JCS 2017/JHFS 2017 Guideline on Diagnosis and Treatment of Acute and Chronic Heart Failure　― Digest Version ―

Abbreviations

ACC	American College of Cardiology
ACCF	American College of Cardiology Foundation
ACE	angiotensin converting enzyme
ACP	advance care planning
ACS	acute coronary syndrome
ADL	activities of daily livings
AHA	American Heart Association
AHI	apnea hypopnea index
ANP	atrial (A-type) natriuretic peptide
ARB	angiotensin II receptor blocker
ASV	adaptive servo-ventilation
BNP	brain (B-type) natriuretic peptide
CABG	coronary artery bypass grafting
CKD	chronic kidney disease
COPD	chronic obstructive pulmonary disease
CPAP	continuous positive airway pressure
CRT	cardiac resynchronization therapy
CS	clinical scenario
CSA	central sleep apnea
CSR	Cheyne-Stokes respiration
CT	computed tomography
DOAC	direct oral anticoagulant
ECMO	extracorporeal membrane oxygenation
ESA	erythropoiesis stimulating agent
ESC	European Society of Cardiology
FiO2	fraction of inspiratory oxygen
HF	heart failure
HFmrEF	heart failure with mid-range ejection fraction
HFpEF	heart failure with preserved ejection fraction
HFrecEF	heart failure with recovered ejection fraction
HFrEF	heart failure with reduced ejection fraction
IABP	intra-aortic balloon pump
ICD	implantable cardioverter defibrillator
IL	interleukin
JCS	Japanese Circulation Society
LVAD	left ventricular assist device
LVEF	left ventricular ejection fraction
MBP	mean arterial pressure
MRA	mineralocorticoid receptor antagonist
MRI	magnetic resonance imaging
NPPV	noninvasive positive pressure ventilation
NSAID	nonsteroidal anti-inflammatory drug
NT-proBNP	N-terminal pro-brain (B-type) natriuretic peptide
NYHA	New York Heart Association
OSA	obstructive sleep apnea
PaO2	arterial partial pressure of oxygen
PCI	percutaneous coronary intervention
PCPS	percutaneous cardiopulmonary support
PDE	phosphodiesterase
QOL	quality of life
SBP	systolic blood pressure
SDB	sleep-disordered breathing
SGLT	single-photon emission computed tomography
SPECT	Evaluation of LIXisenatide in Acute Coronary Syndrome
SpO2	oxygen saturation
TAVI	transcatheter aortic valve implantation
TAVR	transcatheter aortic valve replacement
VAD	ventricular assist device

Preamble

In Japan, the Japanese Circulation Society (JCS) published the “Guidelines for Treatment of Chronic Heart Failure” and the “Guidelines for Treatment of Acute Severe Heart Failure” in 2000, and revised the guidelines for chronic heart failure in 2005 and 2010 to reflect new evidence. In 2011, the JCS published “Guidelines for Treatment of Acute Heart Failure” as a revision of the Guidelines for Treatment of Acute Severe Heart Failure. Similarly to the revised guidelines published by the European Society of Cardiology (ESC) in 2012¹ and the American Heart Association (AHA), the revised guideline covered all aspects of heart failure (Table 1). In the United States, the American College of Cardiology (ACC) and the AHA published the Guidelines for the Evaluation and Management of Heart Failure² in 1995, and revised them in 2001,³ 2005,⁴ and 2009.⁵ The 2009 revision added a new section “the Hospitalized Patient” to align with the 2008 ESC Guideline⁶ and covered acute heart failure. The ACC/AHA revised the guideline in 2013⁷ and 2017.⁸ In Europe, the ESC published the Guidelines for the Diagnosis of Heart Failure⁹ in 1995, and the Treatment of Heart Failure¹⁰ in 1997. In 2001, the ESG revised these documents to publish as one document, the Guidelines for the Diagnosis and Treatment of Chronic Heart Failure¹¹ and revised the document in 2005.¹² In 2005, the ESC published the Guidelines on the Diagnosis and Treatment of Acute Heart Failure,¹³ and then published the Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure to cover both acute and chronic heart failure,⁶ and revised them in 2012¹ and 2016.¹⁴ The ESC’s categorization in heart failure guidelines substantially affected guidelines on acute heart failure published by the AHA and JCS.

Table 1. History of Heart Failure Guidelines in Japan and Western Countries

Year	Japan (The Japanese Circulation Society)	U.S. (ACC/AHA)	EU (ESC)
1995		ACC/AHA guidelines for the evaluation and management of heart failure (Chair: Williams)2	Guidelines for the diagnosis of heart failure (The Task Force on Heart Failure of the European Society of Cardiology)9
1997			The treatment of heart failure (Task Force of the Working Group on Heart Failure of the European Society of Cardiology)10
2000	Guidelines for Treatment of Chronic Heart Failure (Chair: Matsuzaki) Guidelines for Treatment of Severe Acute Heart Failure (Chair: Takekoshi)
2001		ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult (Chair: Hunt)3	Guidelines for the diagnosis and treatment of chronic heart failure (CoChair: Remme and Swedverg),11 covering both diagnosis and treatment
2005	Guidelines for Treatment of Chronic Heart Failure (Chair: Matsuzaki), revised version	ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult (Chair: Hunt)4	Guidelines for the diagnosis and treatment of chronic heart failure (Chair: Swedberg)12 Guidelines on the diagnosis and treatment of acute heart failure (Chair: Nieminen)13
2006	Guidelines for Treatment of Acute Heart Failure (Chair: Maruyama), revised version
2008			Guidelines for the diagnosis and treatment of acute and chronic heart failure (Chair: Dickstein)6
2009		A revised version that contains a new section “The Hospitalized Patient”5
2010	Guidelines for Treatment of Chronic Heart Failure (Chair: Matsuzaki), revised version
2011	Guidelines for Treatment of Acute Heart Failure (Chair: Izumi), revised version
2012			ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 (Chair: McMurray),1 as a revision of the previous version
2013		2013 ACCF/AHA Guideline for the Management of Heart Failure (Chair: Yancy)7
2016			ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2016 (Chair: Ponikowski)14
2017		2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure (Chair: Yancy)8
2018	Guidelines for diagnosis and treatment of acute and chronic heart failure (Chair: Tsutsui), revised version

ACC, American College of Cardiology; ACCF, American College of Cardiology Foundation; AHA, American Heart Association; ESC, European Society of Cardiology.

This revised version of “the Guidelines for Diagnosis and Treatment of Acute and Chronic Heart Failure” was prepared as joint guidelines by the JCS and the Japanese Heart Failure Society (JHFS). The working committee for this project includes members and collaborators involved in the previous versions of the heart failure guidelines and members recommended from 11 societies (the JCS, the JHFS, the Japanese Association for Thoracic Surgery, the Japanese Society of Hypertension, the Japanese Society of Echocardiography, the Japanese Society for Cardiovascular Surgery, the Japanese College of Cardiology, the Japanese Association of Cardiac Rehabilitation, the Japan Society of Ultrasonics in Medicine, the Japan Diabetes Society, and the Japanese Heart Rhythm Society). Also, the working group includes members of “the Study Group on Idiopathic Cardiomyopathy” supported by the Health and Labor Sciences Research Grant on Intractable Diseases and those of “the Study Group on the Multi-center Observational Study of Dilated- phase Hypertrophic Cardiomyopathy”, supported by the “Practical Research Project for Rare/intractable Diseases by the Japan Agency for Medical Research and Development”.

The working group started the process of fully revising the guideline from October 2016, and developed the first draft in January 2017. Members and collaborators reviewed the guideline according to a total of 885 comments based on blinded review, revised 5 times, and further revised according to a total of 141 comments from the independent assessment committee, before being finalized after detailed discussions at 3 study group meetings. The present guidelines intend to describe standard practice for acute and chronic heart failure according to latest information provided in Western guidelines and the evidence and clinical experience accumulated in Japan.

We hope that this document will help all healthcare professionals involved in the diagnosis and treatment of heart failure.

I. Introduction

1. Classes of Recommendations and Levels of Evidence

Classification of recommendations and levels of evidence are described similarly to our previous heart failure guidelines using a style similar to those used in the ACC/AHA guidelines and the ECS guidelines (Tables 2 and 3). In Japan, guidelines for cardiovascular diseases have extensively used a common style that is highly consistent with Western guidelines. On the other hand, the Japan Council for Quality Health Care uses a different style in its Medical Information Network Distribution Service (MINDS) to show grades of recommendations and levels of evidence as described in the “Minds Handbook for Clinical Practice Guideline Development 2007” (Tables 4 and 5).¹⁵ Accordingly, the present document shows classification of recommendations and level of evidence in the tables including both styles; class of recommendation, level of evidence, grade of recommendation (MINDS) and level of evidence (MINDS).

Table 2. Classes of Recommendations

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

Table 3. Level of Evidence

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

Table 4. MINDS Grades of Recommendations

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. 2007¹⁵)

Table 5. MINDS Levels of Evidence (Levels of Evidence in Literature on Treatment)

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. 2007¹⁵)

2. Major Revisions of the Present Guidelines

The most important change is that the guidelines on acute heart failure and chronic heart failure are provided in one document, rather than the conventional two separate documents. This reflects our consensus that describing guidelines in two separate documents are not practical since many cases of acute heart failure represents acute worsening of chronic heart failure, and patients require seamless treatment from acute to chronic phase.

In the present guidelines, the following major revisions were made:

1) The definition of heart failure is further clarified, and an easy-to-understand definition is provided for general population. (Section “ 1. Definition and Classification ” in Chapter “ II. General Principles ”).

2) Stages of heart failure, its risk factors, and treatment goals are described (Section “ 1. Definition and Classification ” in Chapter “ II. General Principles ” and Chapter “ V. Basic Principles for the Treatment of Heart Failure ”).

3) In the classification of heart failure based on left ventricular ejection fraction (LVEF), a new category of heart failure with mid-range ejection fraction (HFmrEF) defined as a LVEF of 40–49%, is added to the conventional two categories of heart failure with reduced ejection fraction (HFrEF), and heart failure with preserved ejection fraction (HFpEF). Another category of patients in whom LVEF recovered after treatment, described as “HFpEF, improved” or “HF with recovered EF”, is added as well (Section “ 1. Definition and Classification ” in Chapter “ II. General Principles ”).

4) An algorithm for the diagnosis of heart failure is newly presented (Section “ 1. Diagnosis ” in Chapter “ III. Diagnosis ”).

5) A new chapter is added to describe how to prevent heart failure for each stage of heart failure (Chapter “ IV. Prevention of Heart Failure ”).

6) An algorithm for the treatment of heart failure is newly presented (Chapter “ V. Basic Principles for the Treatment of Heart Failure ”.

7) Pathophysiology and treatment of comorbidities are described in detail (Chapter “ IX. Pathophysiology and Treatment of Comorbidities ”).

8) A flowchart of the treatment and clinical course over time of acute heart failure is newly presented (Chapter “ X. Acute Heart Failure ”).

9) A flowchart on the use of ventricular assist devices for patients with severe heart failure is newly presented (Chapter “ XI. Surgical Treatment ”).

10) Palliative care is described in detail (Chapter “ XIII. Palliative Care ”)

II. General Principles

1. Definition and Classification

1.1 Definition of Heart Failure

Heart failure is defined as a clinical syndrome consisting of dyspnea, malaise, swelling and/or decreased exercise capacity due to the loss of compensation for cardiac pumping function due to structural and/or functional abnormalities of the heart (Table 6).

Table 6. Definition of Heart Failure (HF)

Definition of HF in the present guidelines	Clinical syndrome consisting of dyspnea, malaise, swelling and/or decreased exercise capacity due to the loss of compensation for cardiac pumping function due to structural and/or functional abnormalities of the heart
Definition of HF for the public (Patient-friendly version)	Heart failure is a heart disease that causes shortness of breath and swelling, gets worse with time, and shortens life expectancy.

Heart failure is a disease condition where the heart is unable to fill with and eject enough blood for various reasons such as epicardial, myocardial or endocardial lesions, valvular disease, coronary arterial disease, aortic disease, arrhythmias, and endocrine disorders. However, in many cases left ventricular dysfunction is associated with heart failure, and is the most important factor in determining monitoring and treatment strategies. Heart failure should thus be defined and classified according to left ventricular function.

The Japanese Circulation Society has decided to classify heart failure mainly according to left ventricular ejection fraction in the present guidelines for the treatment of acute heart failure and chronic heart failure as the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) and the European Society of Cardiology (ESC) do in their guideline documents.^7,16 Heart failure with reduced left ventricular ejection fraction (HFrEF) and heart failure with preserved left ventricular ejection fraction (HFpEF) are defined as follows (Table 7).^7,16

Table 7. Classification of Heart Failure by Left Ventricular Ejection Fraction (LVEF)

Definition	LVEF	Description
Heart failure with reduced ejection fraction (HFrEF)	<40%	The main feature is systolic dysfunction. In many clinical studies, patients with a low LVEF despite standard medical treatment for heart failure are enrolled as patients with HFrEF.
Heart failure with preserved ejection fraction (HFpEF)	≥50%	The main feature is diastolic dysfunction. Other diseases that may cause similar symptoms should be ruled out. No effective treatments have been established.
Heart failure with mid-range ejection fraction (HFmrEF)	40 to <50%	Borderline heart failure. Clinical features and prognosis have not yet been fully characterized. Treatment should be selected on an individual basis.
Heart failure with preserved ejection fraction, improved (HFpEF improved) or heart failure with recovered EF (HFrecEF)	≥40%	Patients with an improvement of LVEF from <40% to ≥40% after treatment. It has been suggested that these patients may have a different prognosis from those with HFrEF, but further studies are required.

(Source: Prepared based on Yancy CW, et al. 2013⁷ and Ponikowski P, et al. 2016¹⁶)

1.1.1 HFrEF

In many large-scale clinical studies in heart failure, HFrEF was defined as heart failure with a left ventricular ejection fraction (LVEF) of ≤35% or <40. In the present guidelines, HFrEF is defined as heart failure with a LVEF of <40%.

HFrEF is characterized with the high prevalence of left ventricular enlargement, which is present in more than 50% of patients, and the relatively high prevalence of left ventricular diastolic dysfunction.

1.1.2 HFpEF

It has been reported that about half of patients with symptomatic heart failure have normal or preserved LVEF.¹⁷ In this guideline document, HFpEF is defined as heart failure with a LVEF of ≥50% to differentiate it clearly from HFrEF. HFpEF may be caused by arrhythmias such as atrial fibrillation, coronary heart disease, diabetes mellitus, and dyslipidemia, but the most common cause of HFpEF is hypertension.¹⁸

Patients with a mild reduction in LVEF may present some degree of systolic dysfunction, but their clinical manifestations are often similar to those of HFpEF. However, unlike patients with HFpEF, such patients with borderline LVEF may respond well to treatments that have been demonstrated to be effective in the treatment of systolic dysfunction in HFrEF. Accordingly, this condition is defined as heart failure with mid-range LVEF (HFmrEF) or HFpEF borderline. In the present guidelines, HFmrEF is defined as heart failure with a LVEF of 40 to 49%.

In some patients with heart failure initially presented with low LVEF, the LVEF may improve over time during treatment or follow-up. This type of heart failure is referred to as “HFpEF improved” or “HF with recovered EF” (HFrecEF).¹⁹ This type of heart failure is often observed in patients with tachycardia-induced cardiomyopathy mainly due to tachycardiac atrial fibrillation, ischemic heart disease, or dilated cardiomyopathy whose cardiac function has improved with β-blockers. In these patients, left ventricular systolic and/or diastolic function, cardiothoracic ratio (CTR), and brain (B-type) natriuretic peptide (BNP) may return to normal levels.

1.2 Stages of Heart Failure

The ACCF/AHA Stages of Heart Failure⁷ is widely used to determine the progression stage of heart failure. The ACCF/AHA created this staging system to help physicians make appropriate treatment intervention, and encourages to treat patients at high risk earlier even when they are asymptomatic. In this guidelines, four stages of heart failure are used according to the ACCF/AHA Stages of Heart Failure: Stage A, asymptomatic patients at high risk of developing heart failure without structural heart disease; Stage B, patients with asymptomatic heart failure who have structural heart disease; Stage C, patients with symptomatic heart failure and structural heart disease, including those with a history of heart failure; and Stage D, patients with refractory heart failure who have had New York Heart Association (NYHA) Class III or IV heart failure despite all available drug therapy or nonpharmacologic therapy with proven efficacy, and are hospitalized for heart failure at least twice a year (Figure 1).²⁰

Figure 1.

Stages in the development and progression of heart failure and treatment goals by stage. ACCF, American Collage of Cardiology Foundation; AHA, American Heart Association; HF, heart failure; LVEF, left ventricular ejection fraction; QOL, quality of life. (Adapted from The Ministry of Health, Labour and Welfare. 2017²⁰ with modifications)

Table 8 outlines a comparison between the JCS stages of heart failure and the NYHA functional classification.^7,20a

Table 8. Comparison Between the Stages of Heart Failure and the NHYA Functional Classification

Stages of HF	NYHA Functional Classification20a
A. At high risk for HF but without organic heart disease	None
B. At high risk for HF and with organic heart disease	None
C. Symptomatic heart failure	I. No limitation of physical activity. Ordinary physical activity does not cause severe fatigue, palpitations, dyspnea or angina.
	II. Slight or moderate limitation of physical activity. Comfortable at rest, but ordinary physical activity causes fatigue, palpitations, dyspnea or angina.
	III. Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitations, dyspnea or angina.
	IV. Unable to carry on any physical activity without symptoms of HF, or symptoms of HF and angina at rest. Even slight activity worsens symptoms.
D. Refractory heart failure	III. Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitations, dyspnea or angina.
	IV. Unable to carry on any physical activity without symptoms of HF, or symptoms of HF and angina at rest. Even slight activity worsens symptoms.

The NYHA functional classification was developed by the New York Heart Association as a system to classify patients with heart diseases according to the severity of symptoms resulting from physical activity, and has been used in the severity classification of heart failure. NYHA class II patients further classified into those with slight limitation of physical activity (IIs) and those with moderate limitation of physical activity (IIm). HF, heart failure; JCS, Japanese Circulation Society; NYHA, New York Heart Association. (Source: Prepared based on Yancy CW, et al. 2013⁷)

1.3 Classification of Heart Failure

The Forrester classification is one of the most common used criteria to classify the severity of heart failure according to hemodynamic measures (Figure 2).²¹ It was originally developed to predict the prognosis of patients with acute heart failure due to acute myocardial infarction, and the correlation between this severity classification and mortality rate has been demonstrated. The Forrester classification is based on objective measures of organ perfusion and congestion and is thus useful in the assessment of pathophysiological condition of non-ischemic heart failure, but invasive measurements are necessary.

Figure 2.

Forrester classification. (Source: Prepared based on Forrester JS, et al. 1976²¹)

Alternatively, the Nohria-Stevenson classification that can assess the severity of heart failure more easily based only on physical findings is commonly used to assess the risk profile of patients with heart failure according to their peripheral hemodynamics and lung auscultation findings (Figure 3).²²

Figure 3.

Nohria-Stevenson classification. (Adapted from Nohria A, et al. 2003²² with modifications)

2. Epidemiology, Etiology, and Prognosis

Heart diseases are the second leading cause of death in Japan, next to malignancy (cancer). Heart failure is the most common cause of death from heart disease.²³ According to a report of the Japanese registry of all cardiac and vascular diseases, the Japanese Registry of All cardiac and vascular Diseases (JROAD) 2015 study,²⁴ the total number of patients hospitalized for heart failure in medical and educational institutions was 238,840 patients in 2015, showing an increase by more than 10,000 each year. The ratio of patients with acute and chronic heart failure was about half and half. Although there are no accurate statistics on the total number of patients with heart failure in Japan, it has been estimated that the number was about 1 million in 2005 and will reach 1.2 million by 2020.²⁵ As the corresponding number in the United States was estimated to be about 5 million in 2005,^26,27 the prevalence of heart failure may be relatively lower in Japan than in the United States. However, it is highly likely that heart failure will increasingly become more common in Japan as the population ages.

In Japan, large-scale registry studies such as the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD; patients registered from 2004 to 2005),²⁸ Chronic Heart failure Analysis and Registry in Tohoku district-1 (CHART-1; 2000 to 2004),²⁹ and CHART-2 (2006 to 2010)^30,31 have been conducted. The average age of registered patients was 71 years in the JCARE-CARD study, 69 years in the CHART-1 study, and 69 years among Stage C or D heart failure in the CHART-2 study, indicating that elderly people account for large percentages of the registered patients.

An observational study in the United States has reported that LVEF was maintained at ≥50% in nearly half of patients with heart failure.¹⁷ In Japan, patients with HFpEF account for more than 50% of all patients with heart failure, and this percentage tends to increase in recent years.³⁰ The prognosis of patients with HFpEF has been reported to be poor similarly, although not identically, to those with HFrEF.^32,33 Physicians should be aware that HFpEF will likely become even more common in the super-aged society.

A variety of diseases cause heart failure (Table 9). Almost all types of heart diseases may lead to heart failure. Heart failure may also result from systemic diseases and myocardial injury due to external causes. The most common cause of heart failure is ischemic heart disease, which is followed by hypertension, and valvular diseases.^28–30 Heart failure due to ischemic heart disease is becoming more common,²⁹ while hypertension is considered as the most common cause of HFpEF.³⁴

Table 9. Causes of Heart Failure

Myocardial disease
Ischemic heart disease 　Ischemic cardiomyopathy, stunning, hibernation, microcirculatory disorder
Cardiomyopathy (including genetic forms) 　Hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, noncompaction, takotsubo cardiomyopathy
Cardiotoxic substances and other factors 　• Addictive and abused substances 　　Alcohol, cocaine, amphetamines, anabolic steroids 　• Heavy metals 　　Copper, iron, lead, cobalt, mercury 　• Drugs 　　Antitumor drugs (e.g., anthracycline), immunosuppressive drugs, antidepressant drugs, antiarrhythmic drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), anesthetic drugs 　• Radiation damage
Infectious diseases 　• Myocarditis 　　e.g., viral, bacterial or rickettsial infections; Chagas’ disease
Immune disorders 　　e.g., rheumatoid arthritis, systemic lupus erythematosus, polymyositis, mixed connective tissue disease
Pregnancy 　• Peripartum cardiomyopathy 　　Including puerperal cardiomyopathy
Infiltrative diseases 　Sarcoidosis, amyloidosis, hemochromatosis, invasive malignant tumors
Endocrine disorders 　e.g., hyperthyroidism, Cushing’s disease, pheochromocytoma, adrenal insufficiency, abnormal growth hormone secretion
Metabolic disorders 　Diabetes mellitus
Congenital enzyme abnormality 　Fabry’s disease, Pompe’s disease, Hurler’s syndrome, Hunter’s syndrome
Muscle disorders 　Muscular dystrophy, laminopathy
Abnormal hemodynamics
Hypertension
Valvular disease, cardiac structural abnormality 　• Congenital conditions 　　Congenital valvular disease, atrial septal defect, ventricular septal defect, other congenital heart diseases 　• Acquired conditions 　　Aortic valve disease, mitral valve disease
Epicardial abnormalities other related conditions 　Constrictive pericarditis, cardiac tamponade
Endocardial abnormalities 　Eosinophilic endomyocardial disease, endocardial fibroelastosis
High-output heart failure 　Severe anemia, hyperthyroidism, Paget’s disease, arteriovenous shunt, pregnancy, beriberi heart
Increased fluid volume 　Renal failure, excessive transfusion
Arrhythmias
• Tachyarrhythmias 　e.g., atrial fibrillation, atrial tachycardia, ventricular tachycardia • Bradyarrhythmias 　e.g., sick sinus syndrome, atrioventricular block

In the assessment of prognosis in the JROAD 2015, in-hospital mortality in patients hospitalized for heart failure was about 8%.²⁴ One-year all-cause mortality in patients with heart failure was 7.3% in the JCARE-CARD and CHART-1 studies. The high rate of rehospitalization due to worsening heart failure is another problem.

