutical Company Limited |
AstraZeneca K.K. Boehringer Ingelheim International GmbH KUREHA CORPORATION Mitsubishi Tanabe Pharma Corporation Nippon Boehringer Ingelheim Co., Ltd. Takeda Pharmaceutical Company Limited |
Takeda Pharmaceutical Company Limited |
|||||||||||
Independent Assessment Committee: Masami Kosuge |
Daiichi Sankyo Company, Limited |
|||||||||||||
Independent Assessment Committee: Morimasa Takayama |
Daiichi Sankyo Company, Limited |
Notation of corporation is omitted.
No potential COI for the following members.
Member: Noboru Fujino
Member: Taiki Higo
Member: Tomomi Ide
Member: Hatsue Ishibashi-Ueda
Member: Chizuko Kamiya
Member: Seiya Kato
Member: Shintaro Kinugawa
Member: Shigetoyo Kogaki
Member: Shouji Matsushima
Member: Miyuki Tsuchihashi-Makaya
Collaborator: Arata Fukusima
Collaborator: Toshiro Kitagawa
Collaborator: Satoshi Kurisu
Collaborator: Hiroyuki Morita
Collaborator: Yoji Nagata
Collaborator: Makiko Nakamura
Collaborator: Yasuyoshi Takei
Independent Assessment Committee: Hitonobu Tomoike