According to the JROAD report that described the epidemiology of acute heart failure in Japan, the number of patients hospitalized for acute heart failure was 85,512 in 2013 and increased substantially to 107,049 in 2016.²⁴

The epidemiology of acute heart failure in Japan has been extensively studied in the Heart Institute of Japan Department of Cardiology – Heart Failure (HIJC-HF) registry,³⁵ the JCARE-CARD study,²⁸ and the Acute Decompensated Heart Failure Syndromes (ATTEND) registry³⁶ in chronological order. The average age of registered patients was over 70 years in all these studies, and many patients had hypertension, diabetes mellitus, dyslipidemia and/or atrial fibrillation. The most common cause of acute heart failure was ischemic heart disease, which accounted for >30% in all studies. As compared with epidemiological findings in other countries, patients with acute heart failure in Japan do not differ substantially from those in other countries in terms of age, gender ratio, and prevalence of hypertension, diabetes, and dyslipidemia.^37,38 However, it should be noted that the prevalence of ischemic heart disease as an underlying cardiac condition is lower in Japanese patients than those in Western countries, while the prevalence of hypertensive heart disease is higher in Japanese patients than Western patients.

Gender differences should be considered in the diagnosis and treatment of heart failure. Both the results of registry studies in Japan and data in Western countries have indicated that women have a better prognosis than men when adjusted for background characteristics of patients.^39–42 In Japan where the population is aging rapidly, more women are expected to experience heart failure, but there are only limited data available on gender difference in the treatment of heart failure.

III. Diagnosis

1. Diagnosis (Algorithms) (Figure 4)

Figure 4.

Flowchart for the diagnosis of chronic heart failure. BNP, brain (B-type) natriuretic peptide; CT, computed tomography; ECG, electrocardiogram; HF, heart failure; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro-brain (B-type) natriuretic peptide.

In the diagnosis of heart failure, patients should be examined first for symptoms, medical history, their family history, physical findings, ECG, and chest X-ray findings.

Next, the concentration of brain (B-type) natriuretic peptide (BNP) or N-terminal pro-brain (B-type) natriuretic peptide (NT-proBNP) in the blood should be determined. Figure 4 outlines the cut-off levels of BNP and NT-proBNP for the diagnosis of heart failure.⁴³ However, physicians should be aware that BNP and NT-proBNP levels may be lower than these cut-off levels in patients with mild heart failure or patients with severe obese and heart failure. Accordingly, echocardiography is a reasonable diagnostic method to examine for heart failure even in patients with a BNP of ≥35 or 40 pg/mL or a NT-proBNP of ≥125 pg/mL who are strongly suspected to have heart failure according to their symptoms, patient history or underlying conditions, physical findings, ECG or chest X-ray findings. Patients should be examined comprehensively to determine whether additional examinations should be conducted or not. Echocardiography should be performed in patients who have heart murmur suggestive of valvular disease or abnormal ECG findings clearly indicative of the presence of old myocardial infarction regardless of the level of BNP or NT-proBNP.

Stress echocardiography should also be considered for patients who complain of symptoms inconsistent with echocardiographic findings at rest. When the causative disease cannot be identified with echocardiography, other modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and nuclear imaging should be used. Since some patients with ischemic heart disease may present only with shortness of breath on effort, patients in whom ischemic heart disease cannot be ruled out should be examined for myocardial ischemia using exercise or pharmacological stress test.

Patients confirmed to have heart failure should receive appropriate treatment according to the causative disease and the stage of heart failure.

2. Symptoms and Signs

Patients with acute heart failure often show symptoms associated with pulmonary venous congestion due to increased left ventricular end-diastolic pressure or increased left atrial pressure, and/or systemic venous congestion due to increased right atrial pressure, as well as symptoms associated with decreased cardiac output. The Framingham criteria for the diagnosis of heart failure are based on symptoms and findings of left heart failure, right heart failure, and low cardiac output (Table 10).⁴⁴ Patients’ symptoms and physical findings should be categorized accordingly to assess their pathophysiological condition (Table 11). Patients with bilateral cardiac failure show signs and symptoms of both left- and right-sided heart failure. The jugular venous pressure can be estimated based on the vertical distance between the horizontal lines drawn from the highest point of internal jugular venous pulse and the sternal angle when the patient is positioned at a 45° incline (Figure 5). The sternal angle is positioned about 5 cm above the right atrium. A vertical distance between the sternal angle and the top of the jugular venous pulse of ≥3 cm indicates an increased central venous pressure.

Table 10. Criteria for Diagnosis of Heart Failure: Framingham Criteria

Major criteria	Major or minor criteria	Minor criteria
Paroxysmal nocturnal dyspnea	Weight loss of 4.5 kg or more in 5 days in response to treatment. When the weight loss is attributable to the treatment of heart failure, it is considered 1 major criterion. Otherwise it is considered a minor criterion.	Lower leg edema
Jugular venous distention		Nocturnal cough
Pulmonary rale		Dyspnea on ordinary exertion
Cardiomegaly on chest X-ray		Hepatomegaly
Acute pulmonary edema		Pleural effusion
Protodiastolic gallop (S3 gallop)		Decrease in vital capacity by one third from maximum recorded
Increased central venous pressure (≥16 cm H2O)		Tachycardia (heart rate ≥120 bpm)
Increased circulation time (≥25 sec)
Hepatojugular reflux
(Pulmonary edema, visceral congestion of cardiomegaly on autopsy)

Diagnosis of heart failure requires the simultaneous presence of at least 2 major criteria or 1 major criterion in conjunction with 2 minor criteria. (Source: Prepared based on Mckee PA, et al. 1971⁴⁴)

Table 11. Symptoms and Signs of Heart Failure

Congestion
Left-sided heart failure	Symptoms	Dyspnea, shortness of breath, tachypnea, orthopnea
	Signs	Bubbling rales, wheezing, pink foamy sputum, third or fourth heart sound
Right-sided heart failure	Symptoms	Right hypochondrium pain, anorexia, abdominal swelling, epigastric discomfort
	Signs	Hepatomegaly, increased hepatobiliary enzymes, jugular venous distention. Signs of pulmonary congestion are not apparent in patients with severe right heart failure.
Low output
Symptoms		Disturbance of consciousness, restlessness, memory disorder
Signs		Cold sweat, cold extremities, cyanosis, hypotension, oliguria, agitated or confused

Figure 5.

How to estimate jugular venous pressure.

The New York Heart Association (NYHA) Functional Classification provides a simple method of classifying the severity of heart failure based on the patient’s symptoms and categorizes patients with heart failure into four groups from Class I to IV. The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines categorize patients with heart failure into four categories from Stage A (asymptomatic patients at risk for heart failure) to Stage D (patients with refractory heart failure and severe symptoms even at rest) (Table 8⁷ in Section “ 1. Definitions and Classification ” in “ II. General Principles ”, and Section “ 8.1. NYHA Functional Classification ” in this chapter). These two classifications are different in nature, but are generally well correlated as can be seen in Table 8.⁷

3. Biomarkers (Table 12)

Table 12. Recommendations and Levels of Evidence for the Use of Biomarkers in Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (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.

Among currently available biomarkers for heart failure, BNP and NT-proBNP are the most significant biomarkers for heart failure and have been used extensively for screening, diagnosis, and prognosis assessment of this condition.

3.1 Biomarkers Reflecting Sympathetic Activity

In patients with heart failure, the sympathetic nervous system is overactivated. Congestion and other conditions caused by heart failure reduce the clearance of noradrenaline, and thereby increase noradrenaline levels in the blood. Plasma noradrenaline levels are an indicator of sympathetic activity of the whole body and may be used to assess the prognosis of patients with heart failure.⁴⁵

3.2 Biomarkers Reflecting the Renin-Angiotensin-Aldosterone System Activity

In patients with heart failure, the renin-angiotensin-aldosterone (RAA) system is overactivated, and angiotensin II is produced excessively. Plasma renin activity may be high in some patients with mild cardiac dysfunction, and may not be high even in patients with severe heart failure. This finding suggests that the tissue RAA system may be activated independently of the circulatory RAA system to play a role in cardiac remodeling.^46–48

On the other hand, aldosterone levels in the blood are not necessarily high in patients with heart failure, and thus cannot be used as a sensitive marker of heart failure. However, there are many unclear points concerning the secretion and action of aldosterone in heart failure, and the significance of aldosterone/mineral corticoid receptor cascade, including the activation of mineral corticoid receptors, should not be underestimated.^49–51 Measurements of renin activity and aldosterone levels is strongly recommend in the diagnosis and treatment of hypertension, and is also expected to help physicians understand the cause and pathophysiology of heart failure.

3.3 Natriuretic Peptides

Natriuretic peptides include atrial (A-type) natriuretic peptide (ANP), BNP, and C-type natriuretic peptide (CNP). ANP and BNP are cardiac hormones that are synthesized mainly in the atrium and ventricle, respectively.^52–54 ANP secretion is stimulated by atrial stretch, while BNP secretion is stimulated mainly by ventricular load. Accordingly, BNP levels in the blood reflect the degree of ventricular burden, and thus can be used as a sensitive biochemical marker.^54–57

Plasma levels of ANP and BNP are high in patients with heart failure because the production of these peptides is enhanced in the heart and their clearance from the blood is delayed. ANP and BNP are degraded through internalization after binding to the natriuretic peptide receptor C (NPR-C) or metabolized by neutral endopeptidase (NEP). No clear relationship has been shown between the metabolism of ANP and BNP and the pathophysiology of heart failure, but the clearance of these peptides is low in patients with renal dysfunction. When comparing BNP and its N-terminal fragment NT-ProBNP, a precursor of BNP with a larger molecular weight, the effect of renal dysfunction is more substantial on NT-proBNP than on BNP (Table 13).

Table 13. Comparison of BNP and NT-proBNP

	BNP	NT-proBNP
Molecular weight	ca. 3,500	ca. 8,500
Hormonal activity	+	−
Cross-reactivity	proBNP
Half-life	About 20 minutes	About 120 minutes
Clearance	NPR-C, NEP, renal	Renal
Blood samples	EDTA plasma	Serum/heparinized or EDTA plasma
Reference level	≤18.4 pg/mL	≤55 pg/mL
Factors that increase BNP and NT-proBNP levels*	Cardiac dysfunction, renal dysfunction, advanced age, systemic inflammation
Factors that decrease BNP and NT-proBNP levels*	Obesity

*Indicating only typical factors that increase or decrease BNP and NT-proBNP levels. Some factors may affect BNP and NT-proBNP levels differently and further studies are needed to characterize the effects of these factors.

BNP, brain (B-type) natriuretic peptide; EDTA; ethylenediamine tetraacetic acid; NEP, neutral endopeptidase; NPR-C, natriuretic peptide receptor-C; NT-proBNP, N-terminal pro-brain (B-type) natriuretic peptide.

BNP is superior to ANP in terms of the sensitivity and specificity as a supportive diagnostic marker for heart failure.⁵⁸ BNP (or NT-proBNP) is useful in confirming the presence and classifying the severity of heart failure, as well as in assessing the prognosis of patients with heart failure.^59–64 It also plays a substantial role as a marker to monitor the efficacy of treatment over time in individual patients who may not compare with others.

The Japanese Heart Failure Society has published a statement entitled “Points to consider when using BNP and NT-pro BNP levels in the blood for the diagnosis and treatment of heart failure” (Figure 6).⁴³ This publication set a cut-off point of 40 pg/mL for plasma BNP concentration (125 pg/mL for NT-proBNP⁴³) to identify patients susceptible to heart failure according to the results of the J-ABS multicenter study, although the upper normal limit for plasma BNP is set at 18.4 pg/mL (55 pg/mL for NT-pro BNP).^65,66 Plasma BNP levels differ among individuals, and tend to remain low in obese patients in whom the severity of heart failure may be underestimated.

Figure 6.

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. (Adopted from Japanese Heart Failure Society⁴³)

3.4 Markers for Myocardial Injury

Cardiac troponin I and T levels in the blood, which are used as biomarkers for myocardial infarction, have been pointed out to increase in patients with non-ischemic myocardial diseases. Continued increase in troponin levels in the blood indicate a poor prognosis.^67,68 High-sensitivity troponin assays are useful in the diagnosis of acute coronary syndrome,^69,70 and are expected also useful in risk assessment in patients with chronic heart failure.^71,72

3.5 Inflammatory Markers

It has been pointed out that immune cells and their production of cytokines are involved in the development of heart failure. In fact, blood levels of tumor necrosis factor (TNF) α and interleukin (IL)-6 are elevated in patients with heart failure, and also are related to their prognosis.^73–75 A report has described that high-sensitivity C-reactive protein (CRP) levels is related to the prognosis of heart failure regardless of whether patients have underlying diseases or not.⁷⁶ In Western countries, a rapid test for ST2, a receptor for IL-33 that is a member of IL-1 family, has been used. Elevated blood levels of ST2 have been reported in patients with acute heart failure, and this is expected to be useful in prognostic assessment of heart failure.⁷⁷

3.6 Oxidative Stress Markers

It is considered that oxidative stress is enhanced in patients with heart failure, and causes endothelial damage and cardiac dysfunction. Reports have described that low density lipoprotein (LDL) levels in the blood and levels of 8-isoprostagrandin F2α (also known as 8-iso-PGF2α or 8-isoprostane) and 8-hydroxy-2’-deoxyguanosine (8-OHdG) in the blood or urine are useful biomarkers of oxidative stress.^78–80

3.7 Uric Acid

Although an association between high uric acid levels and heart failure has been indicated,^81–84 its sensitivity and specificity as a biomarker of heart failure are not high enough. Further studies are awaited to better clarify its benefits and usage in the diagnosis of or risk assessment for heart failure.

3.8 Vasopressin

Vasopressin, a hormone secreted by the posterior pituitary gland, induces vasoconstriction through V₁ receptors and affects fluid balance through V₂ receptors. Vasopressin secretion is stimulated in heart failure. It has been reported that levels of copeptin, a fragment of the vasopressin precursor, in the blood are related to the prognosis of heart failure.⁸⁵

3.9 Others

Metabolic syndrome is a risk factor for ischemic heart disease and heart failure. Reports have described that levels of adiponectin, an adipocytokine related to metabolic syndrome, are high in patients with heart failure and are related to their prognosis.^86–88

Endothelin (ET) is a potent vasoconstrictor.⁸⁹ Plasma levels of ET-1 and big-ET-1 correlate inversely with LVEF, and are determinants of mortality.^90,91

Levels of adrenomedullin in the blood increase as the severity of heart failure progresses, and are related to the poor prognosis of heart failure.⁹² Adrenomedullin is produced in the heart and the systemic vasculature, and has a role in cellular protection.

4. Chest X-ray

Plain chest X-ray has remained as a useful technique to detect the presence of and assess the severity of heart failure (Table 14). Pulmonary congestion is an important X-ray finding of left heart failure, and is used to assess the severity of it (Figure 7). Patients with mild heart failure (pulmonary venous pressure: 15 to 20 mmHg) show redistribution of blood flow towards the apex (cephalization). Patients with interstitial pulmonary edema (pulmonary venous pressure: 20 to 30 mmHg) show peribronchial or perivascular edema (cuffing signs) or Kerley’s A, B, and/or C lines. More advanced patients show alveolar pulmonary edema (pulmonary venous pressure: ≥30 mmHg) with butterfly shadow. Pleural fluid is often found in patients with bilateral cardiac failure, while it is rarely found in patients with right cardiac failure.⁹³ Pleural fluid and pulmonary edema are more commonly found in the right lungs.⁹⁴ Shadows in the mediastinum may be found in association with left atrial enlargement, right ventricular enlargement, or enlarged shadows of the pulmonary artery, but the diagnostic significance of these X-ray findings is not superior to echocardiographic findings.

Table 14. Recommendations and Levels of Evidence on the Use of Chest X-ray in Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Chest X-ray to examine patients with a new-onset or an acute worsening of heart failure	I	C	B	V

Figure 7.

Chest X-ray findings of heart failure (schema).

5. Echocardiography

Echocardiography is used to assess cardiac function and hemodynamics, as well as the cause, pathophysiology, and severity of heart failure. Repetitive measurement is also useful in the assessment of treatment efficacy and prognosis (Table 15). Table 16 lists normal values for transthoracic echocardiographic and Doppler parameters obtained in the Japanese population, which are essential in the assessment of cardiac function in patients with heart failure.^95,96

Table 15. Recommendations and Levels of Evidence for the Use of Echocardiography in Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Echocardiography to assess cardiac function, left ventricular wall motion, valvular disease, right ventricular function, and pulmonary hypertension in patients suspected of having heart failure	I	C	A	IVb
Echocardiography to assess cardiac function in patients with heart failure who are going to receive drug therapy or device therapy	I	C	A	IVb
Repeat echocardiography to assess patients with a change in their clinical condition of heart failure	I	C	A	IVb
Stress echocardiography to assess myocardial viability in patients with HFrEF	IIa	B	B	IVb
Echocardiography to assess whether the limitation of physical activity is attributable to cardiac dysfunction	IIa	B	B	IVb
Echocardiography as a routine follow-up procedure for patients with stable heart failure	III	B	D	IVb
Transthoracic echocardiography in patients who can be diagnosed and assessed with transesophageal echocardiography	III	B	D	IVb

HFrEF, heart failure with reduced ejection fraction.

Table 16. Normal Range of Echocardiographic Indices of Cardiac Function in Japanese Male and Females

	Male	Female
Left ventricular end-diastolic diameter (mm)	48±4	44±3
Left ventricular end-systolic diameter (mm)	30±4	28±3
Left ventricular end-diastolic volume index (mL/m2)	53±11	49±11
Left ventricular end-systolic volume index (mL/m2)	19±5	17±5
Left ventricular ejection fraction (%)	64±5	66±5
Left ventricular mass index (g/m2)	76±16	70±14
Left atrial dimension (mm)	32±4	31±3
Left atrial volume index (mL/m2)	24±7	25±8
Right ventricular end-diastolic diameter (apical four-chamber view at the base level) (mm)	31±5	28±5
Right ventricular area change (FAC, %)	44±13	46±11
Tricuspid annular plane systolic excursion (TAPSE, mm)	24±3.5
Tricuspid annular peak systolic velocity (s′) (cm/sec)	14.1±2.3
E/e′ (septum)	7.4±2.2	7.9±2.2
e′ (septum, cm/sec)	10.0±2.8	10.8±3.2
E/e′ (lateral wall)	5.5±1.8	6.2±1.8
e′ (lateral wall, cm/sec)	13.5±3.9	13.7±4.1

FAC, fractional area change. (Source: Prepared based on Daimon M, et al. 2008⁹⁵ and Lang RM, et al. 2015⁹⁶)

5.1 Assessment of Cardiac Function

5.1.1 Assessment of Left Ventricular Systolic Function

Left ventricular systolic function is assessed with LVEF. Patients with heart failure are classified into those with preserved LVEF (HFpEF), and those with reduced LVEF (HFrEF). LVEF is determined using the modified Simpson method (disc method).

In addition to the LVEF-based assessment of systolic function of the left ventricle as a whole, regional wall motion should also be assessed. Left ventricular global longitudinal strain (GLS) determined with speckle-tracking echocardiography is highly reproducible and useful in early diagnosis of heart failure.⁹⁷

5.1.2 Assessment of Left Ventricular Diastolic Function

Left ventricular diastolic function consists of left ventricular relaxation that defines early diastolic inflow velocity and left ventricular stiffness that defines mid- and end-diastolic inflow velocity. Left ventricular dilation and inflow may be limited not only by diastolic dysfunction due to left ventricular myocardial damage but also by compression due to right ventricular enlargement, constrictive pericarditis, or cardiac tamponade.

Echocardiographic parameters for the assessment of left ventricular diastolic function are based on secondary changes such as an increase in left atrial pressure and morphological changes. As there is no single parameter that can assess left ventricular diastolic function by itself, multiple parameters as listed below should be assessed comprehensively.

a. Left Ventricular Inflow Velocity Pattern (E/A)

In patients with sinus rhythm, peak blood flow velocity in early diastole (the E wave) and peak flow velocity in late diastole caused by atrial contraction (the A wave) are observed. Patients with an initial phase of diastolic dysfunction show “relaxation abnormality patterns”, which are characterized by a low E/A ratio and prolonged E-wave deceleration time (DT). Patients with advanced diastolic dysfunction and increased left atrial pressure show “pseudonormalized filling pattern” with a high E wave and a high E/A ratio. Patients with more advanced diastolic dysfunction with higher left atrial pressure show “restrictive pattern” characterized by an even higher E/A ratio.

b. Early Diastolic Mitral Annular Velocity (e′)

Patients with diastolic dysfunction show a reduction of early diastolic mitral annular velocity (e′). This should be determined at either the septal side or lateral wall side of the mitral valve annuls or the mean of the measurements at the two locations.

c. E/e′ Ratio

E/e′ ratio, the ratio of peak early diastolic left ventricular filling (E) to the peak mitral annular velocity (e′) is useful in the diagnosis of heart failure independent of LVEF, and positively correlates with left atrial pressure.⁹⁸ However, it is noted that the correlation between E/e′ and the severity of heart failure is poor in patients with hypertrophic cardiomyopathy in whom a high E/e′ ratio may not be associated with high left atrial pressure.⁹⁹

d. Left Atrial Volume Index (LAVI)

Left atrial enlargement is considered to reflect long-term left atrial load due to diastolic dysfunction, and correlates with the severity of diastolic dysfunction.¹⁰⁰

e. Tricuspid Regurgitant Velocity

High left atrial pressure causes secondary pulmonary hypertension and an increase in the right ventricular systolic pressure. Tricuspid regurgitation velocity (TRV) may indicate an increase in left atrial pressure in patients without pulmonary arterial hypertension.

f. Assessment of Diastolic Function in HFpEF

The presence/absence of diastolic dysfunction in patients with preserved LVEF may be assessed based on E/e′, e′, TRV, and LAVI (Figure 8).¹⁰¹ Patients diagnosed as having diastolic dysfunction should be examined as instructed for patients with reduced LVEF to estimate left atrial pressure. Constrictive pericarditis is a condition that must be differentiated from diastolic dysfunction associated with myocardial disorder, and usually shows high E waves of left and right ventricular inflow with substantial respiratory changes.

Figure 8.

How to diagnose diastolic dysfunction in patients with HFpEF. HFpEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction. (Source: Prepared based on Nagueh SF, et al. 2016¹⁰¹ with modification)

g. Assessment of Diastolic Function in HFrEF

Diastolic dysfunction is considered present in all patients with low LVEF. E/A, E wave velocity, E/e′, TRV, LAVI, and other parameters are used to assess whether left atrial pressure is high or not (Figure 9).¹⁰²

Figure 9.

Algorithm for the diagnosis of elevated left atrial pressure by echocardiography. CAD, coronary artery disease; LA, left atrium; LAP, left atrial pressure; TR, tricuspid regurgitation. (Adapted from Nagueh SF, et al. 2016¹⁰¹)

5.1.3 Assessment of Right Ventricular Function

Right ventricular function may be assessed with relatively simple parameters, such as fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), and tricuspid annular peak systolic velocity (s′). Right ventricular volume cannot be determined using two-dimensional echocardiography because of its complex morphology. Right ventricular volume and ejection fraction may be determined using three-dimensional echocardiography.

5.2 Assessment of Hemodynamics

a. Right Ventricular Systolic Pressure (Pulmonary Artery Systolic Pressure)

Right ventricular systolic pressure (pulmonary artery systolic pressure) may be estimated based on the sum of systolic right ventricular-atrial pressure gradient, which can be calculated from tricuspid regurgitant velocity, and right atrial pressure. However, it cannot be estimated in patients with tricuspid valve separation causing laminar regurgitation flows. Also, it should be noted that patients with substantial right heart dysfunction might show moderately increased or normal pulmonary artery systolic pressure due to low cardiac output.

b. Right Atrial Pressure

Right atrial pressure may be estimated on the basis of inferior vena cava diameter at a distance of 1 to 2 cm from the right atrium and whether or not the diameter changes with respiration.

c. Cardiac Output

Cardiac output is calculated as a product of outflow tract area and velocity-time integral (VTI).

5.3 Stress Echocardiography

Contractile reserve and cardiac viability cannot be assessed solely with parameters at rest. Dobutamine-stress or exercise echocardiography may be useful in such cases. Exercise echocardiography is also beneficial in assessing the presence of diastolic dysfunction or pulmonary hypertension in patients with shortness of breath on effort.¹⁰³

5.4 Assessment for Causative Conditions

It is important to assess the cause of heart failure and its severity in individual patients. Heart failure may develop in ischemic heart disease, hypertensive heart disease, cardiomyopathy, structural valvular disease, and infective endocarditis. Transesophageal echocardiography should be considered in patients who are suspected to have infective endocarditis but do not show abnormal findings on transthoracic echocardiograms and in patients after valvular surgery whenever necessary.

5.5 Assessment in Acute Heart Failure

Hemodynamics should be assessed in patients with acute heart failure. LVEF may be determined by visual estimation in these cases.

Patients with pericardial effusion should be suspected for cardiac tamponade. Myocarditis should be suspected in patients with pericardial effusion associated with transient ventricular wall thickening and diffuse wall hypokinesis as well as elevated levels of inflammatory markers and myocardial proteins in the blood.

Lung ultrasound assessment has been reported to be beneficial in the diagnosis of pulmonary edema. B-lines, that appears as 8 lines in the right and left lungs, are useful for differentiating dyspnea due to acute heart failure than that due to other causes with a 94% sensitivity and 92% specificity.¹⁰⁴

6. Imaging (MRI, CT, Nuclear Imaging, and PET) (Table 17)

Table 17. Recommendations and Levels of Evidence for the Use of Imaging Techniques in Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
MRI
MRI to assess cardiac anatomy and function 　Patients who cannot be assessed appropriately with echocardiography, patients with congenital heart disease, and patients who require right ventricular assessment	I	C	A	IVb
Delayed-enhancement MRI 　To differentiate between ischemic and non-ischemic cardiomyopathy in patients who cannot be assessed adequately with other procedures	I	C	A	IVb
Delayed-enhancement MRI 　To identify underlying heart disease in patients with non-ischemic myocardiopathy	IIa	C	B	IVb
MRI T2-wighed images 　To assess the severity of myocardial inflammation	IIa	C	B	V
CT
Coronary artery CT 　To rule out coronary artery disease in patients with heart failure whose pre-test probability of coronary artery disease is low or moderate	IIa	C	B	IVa
Nuclear cardiology
SPECT using thallium chloride or technetium- labeled tracers 　To assess myocardial ischemia and myocardial viability in patients with ischemic cardiomyopathy	I	B	A	II
SPECT using thallium chloride or technetium- labeled tracers 　To assess myocardial blood flow in patients with dilated cardiomyopathy	IIb	C	C1	IVa
ECG-gated SPECT 　To assess left ventricular volume and LVEF in patients who cannot be assessed appropriately with echocardiography	IIa	C	B	IVb
I-123-BMIPP scintigraphy 　To differentiate between ischemic and non-ischemic cardiomyopathy based on a mismatch between I-123-BMIPP uptake and blood flow distribution	IIb	C	C1	IVb
I-123-MIBG scintigraphy 　To assess the severity of heart failure	IIa	C	B	IVb
I-123-MIBG scintigraphy 　To predict tolerability/efficacy and assess efficacy of drug therapy in patients with dilated cardiomyopathy	I	A	A	II
Cardiac pool scintigraphy 　To assess LVEF in patients who cannot be assessed adequately with other procedures	I	B	B	III
Cardiac pool scintigraphy 　To assess right ventricular function and anatomy in patients who cannot be assessed adequately with other procedures	IIa	B	B	IVa
FDG PET 　To assess myocardial viability in patients who cannot be assessed adequately with other procedures	IIb	C	C1	IVb
FDG PET 　To detect active lesions of cardiac sarcoidosis	I	C	A	IVb

BMIPP, β-methyl-p-iodophenyl-pentadecanoic acid; CT, computed tomography; FDG PET, fluorodeoxyglucose positron emission tomography; LVEF, left ventricular ejection fraction; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; SPECT, single-photon emission computed tomography.

6.1 Cardiac Magnetic Resonance Imaging (MRI)

6.1.1 Assessment of Cardiac Morphology and Function

Cardiac MRI is the most reliable imaging technique for the assessment of the morphology and ejection fraction of the left and right ventricles, and left ventricular mass because of its accuracy and reproducibility.¹⁰⁵ Cardiac MRI is used to specify the cause of heart failure according to the results of morphologic assessment and ventricular wall motion based on cine images.^106,107 MRI is highly useful in the assessment of right ventricular and complex congenital heart diseases that are often difficult to be assessed correctly with echocardiography.¹⁰⁸ However, MRI should be used alternative to echocardiography only when necessary because of the latter is less time-consuming and inexpensive method that does not require substantial expertise in imaging analysis.

6.1.2 Assessment of Myocardial Tissues

The presence of myocardial fibrosis may be detected with late gadolinium enhancement MRI. The distribution of delayed enhancement is useful information in differentiating from ischemic and non-ischemic cardiomyopathy or in evaluating myocardial viability.^105,107 T1 mapping can be used for similar assessment without using contrast, and is becoming a more common technique.¹⁰⁹ As high signals in T2 weighed images are consistent with edema, this technique can be used in the assessment of inflammation associated with acute myocardial infarction, acute myocarditis, or cardiac sarcoidosis.¹⁰⁷

6.2 Cardiac CT

Cardiac CT can be used to assess the morphology and function of the heart in addition to anatomical features of the coronary arteries. Considering its high specificity for the diagnosis of ischemic heart disease, cardiac CT should be considered for patients with heart failure whose pre-test probability of coronary artery disease is low or moderate or in whom diagnosis is difficult with other non-invasive stress tests to rule out coronary artery disease.^110,111

6.3 Nuclear Imaging

6.3.1 Thallium or Technetium

Patients with ischemic cardiomyopathy should be assessed for myocardial ischemia and viability using thallium chloride or technetium (Tc) labeled radiopharmaceuticals.^111–113 Single-photon emission computed tomography (SPECT) may also provide additional information on cardiac function such as left ventricular volume and LVEF.

6.3.2 I-123 BMIPP and I-123 MIBG

Iodine-123-β-methyl-p-iodophenyl-pentadecanoic acid (I-123 BMIPP), a marker for myocardial fatty acid metabolism, is used to detect myocardial damage associated with infarction, myocardial ischemia, or non-ischemic cardiomyopathy. As washout rate of I-123- metaiodobenzylguanidine (I-123 MIBG) increases and heart/superior mediastinum ratio (H/M) on delayed images decreases in patients with heart failure, this technique can be used in severity assessment.^114–118 I-123 MIBG is useful in predicting the prognosis of heart failure due to dilated cardiomyopathy and hypertrophic cardiomyopathy,^119–121 assessing tolerability of and predicting the efficacy of β-blocker therapy in dilated cardiomyopathy, and evaluating the efficacy of drug therapy in heart failure.^122–124

6.3.3 Tc-99 m Pyrophosphate

Tc-99 m pyrophosphate (PYP) is useful in the detection of myocardial necrosis and the diagnosis of mutant or wild-type transthyretin-related cardiac amyloidosis.¹²⁵

6.3.4 Gallium Scintigraphy

Gallium scintigraphy is used to detect new lesions of cardiac sarcoidosis, but its diagnostic sensitivity is lower than fluorodeoxyglucose positron emission tomography (FDG PET).^123–125 Gallium scintigraphy is used to detect the presence of inflammatory diseases such as myocarditis and infective endocarditis and cardiac lesions of malignant lymphoma.^107,112

6.3.5 Cardiac Blood Pool Scintigraphy

Cardiac blood pool scintigraphy is a technique to determine LVEF using Tc-labeled human serum albumin or Tc-labeled red blood cells,^112,126 and can be used to asses left ventricular diastolic function.¹²⁶ This technique is also useful in assessing the function of the right ventricle, which has a complex anatomy.^127,128 This is used for patients in whom assessment with echocardiography, MRI, CT, and ECG-gated SPECT is difficult.

6.4 PET

PET can be used in combination with N-13 ammonia to assess the severity of myocardial ischemia, and in combination with F-18 FGD to assess myocardial viability and detect active lesions of cardiac sarcoidosis.^129,130

7. Cardiac Catheterization (Hemodynamics and Biopsy)

Common indications for right side heart catheterization, left side heart catheterization, and endomyocardial biopsy in patients with heart failure are summarized in Table 18.

Table 18. Recommendations and Levels of Evidence for the Use of Invasive Approaches With Catheterization in Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Coronary angiography 　Patients with heart failure refractory to drug therapy or complicated with angina pectoris, or those who experienced symptomatic ventricular arrhythmia or cardiac arrest	I	C	B	IVb
Invasive pulmonary artery pressure monitoring 　Patients with ARDS or circulation failure in whom adequate clinical assessment cannot be made	I	C	B	IVb
Coronary angiography 　Patients in whom heart failure is suspected to be caused by ischemia	IIa	C	B	V
Invasive pulmonary artery pressure monitoring 　Patients with acute heart failure who have persistent symptoms or unstable hemodynamics	IIa	C	B	IVa
Endomyocardial biopsy 　For confirmatory diagnosis of specific disease that affect the strategies to treat heart failure	IIa	C	B	V
Invasive pulmonary artery pressure monitoring 　Normotensive patients with symptomatic acute heart failure who respond well to diuretics and vasodilators	III	B	D	II
Coronary angiography or endomyocardial biopsy 　As routine procedures in patients with heart failure	III	C	D	VI

ARDS, acute respiratory distress syndrome.

8. Exercise Tolerance

Exercise tolerance is the most important determinant of functional status in patients with heart failure. Exercise intolerance is a major manifestation in patients with heart failure, which reflects the severity of heart failure, and is closely related to decreases in activities of daily living and quality of life (QOL) in patients. One of the main purposes of heart failure treatment is to improve exercise tolerance, which is a factor of better prognosis.

8.1 NYHA Functional Classification (Table 8)⁷

The New York Heart Association (NYHA) functional classification is used to assess the severity of heart failure based on the level of ADL,¹³¹ and reflects the QOL of patients. However, this is not a quantitative or objective scaling system.

8.2 Specific Activity Scale

Specific activity scale (SAS) describes the amount of exercise to perform a given activity of daily living with the number of metabolic equivalent units (METs) (Table 19).^132,133 With this scale, the minimum amount of exercise that causes symptoms of heart failure may be quantified using a unit of oxygen uptake.

Table 19. Questionnaire on Physical Activity

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

METs, metabolic equivalents. (Excerpted from Sasayama S, et al. 1992¹³² and The Japanese Intractable Diseases Information Center¹³³)

8.3 Six-Minute Walking Test

The six-minute walking test is a maximal exercise test to measure the maximal distance an individual able to walk in 6 minutes. The reference value for the Japanese population is calculated by multiplying [454−0.87×age (years)−0.66×weight (kg)] ±82 (2SD) by height (m).¹³⁴ It has been reported that the six-minute walking distance well correlates with NYHA functional classification and peak oxygen uptake (peak V̇O₂),¹³⁵ and is useful in predicting the prognosis of patients with heart failure.¹³⁶

8.4 Cardiopulmonary Exercise Testing

The most objective index of exercise tolerance is oxygen uptake during maximal exercise. Peak V̇O₂, which is measured during cardiopulmonary exercise testing (CPX),¹³⁷ is suitable parameter in assessing the prognosis of patients with heart failure,^138–141 selecting candidates for heart transplantation,^{138,141–143} and classifying the severity of heart failure.¹⁴⁴ Patients with a Peak V̇O₂ of <14 mL/kg/min have a poor prognosis,¹³⁸ and those with <10 mL/kg/min have an extremely poor prognosis. When peak V̇O₂ is expressed as percentage of age-predicted peak V̇O₂ (% peak V̇O₂), patients with a % peak V̇O₂ of <50% are considered to have a poor prognosis.¹⁴⁵ Table 20 shows the relationship between the NYHA classification, SAS, and % peak V̇O₂.¹³³

Table 20. A Comparison of Major Exercise Capacity Measures in Patients With Heart Failure

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. (Adapted from The Japanese Intractable Diseases Information Center¹³³)

The anaerobic threshold, that is defined as the point during exercise when anaerobic metabolism occurs in addition to aerobic metabolism, accounts for about 50 to 55% of the maximal exercise capacity. This threshold is used as an index of daily activity level,^137,146 on which allowable exercise level¹⁴⁷ and exercise prescriptions¹⁴⁸ are determined.

The V̇E/V̇CO₂ slope indicates the tidal volume needed to eliminate carbon dioxide produced during metabolism, and is considered as a factor related to dyspnea on exertion in patients with heart failure. Patients with a V̇E/V̇CO₂ slope of >35 are considered to have a poor prognosis.¹⁴⁹

Table 21 summarizes recommendations for exercise capacity evaluation in heart failure and their evidence levels.

Table 21. Recommendations and Level of Evidence for Exercise Capacity Evaluation in Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (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

IV. Prevention of Heart Failure

The development, progression (exacerbations), and recurrence of heart failure should be prevented through lifestyle management such as diet and exercise and treatment interventions to control risk factors for heart failure and manage asymptomatic heart failure (Table 22). It is also important that patients are managed continuously in hospitals, local communities, and their home by multidisciplinary approach involving diverse healthcare professionals, including physicians, nurses, pharmacists, dieticians, and physical therapists and hospital-clinic collaborations.

Table 22. Recommendations and Level of Evidence for Interventions to Modify Risk Factors for Preventing Prevent Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Hypertension
Treatment of hypertension including low-salt diet and weight reduction	I	A	A	I
Thiazide diuretics	I	A	A	I
Coronary artery disease
ACE inhibitors in patients with coronary artery disease*	I	A	A	I
Statins in patients with coronary artery disease	I	A	A	I
ACE inhibitors in patients with left ventricular contractile dysfunction	I	B	A	II
β-blockers in patients with myocardial infarction	I	B	A	II
MRAs in patients with myocardial infarction	I	B	A	II
PCI to the culprit lesion of complete occlusion during the period between 3 and 28 days after the onset of myocardial infarction	III	B	C2	II
Obesity and diabetes mellitus
General lifestyle modifications through weight reduction and increased physical activity	I	A	A	I
Treatment with SGLT2 inhibitors (empagliflozin,** canagliflozin***) in patients with type 2 diabetes mellitus and a history of cardiovascular disease	I	A	B	II
Smoking cessation	I	C	B	IVb
Alcoholic control	IIa	C	C1	VI
Physical activity and exercise habits	I	B	B	IVa
Others
Comprehensive multidisciplinary (educational) programs and team medical care	I	C	C1	VI
Preventions of infectious disease including vaccinations	IIa	C	B	IVb

*ARBs are recommended for patients intolerant of ACE inhibitors (especially those with left ventricular dysfunction). **In the EMPA-REG OUTCOME study of empagliflozin,¹⁷⁵ all participants had a history of cardiovascular disease. ***In the CANVAS study of canagliflozin,¹⁷⁸ 34% of the participants were at high risk of cardiovascular events and received the treatment for primary prevention, and 66% of the participants had a history of cardiovascular disease. The dose range of canagliflozin in the CANVAS study was wider than the approved dose range in Japan. ARB, angiotensin II receptor blocker; ACE, angiotensin converting enzyme; MRA, mineralocorticoid receptor antagonist; PCI, percutaneous coronary intervention; SGLT, sodium glucose cotransporter.

1. Hypertension

Antihypertensive treatment has been shown to prevent the development of heart failure and improve the prognosis of patients with hypertension.^150–153 In addition to lifestyle modifications such as low-salt diet and body weight management, patients should be treated with antihypertensive drugs (e.g., angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARBs]), diuretics and β-blockers.¹⁵⁴

2. Coronary Heart Disease

Patients with coronary artery disease should be treated with ACE inhibitors to prevent cardiovascular events including heart failure and improve the ptognosis.¹⁵⁵ Patients after myocardial infarction should be treated with ACE inhibitors,^156–158 β-blockers,¹⁵⁹ statins,^160–162 and/or mineralocorticoid receptor antagonists (MRA)^163–165 as secondary prevention for cardiovascular events.¹⁶⁶ ARBs are indicated for patients who are intolerant to ACE inhibitors, especially those with left ventricular dysfunction.^167,168

In the Occluded Artery Trial (OAT)¹⁶⁹ that investigated the efficacy of percutaneous coronary intervention (PCI) in the prevention of heart failure in patients after acute myocardial infarction with a LVEF of <50%, PCI to the culprit lesion of complete occlusion during the period between 3 and 28 days after the onset was not effective in preventing cardiac accidents including heart failure for four years after PCI.

3. Obesity and Diabetes Mellitus

As obesity and diabetes mellitus are associated with the development of heart failure,^170–173 and diabetes mellitus and metabolic syndromes, which are conditions caused by insulin resistance, are major risk factors for cardiovascular diseases, patients with these conditions should receive comprehensive risk management including lifestyle modifications for weight management and exercise therapy as well as drug therapy.¹⁷⁴

In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin reduced the risk of hospitalization for and death from heart failure in patients with type 2 diabetes mellitus and a history of cardiovascular disease, and reduced the rate of hospitalization for heart failure in patients without a history of cardiovascular events.^175–177 Similarly, in the Canagliflozin Cardiovascular Assessment Study (CANVAS), canagliflozin reduced the risk of hospitalization for heart failure in patients with type 2 diabetes and a high cardiovascular risk (34% of the participants received treatment for the primary prevention of cardiovascular events and the remaining 64% had a history of cardiovascular disease).¹⁷⁸ These findings indicate that SGLT2 inhibitors are effective in preventing heart failure in patients with type 2 diabetes mellitus who have a history of cardiovascular disease, but further studies should be conducted to demonstrate their efficacy in primary prevention of cardiovascular events or in people aged 75 and over.

4. Smoking

Smokers are strongly advised to receive smoking cessation treatment.

5. Alcohol

As there is a U-shaped curve between alcohol consumption and the incidence of heart failure,^179–181 people who have habitual drinking should be advised to drink moderately.

6. Physical Activity and Exercise

A dose-related inverse relation between physical activity and the risk of heart failure has been reported.

7. Others

Patients with stable, Stage C heart failure should be managed appropriately to prevent rehospitalizations due to worsening heart failure. In order to prevent rehospitalizations for heart failure, patients and their family members should be educated well on the nature of heart failure and the importance of keeping treatment adherence, and receive comprehensive programs (such as patient education) through social supports and multidisciplinary healthcare support.

V. Basic Principles for the Treatment of Heart Failure

1. Goals of Heart Failure Treatment (Figure 1)

The present guidelines classify the development and progression of heart failure into 4 stages. Stages A and B represent conditions at high risk of heart failure rather than the presence of heart failure. The guidelines include recommendations on treatment for patients at risk stages because it is critically important to prevent the onset of heart failure. This staging classification is based on the criteria that was first described in the ACC/AHA guidelines in 2005 and the concept of this classification has remained important for more than a decade also in Japan.

The primary goals of treatment for each stage of heart failure are to prevent the progression to the next stage. Specifically, the primary goals are to prevent structural heart disease that may cause heart failure in Stage A (patients at risk of heart failure); to prevent the progression of structural heart disease and prevent the onset of heart failure in Stage B (patients with structural heart disease); and to improve the prognosis and control symptoms of heart failure in Stage C (patients with established heart failure). The primary goals for patients with stage D heart failure (refractory heart failure) are essentially the same for those in Stage C, but controlling symptoms are the most important goal in patients with end-stage heart failure. Stage-based treatment is therefore important to achieve optimal treatment goals for different stages of patients (See Figure 1²⁰ in Section “ 1. Definition and Classification ” in Chapter “ II. General Principles ”).

2. Treatment Algorithms for Heart Failure (Figure 10)

Figure 10.

Treatment algorithm for heart failure. ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; CRT, cardiac resynchronization therapy; HF, heart failure; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; ICD, implantable cardioverter defibrillator; MRA, mineralocorticoid receptor antagonist.

The clinical course of heart failure is generally chronic and progressive. Heart failure often manifests as acute heart failure, and then progresses to compensated, chronic heart failure (Stage C, the stage of heart failure). Patients with established heart failure show chronic progression, and may have repeated episodes of acute decompensated heart failure. Repeated acute exacerbations gradually lead to the development of more severe heart failure. Sudden death may occur during the progression of heart failure. Accordingly, heart failure does not progress linearly from Stage C to Stage D (refractory heart failure), and it is quite difficult to predict how the disease progresses (See Figure 1²⁰ in Section “ 1. Definition and Classification ” in Chapter “ II. General Principles ”). Heart failure progresses in a way quite different from malignant tumors. Patients who do not respond to standard treatment and have exacerbations repeatedly progress to Stage D heart failure. The clinical course from Stage C to D differs substantially among patients depending on the severity of underlying heart disease and comorbidities. This makes it even difficult to predict the course of heart failure.

Patients with Stage C heart failure need treatment both for chronic heart failure and for acute exacerbations of chronic heart failure. As many patients with heart failure are in Stage C and will stay in this stage even after symptomatic improvement, smooth transition from acute-phase to chronic-phase treatment is important. Treatment modalities for Stage C heart failure include those for heart failure with reduced LVEF (HFrEF) and those for heart failure with preserved LVEF (HFpEF) (Figure 10). As treatments for heart failure with mid-range LVEF (HFmrEF) have not been fully evaluated, physicians should select treatments for them according to the individual patient’s condition. Although many patients require diuretics to control their symptoms of heart failure, no evidence has demonstrated that diuretics improve the prognosis of patients with heart failure. Dose adjustment of diuretics based on the severity of organ congestion is important. Patients who still have severe symptoms at rest despite sufficient Stage C treatment and are repeatedly hospitalized for worsening heart failure should receive Stage D treatment.

VI. Pharmacological Therapy

1. Heart Failure With Reduced Ejection Fraction (HFrEF) (Tables 23, 24, and 25)

Table 23. Recommendations and Levels of Evidence for Medications for HFrEF

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (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; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; QOL, quality of life; SGLT, sodium glucose cotransporter.

Table 24. Medications for HFrEF According to Class of Recommendation

Class of Recommendation I

ACE inhibitors: Use in all patients (including asymptomatic patients) unless contraindicated

ARBs: Use in patients intolerable ACE inhibitors

β-blockers: Use in symptomatic patients to improve prognosis

MRAs: Use in patients with NYHA Class II-IV, LVEF <35% who are receiving loop diuretics and ACE inhibitors

Loop diuretics, thiazide diuretics: Use in patients with symptoms of congestion

Class of Recommendation IIa

β-blockers: Use in asymptomatic patients with left ventricular systolic dysfunction

β-blockers or digitalis: Use for rate control in patients with atrial fibrillation with a rapid ventricular response

Vasopressin 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

Digitalis (maintain digoxin concentration in blood at ≤0.8 ng/mL): Use in patients in sinus rhythm

Oral inotropic drugs: Use short-term to improve QOL and discontinue intravenous inotropic drugs

Amiodarone: Use in patients with a history of serious ventricular arrhythmia leading to cardiac arrest

Class of Recommendation IIb

ARBs: Concomitant use with ACE inhibitors

Concomitant use of isosorbide dinitrate and hydralazine: Use as an alternative to ACE inhibitors or ARBs

Oral inotropic drugs: Concomitant use when initiating β-blockers

Other diuretics such as carbonate dehydratase inhibitors and osmotic diuretics: Diuretics other than loop diuretics, thiazide diuretics, and MRAs

Class of Recommendation III

Oral inotropic drugs: Use long term in asymptomatic patients

Calcium channel blockers: Use in patients without angina pectoris or hypertension

Long-term oral treatment with Vaughan Williams Class I antiarrhythmic agents

Use of α-blockers210

ARB, angiotensin II receptor blocker; ACE, angiotensin converting enzyme; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; QOL, quality of life; SGLT, sodium glucose cotransporter.

Table 25. Medications for HFrEF: Drugs and Dosing Regimens

Drugs*	Dosing regimen
ACE inhibitors
Enalapril	Start at 2.5 mg/day, and maintain at 5 to 10 mg/day once daily
Lisinopril	Start at 5 mg/day, and maintain at 5 to 10 mg/day once daily
ARBs
Candesartan	Start at 4 mg/day (2 mg/day in severe cases or renal dysfunction), and maintain at 4 to 8 mg/day once daily (maximum daily dose: 12 mg/day)
MRAs
Spironolactone	Start at 12.5 mg/day, and maintain at 25 to 50 mg/day once daily
Eplerenone	Start at 25 mg/day, and maintain at 50 mg/day once daily
β-blockers
Carvedilol	Start at 2.5 mg/day,** and maintain at 5 to 20 mg/day twice daily
Bisoprolol	Start at 0.625 mg/day,** and maintain at 1.25 to 5 mg/day once daily
Diuretics
Furosemide	40 to 80 mg/day once daily
Azosemide	60 mg/day once daily
Torasemide	4 to 8 mg/day once daily
Tolvaptan	7.5 to 15 mg/day once daily
Trichlormethiazide	2 to 8 mg/day once daily
Antiarrhythmic drugs
Amiodarone	Start at 400 mg/day, and maintain at 200 mg/day once or twice daily
Digitalis
Digoxin	0.125 to 0.25 mg/day once daily
Oral inotropic drugs
Pimobendan	2.5 to 5.0 mg/day once daily

*National Health Insurance-covered medications. **Start at a half dose in severe cases. ARB, angiotensin II receptor blocker; ACE, angiotensin converting enzyme; MRA, mineralocorticoid receptor antagonist.

1.1 Drugs for the Treatment of HFrEF

1.1.1 ACE Inhibitors

The results of large-scale clinical studies such as the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)¹⁸² and the Studies of Left Ventricular Dysfunction (SOLVD) trial^183,184 have demonstrated that angiotensin converting enzyme (ACE) inhibitors improve the prognosis of patients with heart failure due to left heart dysfunction and a reduction of the risk of cardiovascular events. Long-term follow-up of patients who participated in these large-scale studies have demonstrated that ACE inhibitors are also effective in those with asymptomatic left ventricular systolic dysfunction in reducing hospitalizations for heart failure and improving prognosis.¹⁸⁵ ACE inhibitors should thus be given to all patients with left ventricular systolic dysfunction.

1.1.2 Angiotensin II Receptor Blockers (ARBs)

The results of large-scale clinical studies^186–188 have indicated that ARBs are as effective as ACE inhibitors in reducing cardiovascular events in patients with chronic heart failure due to left ventricular systolic dysfunction. Accordingly, ARBs should be used for patients who cannot receive ACE inhibitors because of intolerance or other reasons.

1.1.3 Mineralocorticoid Receptor Antagonists (MRAs)

In two large-scale clinical studies in patients with contractile dysfunction and clinical studies in Japan, the benefits of spironolactone and eplerenone have been confirmed.^{163,164,189,190} Accordingly symptomatic patients with LVEF<35% should be treated with MRAs if not contraindicated. However, it has been reported that the use of spironolactone in combination with ACE inhibitors or ARBs may increase the risk of death and hospitalization through increasing serum potassium levels.¹⁹¹ Spironolactone should not be used in combination with both ACE inhibitors and ARBs. Careful monitoring should be performed when patients with an estimated glomerular filtration rate (eGFR) of <30 mL/min or a serum potassium level of ≥5.0 mEq/L at the start of the treatment with MRAs.

1.1.4 β-Blockers

Large-scale clinical studies have demonstrated that bisoprolol, metoprolol succinate, and carvedilol, a nonselective β-blocker/α₁-blocker, improves prognosis in patients with heart failure.^192–195 Evidence has also been published on the efficacy of β-blockers in patients with left ventricular dysfunction without heart failure symptoms.

Treatment with β-blockers for patients with NYHA class III or IV heart failure should be started in the hospital setting to confirm improvement in fluid retention and until the patient is in a stable condition. The dose should then be gradually titrated upwards in intervals of a few days to 2 weeks. Before initiating β-blocker therapy, the absence of underlying conditions that are contraindicated for β-blockers should be confirmed. Dose escalation should be made according to symptoms, pulse rate, blood pressure, cardiothoracic ratio, and chamber size measured with echocardiography, and patients should be monitored carefully for any signs/symptoms of worsening heart failure, excessive hypotension, and bradycardia.

β-blocker therapy should be initiated in the hospital setting during the recovery phase of acute exacerbation of heart failure.¹⁹⁶ Patients should receive the initial doses in the hospital setting, and the dose should then be escalated in the ambulatory setting. When heart failure worsens during β-blocker therapy, the treatment should be continued whenever possible, but discontinuation may be unavoidable depending on the severity of heart failure. β-blocker therapy should be restarted whenever possible after the condition becomes stable.¹⁹⁷

Large-scale clinical studies of β-blockers in chronic heart failure have demonstrated the efficacy of carvedilol, bisoprolol, and metoprolol succinate. In Japan, the use of carvedilol and bisoprolol in chronic heart failure is covered by the National Health Insurance.

1.1.5 Diuretics

Diuretics are the most effective drugs in the treatment of symptoms of congestion in heart failure, such as dyspnea on exertion and edema. Loop diuretics should be tried first, and thiazide diuretics may be added for patients who do not respond well to loop diuretics. However, these diuretics may cause hypokalemia and hypomagnesemia, increase the risk of digitalis intoxication, and induce serious ventricular arrhythmia. During diuretic therapy, serum levels of potassium and magnesium should be monitored to keep appropriate levels.

Loop diuretics have been used commonly to alleviate congestion during acute exacerbations of heart failure. Many patients with chronic heart failure have routinely received long-term treatment with loop diuretics. Retrospective analyses using data of large-scale clinical studies have concluded that furosemide and other loop diuretics may deteriorate prognosis in patients with heart failure.^198–201 The long-acting loop diuretic azosemide is considered not to affect neurohumoral factors substantially as it does not cause significant hemodynamic changes. In a study that compared azosemide and furosemide in Japan, the primary composite endpoint of cardiovascular death or hospitalization for worsening heart failure occurred less frequently in patients receiving azosemide than those receiving furosemide.²⁰²

Tolvaptan, a vasopressin V₂ receptor antagonist, blocks vasopressin V₂ receptors on renal medullary collecting duct cells, and thereby increases water excretion. In the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST), a randomized, placebo-controlled study of tolvaptan in patients with acute worsening heart failure, the vasopressin V₂ receptor antagonist improved symptoms of congestion but did not improve long-term outcome of patients with heart failure.^203,204

1.1.6 Antiarrhythmic Drugs

Amiodarone is expected to prevent serious ventricular arrhythmias such as ventricular tachycardia and ventricular fibrillation, and reduce the risk of sudden death in patients with heart failure. Patients receiving amiodarone should periodically undergo thyroid function tests, pulmonary function tests, chest X-ray, determination of KL-6 concentration in the blood, and ophthalmological tests to detect adverse drug reactions to amiodarone (e.g., thyroid function disorder, interstitial pneumonia, corneal pigmentation, and abnormal liver function tests) promptly. As the use of amiodarone for the treatment of atrial fibrillation associated with heart failure is covered by the National Health Insurance in Japan, this drug is used also to maintain sinus rhythm or control heart rate.

1.1.7 Vasodilators

Western guidelines recommend combination therapy using hydralazine and isosorbide dinitrate to improve prognosis in patients who cannot receive ACE inhibitors for various reasons.^205,206 In Japan, such combination therapy is not used proactively. Calcium channel blockers are not generally recommended as long-term treatment because calcium channel blockers may worsen heart failure.

1.1.8 Digitalis

In 1997, results from the Digitalis Investigation Group (DIG) trial were published and described that digoxin reduces the risk of hospitalization for worsening heart failure in patients with normal sinus rhythm, but does not improve their prognosis.²⁰⁷ The risk of death related to arrhythmia rather tended to increase with the use of digoxin in this population. On the other hand, patients with heart failure and atrial fibrillation are often treated with digitalis to control heart rate and increase left ventricular filling period. Digitalis is used to relieve symptoms, but there is no evidence regarding whether it may improve the prognosis of patients with left ventricular systolic dysfunction and atrial fibrillation.

1.1.9 Oral Inotropic Drugs

Since 1980 s, large clinical studies have failed to demonstrate the efficacy of oral inotropic drug in heart failure,^208,209 and experts in the United States do not recommend oral inotropic drugs for the treatment of heart failure. However, given the perspective that prolonging the survival is not the sole purpose of the treatment for patients with chronic heart failure, the possible clinical benefits of oral inotropic drugs in this patient population should be reconsidered.

1.2 Dug Therapy for Heart Failure With Mid-Range Ejection Fraction (HFmrEF)

Some data have indicated that β-blockers and other drugs used to treat HFrEF are also effective in the treatment of HFmrEF.³⁴ However, no conclusive evidence has been obtained in this patient population and further studies are awaited.

1.3 Heart Failure Treatment by Stage

1.3.1 Stage C (Symptomatic Heart Failure)

NYHA class II: Introduce β-blockers in addition to ACE inhibitors. Patients with symptoms of fluid retention such as pulmonary congestion and generalized edema should receive diuretics. MRAs should be added to patients with LVEF <35%.

NYHA class III: Similar to NYHA class II patients, ACE inhibitors, β-blockers, and diuretics should be used. MRAs should be added to patients with LVEF <35%.

NYHA class IV: Patients should be hospitalized and receive parenteral medications such as catecholamines, phosphodiesterase (PDE) III inhibitors, diuretics, and carperitide to stabilize the condition. After the condition is stabilized, these regimens should be switched to oral drugs such as ACE inhibitors, diuretics, MRAs, and digitalis. β-blockers should also be tried.

1.3.2 Stage D (Refractory Heart Failure)

Treatment regimens should be reviewed whether the patient is receiving appropriate fluid management and drug therapy. The indication of heart transplantation should be considered (See Section “ 3. Heart Transplantation ” in Chapter “ XI. Surgical Treatment ” Tables 70, 71,⁵²² and 72). Patients who are not indicated for heart transplantation or ventricular assist devices should receive palliative care to alleviate symptoms based on a consent given by the patient and his or her family members (See Chapter “ XIII. Palliative Care ” for details).

2. Heart Failure With Preserved Ejection Fraction (HFpEF) (Table 26)

Table 26. Recommendations and Levels of Evidence for Medications for HFpEF

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Diuretics
Use of diuretics to relieve symptoms of congestion	I	C	C1	VI
Preference of long-acting drugs when using loop diuretics	IIb	C	C1	III
Out-patient use of tolvaptan introduced during hospitalization for acute heart failure to control congestion*	IIa	C	C1	IVb
ACE inhibitors/ARBs
Increasing the dose of ACE inhibitors/ARBs to maximum tolerable level to reduce the risk of clinical events	IIb	C	C1	III
β-blockers
Increasing the dose of β-blockers to maximum tolerable level to reduce the risk of clinical events	IIb	C	C1	III
MRAs
Increasing the dose of MRAs to maximum tolerable level to reduce the risk of clinical events	IIb	C	C1	III
Nitrates
Use of nitrates to improve prognosis and increase activities of daily living	III	B	D	II

*Tolvaptan must be introduced during hospitalization. There are no data on the efficacy and safety of long-term treatment with tolvaptan. ARB, angiotensin II receptor blocker; ACE, angiotensin converting enzyme; MRA, mineralocorticoid receptor antagonist.

No prospective interventional studies on drugs for the treatment of HFpEF have demonstrated a clear reduction in the risk of death or clinical events. At present, patients with HFpEF should be treated to control the causative condition and thereby alleviate heart failure symptoms, and to treat comorbid conditions that may worsen heart failure.

2.1. Interventions to Reduce Disease Burden

2.1.1 Treatment for Congestion

Diuretics are beneficial in improving subjective symptoms caused by congestion. Loop diuretics are used commonly. In the Japanese Multicenter Evaluation of Long-versus short-acting Diuretics in Congestive heart failure (J-MELODIC) trial conducted in Japan, the long-acting loop diuretic azosemide was superior to the short-acting loop diuretic furosemide in improving prognosis, especially in preventing re-worsening heart failure.²⁰² In Japan, an increasing number of patients start tolvaptan therapy during hospitalization for acute heart failure, and continue the treatment after discharge.

2.1.2 Treatment for Hypertension

See Section “ 6. Hypertension ” in Chapter “ IX. Pathophysiology and Treatment of Comorbidities ”.

2.2 Interventions Not Directly Aiming at Reducing the Burden of Heart Failure

ACE inhibitors,²¹¹ ARBs,^212,213 β-blockers,²¹⁴ MRA,²¹⁵ and digitalis²¹⁶ did not reduce the incidence of the primary endpoint in their prospective interventional studies in HFpEF. However, large-scale observational studies and meta-analyses have indicated that ACE inhibitors/ARBs,²¹⁷ and β-blockers,^218,219 improve the prognosis of patients with HFpEF. MRAs also significantly reduced hospitalizations for heart failure.²¹⁵

In addition to the above-described common medications for HFrEF, the efficacy of nitrates in HFpEF has been evaluated. In the NEAT-HFpEF (Nitrate’s Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction) trial, a prospective interventional study, nitrates did not improve exercise capacity of patients with HFpEF, and did reduce their physical activity.²²⁰ In a large-scale observational study, the Swedish Heart Failure Registry, nitrates deteriorated the prognosis of patients with HFpEF.²²¹

VII. Nonpharmacological Therapy

1. Implantable Cardioverter Defibrillator

1.1 Secondary Prevention of Sudden Death ( Table 27)

Table 27. Recommendations and Levels of Evidence for the Use of ICD as Secondary Prevention of Sudden Death

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Patients who meet both of the following criteria: 　(1) Have heart failure associated with structural heart disease 　(2) Sustained ventricular tachycardia, ventricular fibrillation, or resuscitated from sudden cardiac death	I	A	A	I
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

Patients with sustained ventricular tachycardia or ventricular fibrillation associated with heart failure and patients resuscitated from sudden cardiac death are at a high risk of recurrent arrhythmias. Implantable cardioverter defibrillators (ICDs) are highly effective in secondary prevention of sudden cardiac death associated with coronary artery disease in these patients.^222–224 Especially, patients with heart failure and LVEF ≤35% are expected to benefit more from ICDs.^14,225,226 However, sustained ventricular tachycardia or ventricular fibrillation developed during acute phase (within 48 hours after onset) of acute coronary syndrome are not necessarily indicated for ICDs as the risk of recurrent arrhythmias is low after ischemia is treated and arrhythmic substrates are stabilized.²²⁷ As the risk of recurrent arrhythmias is high in patients in whom sustained ventricular tachycardia or ventricular fibrillation developed at least 48 hours after the onset of myocardial infarction, they are indicated for ICDs.^226,227

Although data on ICDs in secondary prevention of sudden death in patients with heart failure associated with non-ischemic dilated cardiomyopathy are limited, these patients are considered to benefit from ICDs similarly as patients with coronary disease are.^222–224

Catheter ablation is now available for hemodynamically unstable patients with ventricular tachycardia or ventricular fibrillation,²²⁸ but ICD therapy should be considered for these patients even after successful ablation.

1.2 Primary Prevention of Sudden Death ( Table 28)

Table 28. Recommendations and Levels of Evidence for the Use of ICD and WCD as Primary Prevention of Sudden Death

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Use of ICDs in patients who meet all the following criteria: 　(1) Have coronary artery disease (at least 40 days post myocardial infarction) or non-ischemic dilated cardiomyopathy 　(2) Receiving optimal medical therapy 　(3) Have NYHA Class II or greater symptoms 　(4) LVEF ≤35% 　(5) Have non-sustained ventricular tachycardia	I	A	B	II
Use of ICDs in patients who meet all the following criteria: 　(1) Have coronary artery disease (at least 40 days post myocardial infarction) or non-ischemic dilated cardiomyopathy 　(2) Receiving optimal medical therapy 　(3) Have NYHA Class II or greater symptoms 　(4) LVEF ≤35%	IIa	B	B	II
Use of ICDs in 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
Use of wearable cardioverter defibrillators (during consideration of ICD implantation and before starting treatment with ICD, <40 days post myocardial infarction, <3 months post-revascularization, or <3 months after starting drug therapy for heart failure) in patients who meet all the following criteria: 　(1) Have acute myocardial infarction or received coronary revascularization for the treatment of cardiac dysfunction, or stated drug therapy for heart failure 　(2) Have a high risk of sudden death 　(3) Expected to show changes in cardiac function during treatment	IIa	C	B	III

ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

The benefits of ICDs in patients with coronary artery disease and low LVEF have been demonstrated in clinical studies conducted mainly in North America,^14,226 including the Multicenter Automatic Defibrillator Implantation Trial (MADIT-I),²²⁹ MADIT-II,²³⁰ Multicenter Unsustained Tachycardia Trial (MUSTT),²³¹ and Defibrillator in Acute Myocardial Infarction Trial (DINAMIT)²³² in patients with coronary artery disease, the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial in patients with non-ischemic dilated cardiomyopathy,²³³ and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) in patients with coronary artery disease or non-ischemic dilated cardiomyopathy.²³⁴

Cohort studies on the prognosis of patients with coronary artery disease in Japan have indicated that patients in Japan generally have a favorable prognosis, and ICDs may not be cost effective if ICD therapy is indicated according to the criteria used in the MADIT-II trial. It is recommended that appropriate evaluations such as electrophysiological testing should be used to stratify the risk of patients with coronary artery disease.^229–231 The use of ICD for primary prevention after myocardial infarction should be considered for patients who survived for at least 40 days after the onset of myocardial infarction.

A meta-analysis of five clinical studies^233–237 in non-ischemic dilated cardiomyopathy (n=1,854) revealed that ICDs significantly reduced relative mortality risk. A recent meta-analysis including the data from the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) trial²³⁸ indicated similar results.

There are only limited data on the incidence of sudden death among patients with non-ischemic heart failure in Japan. However, the results of a cohort study on the outcome of patients with chronic heart failure³⁵ and the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART) trial²³⁹ suggested that the prognosis of heart failure and incidence of sudden death in patients with non-ischemic dilated cardiomyopathy in Japan may be similar to those in Western countries, and thus such patients should be considered for ICD therapy.

2. Cardiac Resynchronization Therapy (Table 29)

Table 29. Recommendations and Levels of Evidence for CRT

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (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.

CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

2.1 Clinical Efficacy

Since 2001, several randomized prospective studies have been conducted to assess the efficacy of cardiac resynchronization therapy (CRT) in heart failure.^{237,240–247} These studies have demonstrated that CRT improves exercise capacity and other QOL measures as well as left ventricular remodeling, and reduced all-cause mortality and hospitalizations for heart failure. A meta-analysis has indicated that CRT reduced all-cause mortality.²⁴⁸ In addition, the RD-CHF trial²⁴⁹ and the Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF) trial²⁵⁰ demonstrated the benefits of CRT in patients with heart failure who are indicated for pacemaker.

2.2 Points to Consider When Planning CRT

2.2.1 Use of Defibrillation Function

No studies have compared a CRT-pacemaker (CRT-P) and a combined CRT defibrillator (CRT-D) in Japan. The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPARISON) trial²³⁷ and a prospective registry in four European medical institutions²⁵¹ demonstrated that CRT-D was superior to CRT-P in reducing the incidence of sudden cardiac death. CRT-D is recommended for many patients, but is more expensive than CRT-P. Cost-effectiveness should also be considered.

2.2.2 CRT in Patients With Atrial Fibrillation

The Multisite Stimulation in cardiomyopathy - Atrial Fibrillation (MUSTIC-AF) trial²⁴² demonstrates the benefits of CRT in patients with heart failure in whom pacing is indicated to treat chronic bradycardic atrial fibrillation. The percentage of ventricular pacing after rate control in atrial fibrillation is also important. The Heart Rhythm Society (HRS)/European Heart Rhythm Association (EHRA)/Asia-Pacific Heart Rhythm Society (APHRS)/Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLAEC) expert consensus recommends to produce the highest achievable percentage of ventricular pacing, preferably ≥98% in ICD patients with biventricular pacing.²⁵² In patients with chronic atrial fibrillation in whom an adequate pacing percentage cannot be obtained in CRT, atrioventricular node ablation should be considered.¹⁴

2.2.3 Effects of CRT by QRS Configuration and Duration

It has been reported that about 30 to 40% of patients undergoing CRT implantation do not respond well to CRT therapy, that is non-responders. A meta-analysis of randomized controlled trials that assessed the influence of QRS configuration on the benefits of CRT therapy has revealed that only patients with a left bundle branch block (LBBB) benefit from CRT.²⁵³ The results of the Cardiac Resynchronization Therapy in Patients with Heart Failure and Narrow QRS (RethinQ) trial²⁵⁴ and the Echocardiography Guided Cardiac Resynchronization Therapy (EchoCRT) trial²⁵⁵ have suggested that CRT therapy is less effective in patients with a QRS duration of <130 msec.^14,226

2.2.4 Indications for Patients With Mild Heart Failure

The Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial,²⁵⁶ the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) trial,²⁵⁷ and the Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT) trial²⁵⁸ have reported that CRT is beneficial in patients with mild heart failure (NYHA class II or greater), and that CRT is especially indicated for patients with a QRS duration of ≥150 msec.

2.2.5 Combination With Drug Therapy

Indication for CRT should be considered only for patients who are receiving optimal medical therapy. Other than exceptional cases, CRT is not indicated for patients who underwent revascularization within the past 3 months and patients who introduced new drugs for the treatment of heart failure within the past 3 months. As some patients can receive higher doses of β-blockers after CRT is introduced,²⁵⁹ patients should be assessed regularly for whether their drug therapy is optimal.

2.3 Telemetry Monitoring ( Table 30)

Table 30. Recommendations and Levels of Evidence for the Use of Telemetry Monitoring of Implantable Device Therapy

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Introduction and management of telemetry monitoring in patients with implantable cardiac devices	IIa	A	B	I

Current implantable devices such as ICD, CRT-P, and CRT-D have telemetry functions that can send data on arrhythmic events and device information to the data center. As telemetry monitoring can send highly accurate data, device malfunctions and arrhythmias can be detected promptly.^260–264 In the Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME) trial in patients with heart failure,²⁶⁵ heart failure management through telemetry monitoring significantly reduced all-cause mortality, but these findings should be interpreted carefully with clear understanding on their methods of intervention. In Japan, only a limited number of medical institutions have introduced telemetry monitoring systems. Further studies are awaited to clarify how to utilize telemetry data in clinical practice.

3. Respiratory Support (Table 31)

Table 31. Recommendations and Levels of Evidence for Adaptive Servo-Ventilation (ASV)

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Use of ASV in the hospital setting to relieve symptoms of congestion in patients receiving guideline-based, optimized treatment for heart failure	IIa	B	B	II
Continued use of ASV in patients satisfying the above criterion who respond well to the ASV and are expected to worsen by discontinuing ASV	IIa	C	B	VI
Continued use of ASV after improvement of heart failure without reviewing its necessity	III	C	C1	VI

Respiratory support for patients with acute decompensated heart failure and patients with sleep-disordered breathing is described in the relevant sections. This section describes respiratory support for patient with chronic heart failure.

In chronic severe heart failure, respiratory support especially positive pressure ventilation improves hemodynamics and symptoms of chronic heart failure independent of improvement of sleep-disordered breathing by 1) reducing pulmonary congestion and left ventricular preload, 2) reducing left ventricular afterload, and 3) reducing the activity of the sympathetic nerve system. Continuous positive airway pressure (CPAP) can promptly increase cardiac output in patients with severe congestion, but there is no evidence on its long-term efficacy in patients with chronic heart failure with no (or only mild) sleep-disordered breathing. As adaptive servo-ventilation (ASV) has an acute effect similar to that of CPAP,²⁶⁶ and may maintain a stable tidal volume, it is considered to be more effective in reducing the activity of the sympathetic nerve system.^267,268 In fact, reports have described that ASV decreases the incidence of cardiac events in patients with heart failure with and without sleep-disordered breathing in Japan.²⁶⁹ In the Confirmatory, Multicenter, Randomized, Controlled Study of Adaptive Servo-Ventilation in Patients with Chronic Heart Failure (SAVIOR-C) trial that evaluated the efficacy of ASV in patients with chronic heart failure with and without sleep-disordered breathing in Japan, LVEF assessed as the primary endpoint did not differ significantly between the ASV and guideline-directed medical therapy, but a clinical composite response assessed as a secondary endpoint improved significantly in the ASV group as compared with the medical therapy group.²⁷⁰ In 2016, the National Health Insurance started to cover the use of ASV for the treatment of congestion in patients with heart failure who meet particular conditions. The Japanese Circulation Society and the Japanese Heart Failure Society published the second statement on appropriate use of ASV to clarify who are indicated for ASV (See Supplement 1).²⁷¹ As the Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure (SERVE-HF) trial²⁷² suggested that ASV may increase the risk of cardiovascular death, patients who meet the inclusion criteria for the SERVE-HF trial should be considered for discontinuing ASV or switching to CPAP when heart failure is stabilized after introducing ASV.

4. Exercise Therapy (Table 32)

Table 32. Recommendations and Levels of Evidence for Exercise Therapy in Patients With Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Patients with HFrEF 　Combination with drug therapy to relieve symptoms and improve exercise capacity	I	A	A	I
Patients with HFrEF 　To improve QOL, reduce cardiac accidents, and improve life expectancy	IIa	B	B	II
Patients with HFpEF with low exercise capacity 　To improve exercise capacity	IIa	C	B	IVa
Patients with heart failure after ICD or CRT-D implantation 　To improve exercise capacity and QOL	IIa	C	B	IVa
Patients with pulmonary hypertension whose symptoms are stable on drug therapy 　Consider supervised exercise therapy at experienced institutions to improve exercise capacity and QOL	IIa	B	B	II
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	B	IVb

ADL, activities of daily living; CRT-D, cardiac resynchronization therapy defibrillator; HFrEF, heart failure with reduced ejection fraction; ICD, implantable cardioverter defibrillator; QOL, quality of life.

4.1 Effects of Exercise Therapy (Supplement 2)¹⁴⁸

Exercise therapy increases peak V̇O₂ by 15 to 30% (mean of about 20%), and also improves anaerobic threshold (AT).^273–283 It has been described that exercise therapy may elevate exercise capacity by increasing the muscular mass and volume density of mitochondria in skeletal muscle,²⁷⁹ enhancing the metabolism and function of skeletal muscles,^278,284 improving the function of respiratory muscles,^285,286 and improving the endothelial function through increased nitric oxide (NO) production,^287,288 among other peripheral mechanisms.^275,279 Exercise therapy also exerts beneficial effects on neurohumoral factors such as the reduction of C reactive protein (CRP), an inflammatory substance,²⁸⁹ and cytokines (e.g., TNF-α and IL-6²⁹⁰), and improves autonomic nervous system dysfunction, which is an important prognostic factor.^291–293 A considerable body of evidence has been accumulated on the beneficial effects of exercise therapy on patients with heart failure through relieving anxiety and depression, and improving QOL.^{273,276,282,294}

The findings from the Exercise Training Meta Analysis of Trials in Chronic Heart Failure (ExTraMATCH) have indicated that exercise therapy improves the prognosis of patients with heart failure.²⁹⁵ In the Participants in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial, a large-scale randomized controlled study,²⁹⁶ exercise therapy reduced the risk of all-cause death or hospitalization by 11% and the risk of cardiovascular death or hospitalization for heart failure by 15% after adjusting for confounding factors. A Cochrane systematic review of exercise-based cardiac rehabilitation for heart failure has indicated that exercise therapy significantly reduces the risk of all-cause and heart-failure-related hospitalizations in patients with heart failure.²⁹⁷

4.2 Heart Failure in Patients With Special Conditions

The findings of randomized controlled traials^298–300 and a meta-analysis³⁰¹ in patients with heart failure with preserved ejection fraction (HFpEF) have indicated that exercise training improves exercise capacity measured by peak oxygen uptake as well as QOL in this patient population. Randomized controlled trials of exercise therapy in patients with implantable devices have reported that patients in the exercise therapy group showed significant improvement in peak oxygen uptake, NYHA functional class, and QOL score, among other measures.^302,303 A recent randomized controlled trial that evaluated effectiveness of exercise therapy in patients with pulmonary hypertension³⁰⁴ reported that patients in the exercise therapy group showed better improvement in exercise capacity and QOL as compared with the control group. The 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension recommend supervised exercise rehabilitation as a Class IIa recommendation.³⁰⁵

4.3 Methodology of Exercise Training

In patients with deconditioning, elderly patients with low muscle strength, and patients with sarcopenia or frailty, resistance training may be highly effective.^306–310 A recent study addressed the efficacy of high-intensity interval training (HIT) in heart failure.³¹¹ However, a randomized controlled study has concluded that HIT is not superior to continuous exercise training in terms of increasing exercise capacity and preventing left ventricular remodeling.³¹²

4.4 Contraindications for Exercise Therapy

Supplement 3¹⁴⁸ lists contraindications for exercise therapy.

4.5 Exercise Prescription

Exercise therapy for patients with heart failure should be conducted according to appropriate exercise prescriptions (Supplement 4).¹⁴⁸ Supervised exercise therapy is required especially for elderly patients and patients with severe left ventricular dysfunction, high-risk arrhythmias, or a risk of ischemia. These patients may benefit from exercise therapy even with low or intermediate intensity (40 to 60% of peak V̇O₂).^148,280,313

VIII. Treatment of Underlying Conditions

1. Basic Treatment Strategies

Heart failure management consists of two strategies. The first strategy is to treat heart failure, and the second is to treat the cause of heart failure. When patients showed signs and symptoms of heart failure, heart failure is related directly to patients’ complaints and sometimes risk of death, and treatment for heart failure should generally be prioritized over treatment for causative disease.

2. Underlying Conditions That May Modify Treatment Strategies

Some underlying cardiac disorders causing heart failure may require special plan for treatment sequencing. Patients with such cardiac disorders show ever-changing conditions should be treated for the causative disease and the conditions simultaneously. These conditions include acute coronary syndrome and pulmonary thromboembolism, for which revascularization is effective, arrhythmias which can be treated well by defibrillation and pacing, and acute myocarditis for which outcome cannot be readily predicted. Other cardiac disorders require careful decongestion because an abrupt change in intravascular volume may compromise hemodynamics. These disorders include structural heart diseases with significant pressure gradient such as aortic valve stenosis; severe right ventricular dysfunction and other right heart disease causing a significant increase in pulmonary vascular resistance; and severe cardiac diastolic dysfunction such as constrictive pericarditis and restrictive cardiomyopathy.

3. Comorbid Conditions Causing Advanced Stage Heart Failure

Lifestyle-related diseases such as hypertension, diabetes mellitus, and dyslipidemia are typical risk factors for Stage A heart failure, while there is little evidence on the management of these factors in Stage C or D heart failure. Conditions affecting non-cardiac organs such as chronic kidney disease and chronic obstructive pulmonary disease (COPD) also modify the risk of heart failure, but treatment strategies for these conditions in patients with heart failure have not been established yet.

IX. Pathophysiology and Treatment of Comorbidities

1. Atrial Fibrillation (Table 33)

Table 33. Recommendations and Levels of Evidence for Treatment of Atrial Fibrillation in Patients With Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Treatment of atrial fibrillation with a rapid ventricular response in patients with acute heart failure
Urgent electrical cardioversion 　To restore to sinus rhythm in the patients with hemodynamically compromised atrial fibrillation in whom heart rate control is difficult with drug therapy	I	C	C1	VI
Landiolol 　To control heart rate	IIa	B	B	II
Digoxin 　To control heart rate	IIa	C	B	II
Oral or intravenous non-dihydropyridine calcium channel blockers 　To control heart rate	III	C	D	II
Sodium channel blockers (with slow activation kinetics) 　To maintain sinus rhythm in patients who returned to sinus rhythm and those who received defibrillation	III	C	D	II
Rhythm control
Oral amiodarone 　To maintain sinus rhythm	IIa	B	B	II
Elective electrical cardioversion 　To treat persistent atrial fibrillation lasting for <1 year without substantial left atrial enlargement	IIa	C	C1	VI
Catheter ablation 　To treat symptomatic atrial fibrillation in patients with heart failure who do not respond well to rate control therapy or drug therapy for heart failure	IIb	C	B	II
Oral sodium channel blockers (with slow activation kinetics) 　To maintain sinus rhythm in patients who returned to sinus rhythm and those who received defibrillation	III	A	D	II
Rate control
Oral β-blockers and oral digoxin 　To control heart rate	IIa	B	A	I
Oral amiodarone 　To control heart rate in patients in whom monotherapy with β-blockers or digoxin or combination of the two drugs are not effective in rate control	IIb	C	C1	VI
Oral non-dihydropyridine calcium channel blockers 　To control heart rate	III	C	D	II
Anticoagulant therapy
Use of the CHADS2 score and the HAS-BLED score to predict the benefits of anticoagulant therapy	I	B	A	II
Oral anticoagulant therapy for the treatment of atrial fibrillation in patients with heart failure (unless contraindicated)	I	A	A	I
Anticoagulant therapy for 3 weeks before and 4 weeks after pharmacological or electrical cardioversion in patients with atrial fibrillation lasting ≥48 hours	I	B	A	II
Electrical cardioversion with heparin after ruling out intracardiac thrombi by transesophageal echocardiography in patients with atrial fibrillation who are not receiving anticoagulant therapy	I	C	A	II
Considering DOACs as first-line therapy	IIa	B	A	II
Concomitant use of DAPT and anticoagulation after coronary intervention in patients with heart failure and ischemic heart disease	IIb	C	C2	II
Use of DOACs in patients using prosthetic valves (mechanical or bioprosthetic valves) and in patients with rheumatic mitral valve disease	III	B	D	II

DAPT, dual antiplatelet therapy; DOAC, direct oral anticoagulant.

1.1 Pathophysiology

Atrial fibrillation is one of the most common types of arrhythmias associated with heart failure, and is known to negatively affect cardiac function and hemodynamics, and worsen heart failure.³¹⁴ A meta-analysis³¹⁵ has revealed that β-blockers for the treatment of atrial fibrillation do not improve the prognosis of patients with severe chronic heart failure associated with atrial fibrillation. Moreover, β-blockers reduced mortality in patients with heart failure in sinus rhythm and achieving a lower heart rate, but it was not observed in patients with atrial fibrillation. However, atrial fibrillation in the patients with acute heart failure which causes or is expected to cause an abrupt disturbance of hemodynamics or worsening symptoms should receive appropriate treatments. Treatment strategies for atrial fibrillation are classified into “rate control” that accepts the presence of atrial fibrillation and controls heart rate, and “rhythm control” that aims to return to and maintain sinus rhythm. As the effect of atrial fibrillation on hemodynamics differs between patients with acute heart failure and patients with chronic heart failure, appropriate treatment strategies should be selected to address the relevant condition.

1.2 Treatment

1.2.1 Treatment for Atrial Fibrillation With a Rapid Ventricular Response Complicated With Acute Heart Failure

When atrial fibrillation develops during the treatment of acute heart failure and is considered highly likely to negatively affect hemodynamics, electrical cardioversion should be performed immediately. Patients who are not receiving appropriate anticoagulation therapy in whom the duration of atrial fibrillation is unknown should undergo transesophageal echocardiography to confirm the absence of thrombus in the left atrium before starting defibrillation.^316–318 Patients with symptoms of heart failure who need rate control therapy immediately may be treated with intravenous digitalis.³¹⁹ Landiolol has been reported to be beneficial effect for controlling the heart rate as compared with digoxin in the atrial fibrillation or atrial flatter with left ventricular dysfunction, and the use of this drug for this indication is covered with the National Health Insurance in Japan.³²⁰ Non-dihydropyridine calcium channel blockers (e.g., verapamil and diltiazem) are contraindicated for patients with decompensated heart failure as they may worsen heart failure via their negative inotropic effects.¹⁶

1.2.2 Rate Control

A meta-analysis of clinical trials in Western countries has concluded that β-blockers do not improve the prognosis of patients with chronic heart failure and atrial fibrillation, but many studies included in the analysis were conducted in patients with severe heart failure such as NYHA Class III or IV and patients with LVEF <30%.³¹⁵ It is likely that atrial fibrillation rather than heart rate affects the prognosis of this patient population. On the other hand, a registry of patients with moderate or severe heart failure associated with atrial fibrillation has reported that β-blockers significantly reduced all-cause mortality, and mortality increased significantly in patients with a heart rate of >100 bpm.³²¹ Accordingly, physicians should be aware that the benefits of β-blockers on prognosis may differ depending on the severity of heart failure. Patients with atrial fibrillation who have severe symptom due to tachycardia, and those with elevated and sustained heart rate of >130 bpm are at high risk for developing heart failure, and thus should receive rate control.³²² In the Guidelines for Pharmacological of Atrial Fibrillation (JCS 2013) proposed by the Japanese Circulation Society, the target heart rate at rest is set at <110 bpm for patients without heart failure. When no improvement in symptoms or cardiac function is observed, the target should be set at <80 bpm at rest and <110 bpm during moderate exercise.³²³

Patients with chronic heart failure and atrial fibrillation with mild symptoms and stable hemodynamic should be considered for rate control in atrial fibrillation first. Carvedilol or bisoprolol is an oral β-blocker of choice, and should be started at a low dose considering the severity of heart failure. Oral digoxin exerts rate control and cardiotonic actions, but unlike β-blockers, may reduce heart rate at night.^324,325

1.2.3 Rhythm Control

Rhythm control is selected for patients in whom rate control cannot be achieved with drug therapy and patients in whom maintaining sinus rhythm is beneficial in maintaining hemodynamics and managing heart failure. Amiodarone is the first-choice of oral drugs for rhythm control used in patients with cardiac dysfunction. In Japan, low-dose amiodarone therapy has been effective in maintaining sinus rhythm and reducing heart rate in patients with heart failure and atrial fibrillation,³²⁶ and this use is covered by the National Health Insurance in Japan. Regardless of whether heart failure is acute or chronic, sodium channel blockers (with slow kinetic activation kinetics), which may exert negative inotropic action, must not be used to maintain sinus rhythm in patients with heart failure and atrial fibrillation.³²⁷

1.2.4 Anticoagulant Therapy

The CHADS₂ score has been used extensively to assess the risk of cerebral infarction and systemic embolism in patients with atrial fibrillation (Supplement 5),³²⁸ and is used when initiating anticoagulant therapy in Japan. As the stroke rate without antithrombotic therapy is as high as 1.9 per 100 patient-years even in patients with a CHADS₂ score of 0,³²⁸ Western countries use the CHA₂ DS₂-VASc score to specify truly low-risk patients.^329,330 As patients with heart failure and atrial fibrillation have a CHADS₂ score of ≥1, anticoagulant therapy should be considered for them unless it is contraindicated.

Atrial fibrillation in patients with heart failure have been treated with anticoagulant therapy using warfarin. However, direct oral anticoagulants (DOACs), that have been launched recently, have changed anticoagulant strategies for atrial fibrillation in patients with heart failure.^331–334 DOACs are as effective as warfarin in patients with heart failure, and are safer than warfarin as the risk of major bleeding such as intracranial hemorrhage is lower in patients treated with DOACs than those treated with warfarin.^335,336 However, DOACs are indicated only for patients with non-valvular atrial fibrillation, and warfarin should be used for patients with severe mitral valve stenosis and patients using valve prostheses (mechanical valves or bioprosthetic valves).³³⁷ As renal function may change as heart failure advances or improves during treatment, the dose of anticoagulant drugs, especially DOACs, should be adjusted carefully according to the criteria for dose reduction or careful administration. The HAS-BLED score has been used to assess the risk of bleeding during anticoagulant therapy.^337a

Patients with heart failure due to ischemic heart disease often receive dual antiplatelet therapy (DAPT) for percutaneous coronary intervention (PCI). When accompanied by atrial fibrillation, anticoagulant therapy is added and the risk of bleeding may further increase.³³⁸ The European Society of Cardiology (ESC) guidelines for the management of atrial fibrillation provide recommendations on the contents and duration of anticoagulant and antiplatelet therapy according to the risk of stroke, the risk of bleeding, and patient characteristics.³³⁹ In the What is the Optimal antiplatelet and anticoagulant therapy in patients with oral anticoagulation and coronary Stenting (WOEST) trial,³³⁸ patients receiving warfarin for the treatment of stable angina underwent PCI were randomized to triple therapy (warfarin, aspirin, and clopidogrel) or duel therapy (warfarin, and clopidogrel). Comparisons between the two groups in terms of the incidence rates of bleeding events and thromboembolic events revealed that all-cause mortality and the incidence of bleeding events were significantly lower in the duel therapy group, and the incidence rates of myocardial infarction, stroke, and in-stent thrombosis did not differ between the two groups.

2. Ventricular Arrhythmias (Table 34)

Table 34. Recommendations and Levels of Evidence for Treatment of Ventricular Arrhythmias in Patients With Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Removal of factors leading to ventricular arrhythmia 　Interventions to reduce mental/physical stress and pain, correct electrolyte imbalance, and reduce myocardial ischemia	I	A	C1	VI
Electrical defibrillation 　To treat ventricular fibrillation and sustained ventricular tachycardia with decompensated hemodynamics	I	C	C1	VI
Intravenous nifekalant or amiodarone 　To prevent recurrence of ventricular tachycardia and ventricular fibrillation	IIa	C	B	IVb
Oral amiodarone 　To avoid implantable cardioverter defibrillator (ICD) shocks for life-threatening arrhythmias in patients with heart failure after ICD implantation	IIa	B	B	I
Catheter ablation 　To avoid ICD shocks for repeated life-threatening arrhythmias in patients heart failure after ICD implantation	IIb	C	B	IVa
Oral antiarrhythmic drugs 　Use in patients with asymptomatic ventricular arrhythmia and low cardiac function	III	A	D	II

Ventricular arrhythmias associated with heart failure includes premature ventricular contractions, non-sustained/sustained ventricular tachycardia and ventricular fibrillation. Especially hemodynamically intolerable ventricular tachycardia and ventricular fibrillation should be treated electrical defibrillation immediately. Intravenous amiodarone and nifekalant, as antiarrhythmic drugs, have a rapid onset of actions and are expected to be highly effective in preventing ventricular arrythmias.^340,341 Also, risk factors and predisposing factors for life-threatening ventricular arrhythmias, such as electrolyte imbalance and use of proarrhythmic drugs, should be identified and treated accordingly. When myocardial ischemia is involved in the development of arrhythmia, revascularization to treat the ischemia is important. Polymorphic ventricular tachycardia with prolonged QT interval³⁴² and torsade de pointes in the patients with heart failure should be confirmed and treated for electrolyte imbalance such as hypokalemia and hypomagnesemia. Intravenous magnesium sulfate is also effective.³⁴³

In patients with an implantable cardioverter defibrillator (ICD), the experience of ICD shocks may cause physical and/or mental stress, leading to frequent ICD shocks. Patients who have three or more episodes of life-threatening ventricular arrhythmia within 24 hours, so-called “electrical storm”, and in case of refractory to ICD therapy should receive percutaneous cardiopulmonary support (PCPS) to stabilize hemodynamics and treat arrhythmias. When sustained ventricular arrhythmia cannot be controlled with drug therapy, catheter ablation should also be considered.^344,345 Oral β-blockers are effective in preventing the recurrence of life-threatening ventricular arrhythmia and sudden death in patients with chronic heart failure.^192–194 Amiodarone is another treatment option,³⁴⁶ but careful observation is required because of its serious adverse drug reactions. Nonpharmacologic therapy using ICDs is mainly used to prevent sudden death in patients with heart failure.²³⁴ Antiarrhythmic drugs are used as adjunctive therapy to reduce the frequency of arrhythmic episodes.

3. Bradyarrhythmia (Table 35)

Table 35. Recommendations and Levels of Evidence for Pacemaker Treatment for Bradyarrhythmia in Patients With Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Pacing for patients with symptomatic heart failure due to bradycardia caused by poor sinus function, sinoatrial block, sinus arrest, or poor rate response during exercise, or caused by second-degree, advanced, or third- degree atrioventricular block (including patients with bradycardia caused by long-term necessary drug therapy)	I	C	A	VI
Pacing for patients with symptomatic heart failure due to bradycardic atrial fibrillation (including patients with bradycardia caused by long-term necessary drug therapy)	I	C	A	VI
Pacing for patients with symptomatic heart failure which has not been confirmed to be caused by bradyarrhythmia	IIa	C	B	VI

When patients have symptoms of cerebral ischemia associated with bradycardia caused by drug therapy, dose reduction should be considered first. The ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure recommend that when sinus arrest lasting for >3 seconds, bradycardia of <50 bpm in sinus rhythm or <60 bpm in atrial fibrillation is occurred, the dose of rate limiting medications should be reconsidered.¹⁶ In patients with atrial fibrillation and heart failure, β-blockers and other drugs are effective in the treatment of heart failure. Patients in whom continuation or dose escalation of β-blocker therapy for heart failure is necessary may be considered for pacemaker implantation. Patients with heart failure and bradyarrhythmia who are indicated for pacemaker should receive atrioventricular synchronization pacing unless permanent atrial fibrillation is present. Some patients with heart failure may have a wide QRS complex as a result of ventricular pacing for the treatment of bradyarrhythmia, and need biventricular cardiac pacing (See Section “ 2. Cardiac Resynchronization Therapy ” in Chapter “ VII. Nonpharmacologic Therapy ”).

4. Coronary Artery Disease (Table 36)

Table 36. Recommendations and Levels of Evidence for Drug Therapy for Heart Failure in Patients With Coronary Artery Disease

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
ACE inhibitors
Use in patients with congestive heart failure or left ventricular systolic dysfunction	I	B	A	I
Use within 24 hours after onset of acute myocardial infarction in patients who are highly likely to have left ventricular dysfunction (LVEF <40%) or heart failure	I	A	A	I
Use in post-myocardial infarction patients with left heart dysfunction	I	A	A	I
Use in patients with myocardial infarction who have normal left heart function, but have hypertension, diabetes mellitus, or a moderate to high risk of developing cardiovascular accidents	I	A	A	I
Use in all patients with acute myocardial infarction within 24 hours after onset	IIa	B	B	II
Use in patients with normal cardiac function and low risk of cardiovascular accidents	IIa	B	B	II
ARBs
Starting treatment in the acute phase of myocardial infarction in patients intolerable to ACE inhibitors who have symptomatic heart failure or LVEF of ≤40%	I	A	A	I
Use in combination with ACE inhibitors for the treatment of myocardial infarction in patients with left ventricular systolic dysfunction in whom the risk of renal dysfunction is considered low	IIb	B	C2	II
β-blockers
Use in patients other than low-risk patients* who are not contraindicated for β-blockers	I	A	A	I
Use with upward dose titration in patients with moderate or severe left heart dysfunction	I	B	A	II
Use in low-risk patients*	IIa	B	B	II
Monotherapy in patients in whom coronary spasm is involved	III	B	C2	V
MRAs
Use at low doses for the treatment of moderate or severe heart failure in patients without renal dysfunction or hyperkalemia	IIa	B	B	II

*Patients after successful revascularization of the culprit artery of myocardial infarction who have normal or nearly normal left heart function and do not have serious ventricular arrhythmia. ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist.

4.1 Pathophysiology

In addition to hypertension and dilated cardiomyopathy, coronary artery disease is one of the most common conditions that underlies heart failure.³⁴⁷ The prevalence of coronary heart disease among patients with heart failure was 23% in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-1 Study in which patients were registered from 2000 to 2004, but increased to 47% in the CHART-2 Study in which patients were registered from 2006 to 2010.^30,348 The prevalence of coronary heart disease among patients with acute heart failure was 31% in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry³⁴⁹ and 32% in the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).³² The prevalence of patients with ischemic heart failure with preserved LVEF is increasing. For example, in the CHART Studies, the prevalence of ischemic heart failure among patients with LVEF ≥50% was increased from 19% in the CHART-1 Study to 45% in the CHART-2 Study.³¹

In the CHART-1 Study, three-year mortality in patients with heart failure following myocardial infarction was 29%, which was higher than that in patients with non-ischemic heart failure (12%).³⁵⁰ In the ATTEND study, the mortality in patients with acute heart failure due to ischemic heart disease was similar to those in patients with acute heart failure due to other diseases among patients with LVEF ≥40%, while it was as high as in patients with acute heart failure due to valvular heart disease, both of which were higher that the mortality in those with acute heart failure due to other diseases among those with LVEF <40%.³⁵¹ Three-year mortality in patients with ischemic heart disease with a NYHA class of II or greater was 29% in the CHART-1 Study, and 15% in the CHART-2 Study, showing a decrease in mortality over time in the CHART Studies.³¹

Myocardial ischemia impairs systolic and dilative functions of the heart, and myocardial injury due to myocardial infection causes ventricular dysfunction. Myocardial ischemia and injury may cause fatal arrhythmias and compromise hemodynamics. Patients with coronary risk factors such as lifestyle-related diseases should be monitored carefully as they are susceptible to arteriosclerosis or cardiac dysfunction. Treatment of ischemic heart disease should aim at the management of 1) cardiac function, 2) myocardial ischemia, 3) arrhythmia, and 4) coronary risk factors.

4.2 Treatment

4.2.1 Acute Heart Failure

a. Heart Failure Associated With Acute Myocardial Infarction

In patients with acute myocardial infarction, an abrupt loss of cardiac pump function may lead to acute heart failure. Accordingly, patients with acute myocardial infarction should also receive oxygen therapy and vasodilators to treat acute heart failure as well (See Section “ 3. Treatment Strategies and Flowcharts ” in Chapter “ X. Acute Heart Failure ”). Whenever necessary, hemodynamics monitoring via Swan-Ganz catheterization should be conducted and PCI, coronary artery bypass grafting (CABG), thrombolysis or other appropriate reperfusion therapy should be conducted to treat myocardial ischemia. Additional treatment should be initiated in the acute phase to prevent left ventricular remodeling, and intra-aortic balloon pumping (IABP) or other circulatory assist devices should also be considered if necessary (See Section “ 2.2. Percutaneous Circulatory Support for Patients With Acute Heart Failure ” in Chapter “ XI. Surgical Treatment ”). Moreover, angiotensin converting enzyme (ACE) inhibitors should be started in acute phase to prevent long-term cardiac remodeling,³⁵² and β-blockers should be started immediately after hemodynamics is stabilized.³⁵³ Treatment of arrhythmias, and surgical treatment of mechanical complications and ischemic mitral valve insufficiency are described in other sections (From Section “ 1. Atrial Fibrillation ” to “ 3. Bradyarrhythmia ” in Chapter “ IX. Pathophysiology and Treatment of Comorbidities ”, and “ 5.5. Treatment of Mechanical Complications Associated With Acute Myocardial Infarction ” in Chapter “ X. Acute Heart Failure ”).

b. Acute Exacerbations of Ischemic Heart Failure

In patients with ischemic heart failure, progression of coronary artery lesions, coronary spasm, anemia due to gastrointestinal bleeding, tachycardia due to paroxysmal atrial fibrillation, and/or excessive daily activities may cause imbalance of oxygen supply and demand, and then myocardial (subendocardial) ischemia may occur, resulting in development of acute heart failure due to acute diastolic or systolic dysfunction.³⁵⁴ Patients with diabetes mellitus or hypertension who have cardiac hypertrophy are susceptible to subendocardial ischaemia,³⁵⁵ and may experience an abrupt onset of pulmonary edema due to acute diastolic dysfunction.³⁵⁶ Such patients should be carefully observed, and should undergo reperfusion therapy such as PCI and CABG whenever necessary. Patients with systolic dysfunction due to chronic myocardial ischemia (myocardial hibernation)³⁵⁷ should also be considered for PCI or CABG.

4.2.2 Chronic Heart Failure

Treatment of chronic ischemic heart failure is basically same as other types of heart failure, and mainly consists of assessment of cardiac function (cardiac protection) and myocardial ischemia, prevention of arrhythmic events, and management of coronary risk factors.

For cardiac protection in patients with ischemic heart failure and reduced LVEF, β-blockers and renin-angiotensin inhibitors (e.g., ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists [MRAs]) are mainly used (Table 36).^{192–194,215,358–360} These drugs should be started at low doses to avoid worsening heart failure. Nitrates have not been demonstrated to improve long-term prognosis,²⁰⁵ but have been shown to improve symptoms of heart failure and hemodynamics³⁶¹ and are the first-line treatment for angina pectoris. Nicorandil and diuretics should also be considered as needed.

Patients with angina symptoms or proven to have ischemia due to cardiac dysfunction should be considered for PCI or CABG.^362,363 A cohort study in Japan have suggested that the CABG is superior to PCI in patients with heart failure associated with severe coronary artery disease.³⁶⁴ According to the recommendations in the Guidelines for Non-Pharmacotherapy of Cardiac Arrhythmias (JCS 2011) issued by the Japanese Circulation Society, indications for ICD should be considered as a primary prevention therapy.³⁶⁵

For management of risk factors of coronary heart disease and details about exercise therapy, see Sections “ 6. Hypertension ” to “ 9. Hyperuricemia/Goat ” in Chapter “ IX. Pathophysiology and Treatment of Comorbidities ” and Section “ 4. Exercise Therapy ” in Chapter “ VII. Nonpharmacologic Therapy ”. Regarding management of dyslipidemia and smoking that are not described in the present guidelines, refer to other relevant guidelines.

5. Valvular Heart Disease (Table 37)

Table 37. Recommendations and Levels of Evidence for the Treatment of Valvular Disease in Patients With Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Valvular replacement/repair in patients with heart failure associated with severe, structural mitral or aortic valve disease (excluding patients at significantly high risk for surgery)	I	B	B	III
Conducting standard heart failure treatment (e.g., drug therapy and CRT) to reduce mitral regurgitation in patients with heart failure and secondary (functional) mitral valve insufficiency	I	C	C1	IVb
Dobutamine-stress or exercise echocardiography to consider for aortic valve replacement in symptomatic patients with low-flow low-gradient aortic stenosis (aortic valve area <1.0 cm2, aortic transvalvular pressure gradient <40 mmHg) and low LVEF	IIa	C	C1	IVb
TAVI in patients with heart failure due to severe aortic stenosis who are determined at high risk for surgery by heart team, and are considered to have a life expectancy of more than 1 year	I	B	B	II

CRT, cardiac resynchronization therapy; LVEF, left ventricular ejection fraction; TAVI, transcatheter aortic valve implantation.

Patients with heart failure and valvular disease are at high risk for poor outcome. If the main cause of heart failure is valvular disease itself, following the treatment strategy for valvular disease are recommended (See the Guidelines for Surgical and Interventional Treatment of Valvular Heart Disease [JCS 2012]).³⁶⁶ Patients with valvular disease secondary to dilated cardiomyopathy or other heart disease should be treated for the relevant underlying cardiac diseases.

5.1 Mitral Valve Insufficiency

In patients with dilated or ischemic cardiomyopathy, mitral valve insufficiency secondary to mitral valve tethering or mitral annular enlargement may lead to further worsening of hemodynamics. However, no consensus has been reached whether interventions for mitral insufficiency may improve the prognosis of patients with moderate or severe secondary mitral valve insufficiency. In 2016, the Cardiothoracic Surgical Trials Network conducted an interventional study and reported that CABG plus mitral valve repair does not improve the outcome in patients with moderate secondary mitral valve insufficiency and ischemic heart disease.³⁶⁷ On the basis of these findings, the ACC/AHA guideline for the management of patients with valvular heart disease, which was revised partially in 2017, describes that the usefulness of mitral valve repair in patients with moderate secondary mitral valve insufficiency and ischemic heart disease who are undergoing CABG is unclear.³⁶⁸

5.2 Tricuspid Valve Insufficiency

As a result of right ventricular overload due to left-sided heart failure or pulmonary hypertension, tricuspid valve insufficiency secondary to tricuspid annular enlargement and tricuspid valve tethering is often observed and is a factor of poor prognosis.³⁶⁹ Patients with secondary tricuspid valve insufficiency should first be treated to correct underlying condition causing heart failure. During surgery for left-sided valve surgery, concomitant tricuspid valve repair is recommended.^366,370,371

5.3 Aortic Valve Stenosis

When aortic stenosis develops in patients with left ventricular systolic dysfunction due to underlying cardiac condition, the severity of aortic stenosis should be examined carefully. Treatment strategies for patients with low-flow, low-gradient aortic stenosis and reduced LVEF should be based on changes in aortic valve area and aortic transvalvular pressure gradient before and after an increase of stroke volume during dobutamine stress echocardiography.

For details about transcatheter aortic valve implantation (TAVI) and transcatheter aortic valve replacement (TAVR), see Section “ 1. Surgical Procedures and TAVI ” in Chapter “ XI. Surgical Treatment ”.

6. Hypertension

6.1 Pathophysiology

Hypertension is a major risk factor on heart disease independent of age and left ventricular dysfunction.^172,372 Appropriate treatment for hypertension reduces the risk of the development of heart failure.^150–152

6.2 Treatment

Patients with hypertension and cardiovascular disease are classified as high risk, and it is recommended to start antihypertensive treatment promptly, as well as lifestyle modifications (e.g., low-salt healthy diet, exercise, weight reduction in obesity patients, and reducing alcohol consumption).¹⁵⁴ However, no clear evidence has been accumulated on treatment goals of blood pressure in patients with heart failure and hypertension, as the etiology and pathophysiology of heart failure are diverse. Although, there have been controversies about optimal blood pressure targets for this patient population,^373,374 and it is difficult to establish common goals for diverse patients, target systolic blood pressure of 110 to 130 mmHg has been supported in the United States,³⁷⁵ and is the same in Japan.

6.2.1 Patients With HFrEF and Hypertension ( Table 38)

Table 38. Recommendations and Levels of Evidence for Drug Therapy for HFrEF in Patients With Hypertension

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
ACE inhibitors	I	A	A	I
ARBs (use in patients intolerable to ACE inhibitors)	I	A	A	I
β-blockers	I	A	A	I
MRAs	I	A	A	II
Diuretics	I	B	A	I
Calcium channel blockers*	IIa	B	B	II

*Calcium channel blockers other than long-acting dihydropyridines should not be used as they have negative inotropic effects. ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; MRA, mineralocorticoid receptor antagonist.

ACE inhibitors^182,184,376 and β-blockers^{193–195,377,378} have been demonstrated to improve the long-term prognosis of patients with heart failure and hypertension, and monotherapy or combination therapy of these drug classes are first-line treatment. Patients intolerable to ACE inhibitors may be treated with ARBs.^168,187,188 Treatment with β-blockers should be started at low doses, and the dose should be titrated gradually based on tolerability. In patients who do not respond well to antihypertensive drugs or patients with heart failure associated with organ congestion, diuretics should be added, and MRAs added to standard therapy is expected to improve prognosis in patients with severe conditions.^163,164,189 Among calcium channel blockers, long-acting dihydropyridines can be used safely without compromising the prognosis of patients with heart failure,³⁷⁹ but other types of calcium channel blockers with negative inotropic effects should be avoided.

6.2.2 Patients With HFpEF and Hypertension ( Table 39)

Table 39. Recommendations and Levels of Evidence for Drug Therapy for HFpEF in Patients With Hypertension

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Appropriate blood pressure management	I	B	B	II
Identification and treatment of underlying disease	I	C	B	VI

As heart failure with preserved ejection fraction (HFpEF) is generally caused by both cardiovascular diseases (e.g., atrial fibrillation, hypertension, coronary artery diseases, and pulmonary hypertension) and non-cardiovascular diseases (e.g., diabetes, chronic kidney disease, anemia, and COPD), patients should be examined for these underlying conditions and should be treated accordingly.^380,381

As hypertension is one of the most common underlying conditions of HFpEF,³⁸² blood pressure control is considered essential. However, there is no sufficient evidence regarding optimal antihypertensive regimens or treatment targets for this patient population, and patients should be treated individually to control blood pressure.

6.2.3 Acute Heart Failure

Patients with acute heart failure except for those corresponding to the clinical scenario (CS) #3 are treated with vasodilators and diuretics according to their conditions. See Chapter “ X. Acute Heart Failure ” for detail.

7. Diabetes Mellitus

7.1 Pathophysiology

The prevalence of diabetes mellitus among patients with heart failure increased from 13% in 1989 to 47% in 1999.³⁸³ Also, about half of patients with diabetes mellitus have been reported to have left ventricular diastolic dysfunction³⁸⁴ and poor cardiovascular outcome including heart failure.³⁸⁵

As diabetes mellitus is an independent risk factor for heart failure,³⁸⁶ interventions for diabetes mellitus are needed to prevent the development or progression of heart failure.

7.2 Treatment

7.2.1 Treatment of Heart Failure in Patients With Diabetes Mellitus

Although no clinical studies have evaluated the effectiveness of ACE inhibitors, ARBs, or β-blockers with proven efficacy in heart failure in patients with heart failure and diabetes mellitus, sub-analyses of large-scale clinical trials of ACE inhibitors and ARBs have demonstrated efficacy in patients with heart failure with or without diabetes mellitus.^187,387,388 β-blockers are expected to exert similar efficacy regardless of whether diabetes mellitus is present or not.^389,390 The efficacy of MRAs in the treatment of heart failure has also been demonstrated in patients with and without diabetes mellitus.^164,391

These findings suggest that patients with heart failure and diabetes mellitus should be treated similarly to those without diabetes mellitus.

7.2.2 Treatment of Diabetes Mellitus in Patients With Heart Failure ( Table 40)

Table 40. Recommendations and Levels of Evidence for the Treatment of Diabetes Mellitus in Patients With Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Comprehensive approach including life style modification such as diet and exercise	I	A	A	I
SGLT2 inhibitors (empagliflozin,* canagliflozin**)	IIa	A	B	II
Thiazolidinediones	III	A	D	I

*In the EMPA-REG OUTCOME trial of empagliflozin,¹⁷⁵ all participants had a history of cardiovascular disease. **In the CANVAS trial of canagliflozin,¹⁷⁸ 34% of the participants were at high risk of cardiovascular events, and 66% of the participants had a history of cardiovascular disease. The dose range of canagliflozin in the CANVAS study was wider than the approved dose range in Japan. SGLT, sodium glucose cotransporter.

Although no evidence has been obtained on the efficacy of specific treatment strategies to control diabetes mellitus in patients with heart failure, comprehensive approach depending on individual pathology using guidelines-based antidiabetic drugs, as well as lifestyle modifications such as diet and exercise, is important.

In cardiovascular outcome trials of most of the currently available incretin-based drugs, neither beneficial effects on heart failure nor increased the risk of poor outcome was observed in patients with heart failure. However, in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus - Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial,³⁹² the incidence of hospitalizations for heart failure increased significantly in patients receiving saxagliptin.³⁹³

Among currently available SGLT2 inhibitors, empagliflozin¹⁷⁵ and canagliflozin¹⁷⁸ have been demonstrated to reduce the composite endpoint of major adverse cardiovascular events including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, and the number of hospitalizations for heart failure in patients with type 2 diabetes mellitus and high cardiovascular risk, and are expected to improve the cardiovascular prognosis of patients with type 2 diabetes mellitus and high cardiovascular risk regardless of the presence or absence of heart failure.^176,177 However, as patients complicated with heart failure account for only 10 to 15% of patients enrolled in these large-scale clinical studies of SGLT2 inhibitors, further studies are necessary to clarify the beneficial effects of these drugs on heart failure. Also, as there has been no evidence indicating that these results reflect class effects of SGLT2 inhibitors, the results of large-scale clinical studies of other SGLT2 inhibitors are awaited. In addition, further studies should be conducted to clarify the efficacy of SGLT2 inhibitors in patients aged 75 and over.

Accordingly, physicians should treat patients with diabetes mellitus and heart failure carefully considering pharmacological characteristics of antidiabetic agents and results of clinical trials while avoiding hypoglycemia.

8. CKD and Cardiorenal Syndrome

8.1 Pathophysiology

As patients with heart failure often have renal dysfunction, treatment strategies should be developed based on the patient’s estimated glomerular filtration rate (eGFR), a clinical indicator of renal function.

The present guidelines describe the benefits of drugs according to chronic kidney disease (CKD) stages that are based on eGFR. Patients with an eGFR of <60 mL/min/1.73 m² are classified into CKD stage 3 (eGFR: 30 to 59 mL/min/1.73 m²), stage 4 (15 to 29 mL/min/1.73 m²) and stage 5 (<15 mL/min/1.73 m²).

8.2 Treatment ( Table 41)

Table 41. Recommendations and Levels of Evidence for Drug Therapy for Patients With Chronic Kidney Disease (CKD) and Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
CKD Stage 3 (eGFR 30 to 59mL/min/1.73 m2)
β-blockers	I	A	A	I
ACE inhibitors	I	A	A	I
ARBs	I	B	A	II
MRAs	I	A	A	I
Loop diuretics	I	C	C1	VI
CKD Stage 4 to 5 (eGFR <30 mL/min/1.73 m2)
β-blockers	IIa	B	B	II
ACE inhibitors	IIb	B	C1	III
ARBs	IIb	C	C1	IVb
MRAs	IIb	C	C2	V
Loop diuretics	IIa	C	C1	VI

ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; CKD, chronic kidney disease; MRA, mineralocorticoid receptor antagonist.

Many large-scale clinical studies in acute or chronic heart diseases excluded patients with renal dysfunction. In general, patients with CKD stage 3 can be treated almost similarly to patients without CKD. However, little evidence has been obtained in terms of treatment of heart failure in patients with CKD stage 4 or 5, and such patients are treated at the discretion of the attending physicians and/or consulting specialists.

8.2.1 β-Blockers

The efficacy of β-blockers in the treatment of heart failure has been established. A meta-analysis of the data from the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS ) trial³⁹⁴ and Carvedilol Post-infarct Survival Controlled Evaluation (CAPRICORN ) trial¹⁵⁹ that assessed the efficacy of carvedilol in patients with heart failure revealed that carvedilol significantly improved the prognosis of patients with CKD stage 3 with an eGFR of 45 to 60 mL/min/1.73 m².³⁹⁵ In a sub-analysis of the Cardiac Insufficiency Bisoprolol Study II (CIBIS II) trial that assessed the efficacy of bisoprolol, the drug improved the prognosis of patients with an eGFR of <45 mL/min/1.73 m² or 45 to 60 mL/min/1.73 m².³⁹⁶ In a cohort study investigating the efficacy of β-blockers in patients with heart failure who are undergoing hemodialysis, oral β-blockers significantly improved the prognosis of this patient population.³⁹⁷

8.2.2 ACE Inhibitors and ARBs

The efficacy of angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in patients with heart failure has been established. In the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) trial¹⁸² in which patients with a serum creatinine level of ≥3.4 mg/dL were excluded, participants had a mean serum creatinine level of 1.4 mg/dL and an eGFR of about 45 mL/min/1.73 m², which indicate that CKD was prevalent among the participants. In a subanalysis that dichotomized patients according to mean serum creatinine level, the efficacy of enalapril was comparable between patients with higher and lower serum creatinine levels. In a study in patients with heart failure with a serum creatinine level of ≥2.4 mg/dL or a creatinine clearance of <30 mL/min (CKD stage 4 or 5), renin-angiotensin (RA) system inhibitors significantly improved the prognosis of these patients.³⁹⁸ It has also been reported that addition of oral RAS inhibitors improved the prognosis of hemodialysis patients receiving oral β-blockers as compared with no addition of RAS inhibitors.³⁹⁷ As ACE inhibitors and ARBs may rarely reduce renal function or cause hypokalemia in patients with CKD stage 4 or 5 and elderly patients with CKD, these drugs should be started at low doses.³⁹⁹

8.2.3 MRAs

The Randomized Aldactone Evaluation Study (RALES) trial¹⁸⁹ and the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS-HF) trial¹⁶³ have reported the benefits of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure, but patients with a serum creatinine level of ≥2.5 mg/dL and patients with an eGFR of <30 mL/min/1.73 m² were excluded respectively and almost no evidence is available on the benefits of MRAs in patients with CKD stage 4 or 5. However, in patients with CKD stage 3 (eGFR <60 mL/min/1.73 m²), who accounted for 48% and 33% of the participants in the RALES and EPHESUS-HF trials, MRAs improved prognosis in a similar degree to patients with an eGFR ≥60 mL/min/1.73 m².^400,401 MRAs should be used carefully in patients receiving ACE inhibitors or ARBs because of concern about hyperkalemia or renal dysfunction.

8.2.4 Diuretics

Diuretics are often prescribed to patients with heart failure, and loop diuretics are essential for treatment of patients with congestive heart failure. However, as overuse of loop diuretics may reduce renal function and worsen the prognosis of patients,^200,402 loop diuretics should be limited to the minimum required for treatment.

8.2.5 Other Drugs

No evidence is available on the efficacy of digitalis in patients with a serum creatinine level of ≥3.0 mg/dL. When digitalis is administered to patients with renal dysfunction, they should be carefully observed for signs of digitalis intoxication.⁴⁰³ In the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) trial,⁴⁰⁴ aliskiren, a direct renin inhibitor, reduced renal function.

8.2.6 Drugs Mainly Used for the Treatment of Acute Heart Failure

In Japan, carperitide is often used for the treatment of acute heart failure, but no conclusion has been reached on whether carperitide has a renal protective effect.⁴⁰⁵ Tolvaptan, a vasopressin V₂ receptor antagonist, has been reported to reduce the dose of furosemide in patients with CKD stage 3/4 with an eGFR of 15 to 60 mL/min/1.73 m² in a small study.⁴⁰⁶ Hemofiltration should be considered for patients with acute heart failure in whom drug therapy do not lead sufficient diuresis, or do not improve hemodynamics or symptoms.

9. Hyperuricemia/Gout

9.1 Pathophysiology

Hyperuricemia is a common comorbid condition in patients with heart failure. Hyperuricemia is defined as a serum uric acid level of >7.0 mg/dL regardless of gender or age.⁴⁰⁷ Patients with heart failure have serum uric acid levels higher than healthy individuals in genral.⁸⁴ It has been suggested that hyperuricemia in heart failure may be explained by excessive production and reduced excretion of uric acid. Xanthine oxidase (XO), the enzyme involved in the final process of uric acid production, is present in a small amount in the myocardium. In patients with myocardial ischemia or heart failure, XO activity is elevated, and uric acid production is enhanced, while uric acid excretion is reduced by decrease in renal blood flow and glomerular filtration rate. Moreover, furosemide and other diuretics that are commonly used for the treatment of heart failure may suppress the uric acid excretion and elevate serum uric acid level even further.

Although a relationship between serum uric acid level and prognosis has been suggested in patients with heart failure and the pathophysiological significance of uric acid in heart failure has gained attention, the details have not been revealed yet. Anker et al⁸¹ conducted a prospective study to investigate a possible relationship between uric acid level and life expectance in 112 patients with heart failure and concluded that a serum uric acid level of ≥9.5 mg/dL may predict poor prognosis. In a subsequent interventional trial of allopurinol in patients with heart failure, the treatment reduced uric acid levels but did not result in an improvement of cardiovascular outcomes.⁴⁰⁸ Studies on novel drugs that decrease uric acid production such as febuxostat and topiroxostat have been conducted to investigate their effects in patients with heart failure, but no conclusive evidence has been found on whether high uric acid levels and the use of these drugs to reduce uric acid levels may affect the pathophysiology and prognosis of heart failure (Table 42).

Table 42. Recommendations and Levels of Evidence for the Management of Hyperuricemia in Patients With Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Use of serum uric acid level as a prognostic marker for heart failure	IIa	B	B	IVa
Treatment intervention to hyperuricemia in patients with heart failure	IIb	B	C1	II

9.2 Treatment

Many patients with heart failure also have underlying diseases such as hypertension, ischemic heart disease, diabetes mellitus, and chronic kidney disease. In Japan, an intervention to control hyperuricemia, consisting of lifestyle modification followed by pharmacotherapy if needed, is recommended for patients with gouty arthritis or gouty tophus with a serum uric acid level of >7.0 mg/dL and patients with underlying disease such as renal dysfunction, hypertension, ischemic heart disease and diabetes mellitus with a serum uric acid level of ≥8.0 mg/dL.⁴⁰⁷ Although no evidence has been found regarding the optimal goal of serum uric acid level in patients with chronic heart disease, it would be appropriate to set a goal of ≤7.0 mg/dL considering the above findings.

10. COPD and Asthma (Table 43)

Table 43. Recommendations and Levels of Evidence for Examinations and Treatment for Patients With Heart Failure and COPD or Bronchial Asthma

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Examinations
Measurement of BNP levels for the diagnosis of HFrEF in patients who also have COPD or bronchial asthma	I	A	A	I
Treatments
Use of ACE inhibitors or ARBs for the treatment of HFrEF in patients who also have COPD or bronchial asthma	I	A	A	I
Use of β-blockers for the treatment of HFrEF in patients who also have COPD	I	A	A	I
Careful administration of β1 selective blockers for the treatment of HFrEF in patients who also have bronchial asthma	IIa	B	B	II
Continuing treatment of COPD or bronchial asthma during treatment of HFrEF	IIa	B	B	III

ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; COPD, chronic obstructive pulmonary disease; HFrEF, heart failure with reduced ejection fraction.

10.1 Pathophysiology

In patients with bronchial asthma, chest X-ray findings are usually normal, and severe symptoms develop during asthma attack.⁴⁰⁹

Chronic obstructive pulmonary disease (COPD) is observed in about 20 to 30% of patients with left-sided heart failure,^410–412 and is an independent risk factor for the development of left-sided heart failure and cardiovascular death associated with heart failure.^413,414 BNP or NT-proBNP is a useful tool to differentiate heart failure from exacerbation of COPD in patients with respiratory failure.^412,415

10.2 Treatment

10.2.1 Treatment of Heart Failure in Patients With Heart Failure and COPD

Treatment with ACE inhibitors, ARBs, β-blockers and/or diuretics are also recommended for patients with heart failure and COPD.^410,412 β-blockers can be used safely in most patients with heart failure and COPD.^{192,412,415–417} β-blocker therapy should be initiated using β₁ selective blockers at low doses, and the dose should be titrated upward slowly. β-blockers should be used carefully in patients with COPD and uncontrolled asthma.⁴¹⁸

10.2.2 Treatment of Heart Failure in Patients With Bronchial Asthma

Treatment with ACE inhibitors, ARBs, and/or diuretics are also recommended for patients with heart failure and bronchial asthma.^409,419

10.2.3 Treatment of COPD in Patients With Heart Failure

Monotherapy or combination therapy using long-acting β₂ agonists and long-acting anticholinergics for the treatment of COPD should be continued in combination with treatment for heart failure.⁴¹⁰

10.2.4 Treatment of Bronchial Asthma in Patients With Heart Failure

Inhaled corticosteroids for the treatment of bronchial asthma are safe and recommended for patients with asthma and heart failure.⁴⁰⁹

11. Anemia (Table 44)

Table 44. Recommendations and Levels of Evidence for the Treatment of Anemia in Patients With Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Red blood cell transfusion in patients in whom anemia worsens heart failure and blood transfusion is expected to improve the condition	IIb	C	C1	V
Oral iron supplementation	III	B	D	II
Erythropoiesis stimulating agent	III	B	D	II

Patients with heart failure often have anemia, defined as hemoglobin levels of <13.0 g/dL in men and <12.0 g/dL in women by World Health Organization (WHO). Anemia is an independent prognostic factor in heart failure.^420,421

Anemia in patients with heart failure is treated with red blood cell transfusion, iron supplementation, and/or erythropoiesis stimulating agents (ESAs). Table 44 lists recommendations and levels of evidence for the treatment of anemia in patients with heart failure.

12. Sleep-Disordered Breathing

The most common pathology of sleep-disordered breathing (SDB) is sleep apnea, which is classified into obstructive sleep apnea (OSA) caused by the obstruction of the upper airway and central sleep apnea (CSA) caused by the loss of respiratory drive. Patients with CSA and heart failure often have Cheyne-Stokes respiration (CSR), which is referred to as central sleep apnea with Cheyne-Stokes respiration (CSR-CSA).

12.1 Pathophysiology

12.1.1 Prevalence of SDB in Patients With Heart Failure

The prevalence of OSA is high among patients with cardiovascular diseases including heart failure. In addition to OSA, CSR-CSA is frequently found in patients with heart failure (about 50%).^422–426 A considerable percentage of patients with heart failure have both OSA and CSR-CSA.

12.1.2 Effects of SDB on the Onset and Progression of Heart Failure

OSA increases the risk of the onset or exacerbation of cardiovascular diseases through different mechanisms such as hypoxemia associated with apnea, sympathetic hyperactivity, increased left ventricular afterload due to intrathoracic negative pressure, endothelial dysfunction, oxidative stress, inflammation, hypercoagulability, obesity, and insulin resistance,^427–429 and is involved in the development of heart failure.⁴³⁰ CSR-CSA is caused by the occurrence of low arterial partial pressure of carbon dioxide (PaCO₂) due to pulmonary congestion and excessive response to low PaCO₂,^427,431 as well as prolonged circulation time. Nocturnal rostral leg fluid displacement⁴³² worsen OSA by causing upper airway edema that narrows the airways and CSA by pulmonary congestion.

12.1.3 Effects of SDB on the Prognosis of Patients With Heart Failure

Moderate or severe OSA is associated with a poor prognosis in patients with heart failure,⁴³³ and the presence of even mild or severer CSR-CSA is a prognostic factor in patients with heart failure.⁴³⁴

12.2 Treatment

12.2.1 Screening for SDB in Patients With Heart Failure

As SDB is often asymptomatic in patients with heart failure,⁴³⁵ screening for SDB is recommended for patients with heart failure who do not respond well to standard treatment to identify underlying conditions. See the Guidelines for Diagnosis and Treatment of Sleep Disordered Breathing in Cardiovascular Disease (JCS 2010)⁴²⁷ for detail.

12.2.2 Treatment of Heart Failure

Modifications of lifestyle as risk factors or worsening factors of OSA should be tried first as they are beneficial for the treatment of heart failure. As CSR-CSA is caused by heart failure, optimization of treatment for heart failure is most important.

12.2.3 Positive Pressure Ventilation for the Treatment of SDB in Patients With Heart Failure

a. Positive Pressure Ventilation for OSA ( Table 45)

Table 45. Recommendations and Levels of Evidence for the Treatment of OSA in Patients With Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Guideline-based CPAP treatment in patients with symptomatic OSA	I	A	A	I
CPAP treatment in patients with HFrEF and moderate* or severe OSA to improve left ventricular function	IIa	A	B	I
CPAP treatment in patients with heart failure and moderate* or severe OSA to improve prognosis	IIb	C	C2	III

*Moderate OSA is commonly defined as AHI ≥15, but the National Health Insurance in Japan covers OSA treatment for patients with AHI ≥20. CPAP, continuous positive airway pressure; OSA, obstructive sleep apnea.

In randomized controlled trials and meta-analyses of continuous positive airway pressure (CPAP) in patients with OSA and reduced LVEF, CPAP improved LVEF.^436,437 Observational studies have reported that positive pressure ventilation improves the prognosis of patients with heart failure,^438,439 no large-scale clinical studies have been conducted to date.

At present, OSA should be treated according to the guidelines for the treatment of SDB even in patients with heart failure. CPAP should be considered in patients with heart failure with reduced LVEF and moderate or severe OSA to improve LVEF.

b. Positive Pressure Ventilation for Patients With Heart Failure and CSR-CSA ( Table 46)

Table 46. Recommendations and Levels of Evidence for Treatment for Patients With CSR-CSA and Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Optimization of heart failure treatment according to the heart failure guideline	I	A	A	I
CPAP treatment in patients with heart failure and moderate or severe CSR-CSA to improve symptoms, exercise capacity, and left ventricular function	IIa	B	B	II
ASV treatment in patients with HFpEF and moderate or severe CSR-CSA who are intolerable or refractory to CPAP to improve symptoms and exercise capacity	IIa	B	B	II
ASV treatment Use in patients with HFrEF (LVEF ≤45%) and moderate or severe CSR-CSA who are intolerable or refractory to CPAP to improve symptoms and exercise capacity	IIb	B	B	II
Aimless continuation of ASV treatment in patients with HFrEF (LVEF ≤45%) and CSR-CSA to aimlessly continue ASV as CSR-CSA treatment even after improvement or stabilization of heart failure	III	A	C1	II

ASV, adaptive servo-ventilation; CSR-CSA, central sleep apnea with Cheyne-Stokes respiration; CPAP, continuous positive airway pressure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; OSA, obstructive sleep apnea.

Positive pressure ventilation is generally considered for patients who still have CSR-CSA even after optimal treatment for heart failure. In the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure (CANPAP) study that investigated the effects of CPAP on the prognosis of patients with CSR-CSA and HFrEF (LVEF ≤45%),⁴⁴⁰ the severity of CSR-CSA decreased by about 50% and LVEF increased in patients receiving CPAP, but no improvement in prognosis was observed. However, patients in whom CPAP suppressed CSA at 3 months showed better prognosis than in patients in the control group.⁴⁴¹

Adaptive servo-ventilation (ASV) has been reported to be more effective in suppression of CSR-CSA, and randomized controlled trials and meta-analyses have indicated that ASV improves LVEF in patients with CSR-CSA and HFrEF (LVEF ≤45%) and decreases BNP.^442–445 A prospective observational study has reported that ASV may improve the prognosis of patients with heart failure and CSR-CSA,⁴⁴⁶ while in the Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure (SERVE-HF) trial,²⁷² a randomized clinical trial of ASV in patients with heart failure with LVEF ≤45% and predominant CSA, ASV did not improve long-term prognosis, and did significantly increased all-cause deaths and cardiovascular deaths. Accordingly, the 2016 ESC guidelines and the 2017 ACC/AHA/HFSA guidelines descried that ASV is not recommended for patients with chronic heart disease with LVEF ≤45% and predominant CSA.^8,14 However, in Japan, the use of ASV in this patient population is covered with the National Health Insurance even with certain limitations, and the Japanese Circulation Society and the Japanese Heart Failure Society have published a statement (second report) for appropriate use of ASV with a consideration of the requirement for NHI coverage (Supplement 1).²⁷¹

12.2.4 Oxygen Therapy ( Table 47)

Table 47. Recommendations and Levels of Evidence for Home Oxygen Therapy for Patients With Sleep-Disordered Breathing (SDB) and Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Home oxygen therapy in patients with moderate* or severe CSR-CSA and NYHA Class III or VI HFrEF (LVEF ≤45%) to improve cardiac function and symptoms	IIa	B	B	II

*Moderate OSA is commonly defined as apnea hypopnea index (AHI) ≥15, but the National Health Insurance in Japan covers OSA treatment for patients with AHI ≥20. CSR-CSA, central sleep apnea with Cheyne-Stokes respiration; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

Oxygen therapy increases arterial partial pressure of oxygen (PaO₂), which reduces central carbon dioxide (CO₂) sensitivity and hyperventilation and slightly increases PaCO₂,⁴⁴⁷ and thereby suppresses CSR-CSA. Short-term studies have reported that nocturnal oxygen therapy is effective in suppressing CSR-CSA, reducing sympathetic nerve activity, improving exercise capacity, and reducing BNP levels in patients with chronic heart failure.^448,449 In a multicenter clinical study of oxygen therapy in patients with CSR-CSA and HFrEF (LVEF ≤45%) in Japan, three-month oxygen therapy reduced the severity of CSR-CSA and improved the Specific Activity Scale score, and the efficacy of treatment was maintained in patients who continued oxygen therapy for one year.^450,451 In Japan, oxygen therapy for patients with NYHA class III or IV chronic heart failure and CSR with an apnea hypopnea index (AHI) of ≥20 is covered with the National Health Insurance.

X. Acute Heart Failure

1. Definition and Classification

1.1 Definition

Acute heart failure is defined as the rapid onset or exacerbation of signs and symptoms caused by acute disturbance of pump function that leads to insufficient or inadequate blood filling and poor blood delivery to peripheral tissues due to structural and/or functional abnormalities of the heart.

1.2. Classification

1.2.1 Clinical Classification of Acute Heart Failure in Initial Management: CS Classification

The clinical scenario (CS) classification is a tool to classify patients with acute heart failure according to pathophysiological condition with reference on systolic blood pressure, and provide appropriate initial management for each type of patients.⁴⁵²

1.2.2 Pathophysiological Classification of Acute Heart Failure

1) Acute pulmonary edema

2) Systemic fluid retention (congestion)

3) Low cardiac output/hypoperfusion (including cardiogenic shock)

1.2.3 Classification by History of Hospitalization for Heart Failure

1) De novo heart failure (patients with no history of hospitalization for heart failure)

2) Rehospitalization for heart failure (patients with history of hospitalization for heart failure)

1.2.4 Killip Classification ( Table 48)⁴⁵³

Table 48. Killip Classification

Class I	No clinical signs of heart failure
Class II	Mild to moderate heart failure. Rales up to 50% of lung fields or S3 heart sound
Class III	Severe heart failure. Frank pulmonary edema with rales more than 50% of lung fields
Class IV	Cardiogenic shock. Signs include hypotension (systolic blood pressure <90 mmHg), oliguria, cyanosis, cold and wet skin, and loss of consciousness

(Source: Prepared based on Killip T, et al. 1967⁴⁵³)

Killip classification is a tool to classify patients after acute myocardial infarction according to their objective findings. It is also important to identify factors predicting prognosis of heart failure (Table 49).

Table 49. Precipitating Factors of Heart Failure

• Acute coronary syndrome • Tachyarrhythmia (e.g., atrial fibrillation, atrial flutter, and ventricular tachycardia) • Bradyarrhythmia (e.g., complete atrioventricular block, and sick sinus syndrome) • Infections (e.g., pneumonia, infective endocarditis, and sepsis) • Poor adherence (e.g., insufficient salt/water restriction and noncompliance) • Acute pulmonary thromboembolism • Acute exacerbation of chronic obstructive pulmonary disease • Drugs (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], negative inotropes, and cancer chemotherapy) • Excessive stress or overwork • Excessive blood pressure elevation • Endocrine or metabolism disorders (e.g., hyperthyroidism/hypothyroidism, adrenal dysfunction, and peripartum cardiomyopathy) • Mechanical complications (e.g., cardiac rupture, acute mitral valve insufficiency, chest trauma, and acute aortic dissection)

2. Diagnosis

2.1 Diagnosis ( Table 50)

Table 50. Recommendations and Levels of Evidence for the Diagnosis of Acute Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Measurement of BNP or NT-proBNP levels at a clinic visit for differential diagnosis	I	A	A	I
Evaluation of ECG, chest X-ray, troponin, blood urea nitrogen, creatinine, electrolytes, blood glucose, blood cell count, liver function test, and thyroid function test at a clinic visit	I	C	B	VI
Evaluation of cardiac function using echocardiography	I	C	B	VI
Evaluation of pulmonary edema and pleural fluid using lung ultrasound	IIa	B	B	III

BNP, brain (B-type) natriuretic peptide; ECG, electrocardiogram; NT-proBNP, N-terminal pro-brain (B-type) natriuretic peptide.

The diagnosis of acute heart failure is based on signs and symptoms and the levels of natriuretic peptides (BNP or NT-proBNP). Biomarkers such as BNP and NT-proBNP are important indicators for diagnosis, treatment, and prognosis of patients with acute heart failure. Acute heart failure is unlikely in patients with BNP of ≤100 pg/mL or NT-proBNP of ≤400 pg/mL.⁴³

2.2 Signs and Symptoms

2.2.1 Congestion

Almost all patients with acute heart failure are hospitalized with congestion such as pulmonary edema and systemic fluid retention. Symptoms of congestion develop when intracardiac pressure abruptly increases from the baseline level.

2.2.2 Low Cardiac Output/Hypoperfusion

Symptoms of low cardiac output include fatigue, feeling of weakness, oliguria, cyanosis, cold extremities, and/or anorexia.

3. Treatment Strategies and Flowcharts

During initial management including diagnosis of acute heart failure, patients should be evaluated carefully to clarify pathological characteristics and communicate the findings with healthcare professionals involved in acute phase treatment and ensure the earliest possible intervention. Clinical evaluation should be repeated whenever necessary to facilitate early improvement.

3.1 Initial Management

Table 51 lists the purpose of initial management for patients arriving at hospital. Arterial blood gas analysis should be performed whenever necessary, and appropriate oxygen therapy should be initiated promptly (Table 52).

Table 51. Purpose of Initial Management for Patients With Acute Heart Failure

1. Rescue and stabilize vital signs 2. Improve hemodynamics and maintain oxygenation 3. Relieve dyspnea and other signs and symptoms of congestion 4. Diagnose acute heart failure and rule out acute coronary syndrome or pulmonary thromboembolism 5. Prevent the progression of cardiac disorder and other organ disorders 6. Shorten the duration of ICU/CCU treatment through early intervention to achieve early improvement

CCU, coronary care unit; ICU, intensive care unit.

Table 52. Recommendations and Levels of Evidence for Oxygen Therapy and Respiratory Management in Patients With Acute Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Measurement of pH, CO2, and lactic acid levels in venous blood in patients who also have pulmonary edema or COPD. Measurement of pH, CO2, and lactic acid levels in arterial blood in patients with cardiogenic shock	IIa	C	B	IVb
Oxygen therapy for patients with SpO2 <90% or PaO2 <60 mmHg to treat hypoxemia	I	C	B	VI
Prompt introduction of noninvasive positive pressure ventilation (NPPV) in patients with dyspnea (respiratory rate >25 breaths per minute, SpO2 <90%) to alleviate difficult breathing and avoid tracheal intubation	I	A	A	I
Tracheal intubation for patients who cannot control the following conditions despite above-described treatment: • Hypoxemia (PaO2 <60 mmHg) • CO2 retention (PaCO2 >50 mmHg) • Respiratory acidosis (pH <7.35)	I	C	B	VI

COPD, chronic obstructive pulmonary disease; PaCO₂, arterial partial pressure of carbon dioxide; PaO₂, arterial partial pressure of oxygen; SpO₂, oxygen saturation.

Monitoring of vital signs, hemodynamics and respiratory function should be initiated immediately after hospitalization to examine whether peripheral circulation and organ perfusion are maintained (Figure 11).⁴⁵⁴ Oxygen saturation, blood pressure, body temperature, respiratory rate, and ECG must be monitored. Urine volume should be monitored whenever possible. In initial management, presence of cardiogenic shock and respiratory failure should be examined and treated appropriately. It is important to rule out specific conditions such as acute coronary syndrome (ACS) and acute thromboembolism. Table 53 lists patients indicated for CCU/ICU care.

Figure 11.

Flowchart from initial to acute phase management of acute heart failure. ACS, acute coronary syndrome; BNP, brain (B-type) natriuretic peptide; BP, blood pressure; CAG, coronary angiography; CCU, coronary care unit; CT, computed tomography; ECG, electrocardiography; ECMO, extracorporeal membrane oxygenation; HR, heart rate; IABP, intra-aortic balloon pumping; ICU, intensive care unit; NPPV, noninvasive positive pressure ventilation; NT-proBNP, N-terminal pro-brain (B-type) natriuretic peptide; PCI, percutaneous coronary intervention; RR, respiratory rate; SpO₂, oxygen saturation. (Source: Prepared based on Mebazaa A, et al. 2016⁴⁵⁴)

Table 53. Indications for CCU/ICU Treatment for Acute Heart Failure

1. Patients who require or have already received tracheal intubation 2. Patients with hypotension (systolic blood pressure <90 mmHg or mean arterial pressure <65 mmHg) or shock 3. Patients with oxygen saturation <90% despite oxygen therapy 4. Patients with forced breathing and respiratory rate >25/min 5. Patients with uncontrolled dangerous arrhythmias

Management strategies for the specific conditions are as follows:

1) Myocarditis: With the possibility of fulminant myocarditis in mind, patients should be monitored with ECG and echocardiography. Even in fulminant cases, prompt treatment may help improve the prognosis for many patients. Mechanical circulatory support including ventricular assist devices should be used when necessary. See the Guidelines for Diagnosis and Treatment of Myocarditis (JCS 2009) for detail.⁴⁵⁵

2) Right-sided heart failure: It is important to identify the cause of right-sided heart failure, and select appropriate treatment strategies accordingly. Patients diagnosed as having severe pulmonary arterial hypertension should be treated mainly with intravenous prostacyclin analogs, and the introduction or dose-escalation of the remaining two types of anti-pulmonary hypertension drugs should be considered. Other drugs such as dobutamine should be used whenever necessary to maintain or improve cardiac output. Right-sided heart failure due to constrictive pericarditis or other heart diseases should be differentiated from that due to pulmonary arterial hypertension.

3) Acute Coronary syndrome: Acute heart failure due to acute coronary syndrome should be diagnosed and treated according to the guidelines for the management of patients with ST-elevation acute myocardial infarction (JCS 2013)⁴⁵⁶ and the Guidelines for Management of Acute Coronary Syndrome without Persistent ST Segment Elevation (JCS 2012).⁴⁵⁷

4) Hypertensive emergency: Vasodilators should be administered intravenously to reduce blood pressure promptly. Diuretics should be added to patients with systemic fluid retention.

5) Arrhythmias: Patients with acute heart failure due to ventricular tachycardia and other types of tachyarrhythmias should be treated with intravenous amiodarone or direct current defibrillation. Patients with acute heart failure due to severe bradycardia should be treated with external pacing.

6) Acute Mechanical causes: Acute mechanical causes include free wall rupture, ventricular septal perforation, or papillary muscle rupture associated with ACS, PCI complications such as coronary artery obstruction or perforation, acute aortic dissection, infective endocarditis, malfunctioning mechanical valves, and chest injuries. Echocardiography is essential for the diagnosis of these complications and emergency surgery is often needed.

7) Acute Pulmonary thromboembolism: Acute pulmonary thromboembolism should be diagnosed and treated according to the Guidelines for Diagnosis, Treatment and Prevention of Pulmonary Thromboembolism and Deep Vein Thrombosis (JCS 2009).⁴⁵⁸

8) High output heart failure: High output heart failure may be caused by sepsis, thyrotoxicosis, anemia, cardiac shunts, beriberi heart, or Paget’s disease. Pathological assessment should be performed, and causative disease should be diagnosed and treated promptly.

3.2 Basic Principle for Acute Phase Treatment (Table 54, Figure 12)^452,459

Table 54. Recommendations and Levels of Evidence for Monitoring in Patients With Acute Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Measurement of body weight and volume balance on the day of hospitalization and daily during the hospital stay	I	C	B	VI
Daily assessment for signs/symptoms of heart failure (dyspnea, moist rales, peripheral edema, body weight) on daily basis	I	B	B	IVb
Measurement of renal function (blood urea nitrogen and creatinine), electrolytes (Na and Cl) (especially in patients receiving diuretics or renin-angiotensin- aldosterone system inhibitors)	I	B	B	IVb
Echocardiography to estimate hemodynamics and causative disease	I	C	B	VI
Arterial pressure monitoring in patients with unstable hemodynamics	IIa	C	C1	VI
Swan-Ganz catheterization to determine hemodynamics 1) In patients with cardiogenic shock not responding promptly to appropriate fluid therapy 2) In patients with pulmonary edema associated with shock/near shock that does not respond to appropriate treatment measures 3) Use as a diagnostic measure to confirm whether the cause of pulmonary edema is cardiogenic or noncardiogenic	I	C	B	IVb
Swan-Ganz catheterization to determine hemodynamics in patients with repeated hypotension and hypoperfusion despite drug therapy	IIa	C	B	IVa
Swan-Ganz catheterization to determine hemodynamics As routine procedure	III	B	D	II

Figure 12.

Basic treatment strategies from initial to acute phase management of acute heart failure. ACS, acute coronary syndrome; BP, blood pressure; SBP, systolic blood pressure. (Source: Prepared based on Mebazaa A, et al. 2008⁴⁵² and Stevenson LW. 1999⁴⁵⁹)

Patients who received initial management in the ICU/CCU should be reassessed for changes in pathological conditions including symptoms of heart failure and body weight, and their treatments should be modified whenever necessary.

3.3 Pathological Conditions and Treatment Strategies in Acute Heart Failure ( Figure 12)^452,459

Although there are various diseases that can cause acute heart failure, the conditions of acute heart failure may be generally classified into three categories: acute cardiogenic pulmonary edema, systemic fluid retention, and hypoperfusion due to low cardiac output.

3.3.1 Acute Cardiogenic Pulmonary Edema

Acute cardiogenic pulmonary edema is a CS 1 condition. Patients often have orthopnea and an oxygen saturation (SpO₂) of <90%. Noninvasive positive pressure ventilation (NPPV) is effective in alleviating symptoms, increasing arterial blood oxygenation, and improving hemodynamics (Table 52). Before intravenous access is established, NPPV, sublingual nitrates, or nitrate spray should be used to treat dyspnea and improve oxygenation promptly. If pulmonary edema persists, vasodilators should be infused intravenously while avoiding an abrupt lowering in blood pressure. Physicians should keep in mind that about 50% of patients with CS 1 have low LVEF,⁴⁶⁰ and are at risk of low cardiac output during treatment.

3.3.2 Systemic Fluid Retention

Systemic fluid retention is a CS 2 condition. Patients have excessive systemic fluid overload with peripheral edema. Their treatment should be mainly performed by diuretics.

3.3.3 Low Cardiac Output/Hypoperfusion

Low cardiac output or hypoperfusion is a CS 3 condition. The main symptoms are cold extremities, general fatigue, anorexia and reduced physical activity, but some patents may not complain of severe dyspnea or edema and thus treatment should be initiated carefully to avoid abrupt change in hemodynamics. Patients receiving β-blockers should continue treatment unless they present with shock. The use of phosphodiesterase (PDE) III inhibitors⁴⁶¹ and dobutamine should be considered for such patients as needed.

3.3.4 Cardiogenic Shock ( Table 55)

Table 55. Recommendations and Levels of Evidence for the Treatment of Patients With Cardiogenic Shock

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Transfer to ICU/CCU where mechanical circulatory support is available	I	C	B	VI
Continuous monitoring of ECG and arterial blood pressure	I	C	B	VI
Rapid intravenous infusion of physiological saline or Ringer solution (≥200 mL over 15 to 30 min) in patients w ithout fluid retention	I	C	B	V
Treatment with inotropic drugs (dobutamine) to increase cardiac output	IIa	B	B	III
Treatment of vasoconstrictors (norepinephrine) to maintain systolic blood pressure in patients with persistent peripheral hypoperfusion	IIa	B	B	III
Routine use of IABP	III	B	D	II
Short-term use of mechanical circulatory support considering the age, higher brain function, complications and social factors	IIb	C	C1	VI

See the Guidelines for the Management of Patients with ST-Elevation Acute Myocardial Infarction (JCS 2013)⁴⁵⁶ and the Guidelines for Management of Acute Coronary Syndrome without Persistent ST Segment Elevation (JCS 2012)⁴⁵⁷ for management of ACS.

ACS, acute coronary syndrome; CCU, coronary care unit; IABP, intra-aortic balloon pump; ICU, intensive care unit.

Cardiogenic shock is defined as a systolic blood pressure of <90 mmHg or a mean arterial blood pressure of <65 mmHg with signs of tissue hypoperfusion in the absence of decrease in circulatory plasma volume or lack of preload due to bleeding or dehydration. In addition to physical findings, an increase in blood lactate levels (>2 mmol/L, 18 mg/dL) suggests hypoperfusion. All patients with cardiogenic shock must undergo emergency 12-lead ECG and echocardiography to identify the causative condition and treat it accordingly. Rehydration should be attempted in patients without fluid retention. Dobutamine is a first-line drug for this patient population. Addition of PDE III inhibitors can be considered for patients with biventricular cardiac failure. Mechanical circulatory support should be considered in patients who do not respond well to these drugs. The prognosis of patients often depends on the cause and conditions of cardiogenic shock rather than the treatment itself.

3.4 Management During Transition Period From Acute Heart Failure to Chronic Phase

In patients transferred from the CCU/ICU to the general ward with stable condition, treatment for the causative conditions should be continued.

Table 56 summarizes the goal of in-hospital treatment for heart failure during transition from acute heart failure to chronic phase. Management to avoid worsening heart failure is important, and patients should be assessed accurately for symptomatic improvement in orthopnea, jugular venous distention, coarse crackles in the lung fields, peripheral edema, and general fatigue at discharge.

Table 56. Treatment Goals for Hospitalized Patients During Transition From Acute to Chronic Heart Failure

1. Identify the cause of heart failure and complications and treat them accordingly 2. Treat the patient to alleviate signs/symptoms of heart failure and improve cardiac function (e.g., treatment with diuretics or vasodilators) 3. For patients with HFrEF, start treatment with RAAS inhibitors and β-blockers and then increase the doses to the target levels. For patients with HFpEF, standard drug therapy has not been established and focus on the management of risk factors such as hypertension. 4. Consider device treatment such as ICD and CRT/CRT-D, if indicated.

ICD, implantable cardioverter defibrillator; CRT, cardiac resynchronization therapy; CRT-D, cardiac resynchronization therapy defibrillator; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; RAAS, renin-angiotensin-aldosterone system.

3.5 From Discharge to Ambulatory Care

As rehospitalization due to worsening heart failure often occurs during early period after discharge from hospital, early clinic visit should be scheduled after discharge whenever the patient’s conditions permit. It is desirable to continue multidisciplinary heart failure team care after discharge.

Treatment goals after discharge are as follows:

1) To prevent worsening symptoms and decline in QOL, and improve prognosis.

2) To prevent rehospitalization early phase after discharge.

3) To develop a comprehensive clinical path to help the hospital and clinics collaborate to provide lifestyle modification intervention for each patient.

4) To try increasing the doses of standard treatments such as β-blockers to target levels, even after hospital discharge.

5) To consider for the indication of device therapy, whenever necessary.

4. Pharmacological Therapy

Tables 57 and 58 list the indications and recommended dosage regimens of drugs used for the treatment of acute heart failure in Japan.

Table 57. Recommendations and Levels of Evidence for Drug Therapy for Patients With Acute Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (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

MRA, mineralocorticoid receptor antagonist; PDE, phosphodiesterase.

Table 58. Intravenous Drugs and Dosage Regimens for Patients in the Acute Phase of Acute Heart Failure

Drugs	Dosage regimens
Morphine	Dilute an ampule of 5 to 10 mg, and administer 2 to 5 mg intravenously over 3 minutes.
Furosemide	Start treatment with a bolus dose of 10 to 120 mg or an infusion at 1 to 2 mg/hr, then infuse continuously at 1 to 5 mg/hr.
Potassium canrenoate	Dissolve 100 to 200 mg in 10 to 20 mL solution to administer by slow intravenous injection. Do not continue treatment unnecessarily. Limit the daily dose to 600 mg.
Digoxin	Administer 0.125 to 0.25 mg by slow intravenous injection.
Dopamine	Start infusion at 0.5 to 5 μg/kg/min and maintain at 0.5 to 20 μg/kg/min. When discontinuing the infusion, reduce the dose gradually. Limit the dose and treatment duration to minimum necessary.
Dobutamine	Start infusion at 0.5 to 5 μg/kg/min and maintain at 0.5 to 20 μg/kg/min. When discontinuing the infusion, reduce the dose gradually. Limit the dose and treatment duration to minimum necessary.
Norepinephrine	Start and continue infusion at 0.03 to 0.3 μg/kg/min.
Milrinone	Start infusion at 0.05 to 0.25 μg/kg/min and maintain at 0.05 to 0.75 μg/kg/min.
Olprinone	Start infusion at 0.05 to 0.2 μg/kg/min and maintain at 0.05 to 0.5 μg/kg/min.
Colforsin daropate	Start and continue infusion at 0.1 to 0.25 μg/kg/min.
Nitroglycerin	Start and continue infusion at 0.5 to 10 μg/kg/min.
Isosorbide dinitrate	Start and continue infusion at 1 to 8 mg/hr.
Nicorandil	Start and continue infusion at 0.05 to 0.2 mg/kg/min.
Nitroprusside	Start and continue infusion at 0.5 to 3 μg/kg/min.
Carperitide	Start infusion at 0.0125 to 0.05 μg/kg/min and maintain at ≤0.2 μg/kg/min.
Landiolol	Start infusion at 1 μg/kg/min, adjust the dose according to heart rate and blood pressure, and maintain at 1 to 10 μg/kg/min.

4.1 Sedation

4.1.1 Morphine Hydrochloride

Through its central actions, morphine diminishes excessive sympathetic tone and thereby decreases myocardial oxygen demand. It reduces afterload by dilating arterioles, and improves pulmonary congestion by dilating veins and thereby reducing venous return.⁴⁶² Morphine should be administered carefully in patients with hypotension, bradycardia or high-grade atrioventricular block. In patients with intracerebral hemorrhage, decreased consciousness, bronchial asthma, or COPD, morphine should generally be avoided. Based on the reported effects of morphine on prognosis,^463,464 morphine should not be used as a routine treatment.

4.2 Diuretics

4.2.1 Loop Diuretics

a. Furosemide

Loop diuretics alleviate symptoms of heart failure such as pulmonary congestion and edema, and decreases left ventricular end-diastolic pressure by reducing preload. Furosemide has a rapid onset of action in patients with acute heart failure.⁴⁶⁵ Western guidelines^7,16 recommend diuretics for patients with symptomatic left ventricular systolic heart failure. Findings from an observational study in Japan have indicated the importance of early treatment of congestion to shorten the duration of congestion.⁴⁶⁶

Patients with severe heart failure and renal dysfunction should receive diuretics at higher doses.⁴⁶⁷ A study has suggested that patients in whom adequate diuresis was not obtained with a single bolus dose of furosemide may respond well to continuous intravenous infusion of the drug.⁴⁶⁸

The dose of loop diuretics should be limited to minimum necessary. The method of administration, i.e., bolus injection vs. continuous infusion, should be selected based on the individual patient’s condition. The dose should be adjusted based on LVEF or other pathological features.

Loop diuretics are less effective in patients with hypotension (systolic blood pressure: <90 mmHg), hyponatremia, hypoalbuminemia, or acidosis. Patients who do not respond well to loop diuretics may respond to diuretics which have different site of action. However, non-loop diuretics should be used carefully as they may cause electrolyte imbalance and an increase in blood urea nitrogen more frequently than loop diuretics.

4.2.2 Vasopressin V₂ Receptor Antagonists (AVP Antagonists)

Tolvaptan is an oral drug that inhibits arginine vasopressin (AVP) type 2 receptors. In Japan, it is indicated for patients with heart failure who are resistant to other diuretics. AVP antagonists suppress hyponatremia and are beneficial in the treatment of patients with intractable heart failure, especially those with heart failure and hyponatremia. Although AVP antagonists are considered effective in fluid management in patients with diuretic-resistant heart failure and severe congestion, the dose should be limited to the minimum necessary. Patients should be observed carefully for adverse reactions such as thirst and hypernatremia.

4.3 Vasodilators

Vasodilators, like diuretics, are effective in the treatment of acute cardiogenic pulmonary edema. In general, vasodilators are the first choice, but diuretics should mainly be used in patients with severe congestion due to fluid retention such as those with acute exacerbation of chronic heart failure. On the other hand, vasodilators may be preferred for patients with high blood pressure, those with myocardial ischemia, and those with mitral valve regurgitation, among others. Vasodilators should not be used for patients with cardiogenic shock with a systolic blood pressure of <90 mmHg. Since excessive hypotension may worsen renal function, the dose of vasodilators should be titrated carefully, and careful monitoring after dosing is crucial. Especially, patients with renal dysfunction, elderly patients, and patients with aortic valve stenosis should be carefully observed for hypotension.

4.3.1 Nitrates

Sublingual, spray or intravenous administration of nitroglycerin or isosorbide dinitrate are effective in alleviating pulmonary congestion in patients with acute heart failure and patients with acute exacerbation of chronic heart failure (Table 57). Nitrates dilate venous capacitance vessels at low doses and arterial resistance vessels at high doses, reducing preload (pulmonary capillary pressure) and afterload (a slight increase in cardiac output associated with reduced peripheral vascular resistance). As nitrates dilate coronary arteries, they are often used for the treatment of acute heart failure due to ischemic heart disease.

Adverse drug reactions to nitrates include hypotension, and decrease in arterial oxygen saturation due to increased intrapulmonary shunting. Physicians should be aware that nitrate tolerance may develop rapidly when administered intravenously.

4.3.2 Nicorandil

Nicorandil dilates both veins and arteries, and, like nitrates, reduces pulmonary artery wedge pressure. Nicorandil is less likely to develop tolerance^469,470 and cause excessive hypotension than nitrates.⁴⁷¹

4.3.3 Carperitide

Carperitide, a recombinant human atrial natriuretic peptide (hANP), reduce cardiac load by vasodilation, sodium diuresis, and inhibition of renin and aldosterone synthesis. The drug is indicated for the treatment of pulmonary congestion and is also used in combination of catecholamines or other inotropic drugs for the treatment of refractory heart failure. As with other vasodilators, carperitide have not been demonstrated to improve the prognosis of patients with acute heart failure and further studies are needed to identify patients in whom the drug may improve prognosis.

Carperitide may cause hypotension at the beginning of treatment, carperitide should be administered by continuous intravenous infusion at a low dose, i.e., 0.025 to 0.05 μg/kg/min, and 0.0125 μg/kg/min for some cases. A prospective study in Japan has reported that carperitide is often administered at a dose of 0.05 to 0.1 μg/kg/min (maximum recommended dose is 0.2 μg/kg/min), and improves clinical conditions in 82% of patients.⁴⁷² The efficacy is especially high in patients with decompensated heart failure due to cardiomyopathy, hypertensive heart disease, or valvular diseases. Carperitide is contraindicated for patients with serious hypotension, cardiogenic shock, acute right ventricular infarction, or dehydration.

4.4 Inotropes and Vasopressors

Drugs with inotropic action are indicated for patients with hypotension, patients with peripheral circulatory failure, and patients not responding to treatment to optimize circulating volume. Inotropes are effective in improving hemodynamics and clinical conditions in the short term, and are often administered to patients with left ventricular enlargement and reduced LVEF. However, these drugs increase myocardial oxygen demand and cause myocardial calcium loading, which may result in arrhythmias, myocardial ischemia or myocardial injury and poor prognosis. Accordingly, it is desirable that dose and duration of inotropic treatment should be limited to minimum necessity.

4.4.1 Catecholamine Inotropes

Catecholamines bind to adrenergic receptors (e.g., α₁, α₂, β₁, and β₂) and exerts various physiological effects. β-receptors on myocytes are mainly β₁ receptors, and catecholamines enhance myocardial contraction, accelerate myocardial relaxation, increase heart rate, and increase myocardial conduction velocity via β₁ receptors. On the other hand, catecholamines dilate peripheral vessels by stimulating β₂ receptors on vascular smooth muscle cells, exert vasoconstriction through α₁ receptors mainly located in the vascular smooth muscle, and enhance cardiac contraction mildly through the α₁ receptors on myocytes.

a. Dobutamine

Dobutamine is a synthetic catecholamine that stimulates β₁, β₂, and α₁ receptors. As a β₂ receptor stimulant, dobutamine at 5 μg/kg/min or lower doses acts as a mild vasodilator to decrease systemic peripheral vascular resistance and pulmonary capillary pressure. As dobutamine does not increase heart rate or myocardial oxygen demand substantially at 10 μg/kg/min or lower doses, the drug can be used for the treatment of ischemic heart disease. Dobutamine reduces pulmonary artery diastolic pressure more substantially than dopamine does, and is effective in the treatment of pulmonary congestion.⁴⁷³ In patients with unstable blood pressure, consideration for addition of dopamine or noradrenaline is necessary. Dobutamine may increase the number of eosinophils in the myocardium and blood.⁴⁷⁴ When dobutamine therapy is discontinued, the dose should be tapered gradually. A study evaluated the effect of dobutamine on long-term prognosis have suggested that dobutamine may increase the risk of cardiac accidents.⁴⁷⁵ The dose and duration of dobutamine therapy should be limited to minimum necessity.

b. Dopamine

Dopamine is an endogenous catecholamine and a precursor of noradrenaline. Studies with animal model and healthy subjects show that at low doses (≤2 μg/kg/min), dopamine induces diuresis through its vasodilative effects on renal arteries and direct action to renal tubules. At intermediate doses (2 to 10 μg/kg/min), dopamine exerts positive inotropic effects, increases heart rate, and constricts vessels and at high doses (10 to 20 μg/kg/min), increase vascular resistance.

It is unclear whether low-dose dopamine is beneficial in patients with heart failure in terms of increasing urine volume or protecting renal function.^476–479

c. Norepinephrine

Norepinephrine is an endogenous catecholamine, and enhances myocardial contraction and increases heart rate by stimulating β₁ receptors and also acts as a potential vasoconstrictor by α receptors located on peripheral veins. Patients in refractory cardiogenic shock should be treated with continuous intravenous infusion of noradrenaline starting at a dose of 0.03 to 0.3 μg/kg/min. Norepinephrine is well indicated for patients with septic shock. As the drug increases afterload and myocardial oxygen consumption and reduces blood flow to the kidneys, brain and other organs, monotherapy with norepinephrine as an inotrope should be avoided, and the dose and duration of noradrenaline therapy should be limited to minimum necessity. In patients who require large doses of noradrenaline, mechanical support such as intra-aortic balloon pump (IABP) and percutaneous cardiopulmonary support (PCPS) should be introduced to decrease the dose of noradrenaline.

4.4.2 Digitalis

Digoxin is beneficial in improving hemodynamics in a short period of time.⁴⁸⁰ Digoxin is not expected to improve long term prognosis, but will reduce the frequency of rehospitalizations in keeping attentions to blood concentration.²⁰⁷ In patients with acute heart failure, digitalis is indicated for the treatment of heart failure induced by tachycardias such as atrial fibrillation. Treatment with digitalis is not recommended for patients with acute heart failure due to acute myocardial infarction or myocarditis.

In general, digoxin is administered slowly intravenously to control heart rate in patients with atrial fibrillation or other conditions at a dose of 0.125 to 0.25 mg while avoiding digitalis toxicity.

Digitalis is contraindicated for patients with bradycardia, second or third degree atrioventricular block, sick sinus syndrome, Wolff-Parkinson-White (WPW) syndrome, hypertrophic obstructive cardiomyopathy, hypokalemia, or hypercalcemia.

4.4.3 PDE III Inhibitors

Strengths of PDE III inhibitors include: 1) they are effective even in patients not responding to catecholamines; 2) they possess both vasodilative and positive inotropic effects and are associated with a smaller increase in myocardial oxygen consumption as compared with catecholamines; 3) and they are less likely to develop tolerance than nitrates. PDE III inhibitors exert rapid onset of action after the initiation of intravenous administration and improve hemodynamics almost in a dose-dependent manner.⁴⁸¹

For acute worsening heart failure in patients who are receiving β-blockers, PDE inhibitors and adenylate cyclase activators favorably increase cardiac output and decrease pulmonary capillary pressure because their actions are not mediated by β-receptors.⁴⁸²

As with the catecholamine inotropes, PDE III inhibitors should be carefully used for the treatment of appropriate conditions, and the dose and duration of treatment should be limited to minimum necessity. In general, treatment with PDE III should be initiated with continuous intravenous infusion, and patients should be observed carefully for hypotension and arrhythmias.

4.4.4 Adenylate Cyclase Activators (Colforsin Daropate)

Adenylate cyclase activators are inotropes available only in Japan. They act as inodilators, but have slower onset of action and induce a larger increase in heart rate as compared with PDE inhibitors. Physicians should be aware that they may induce arrhythmias.

4.4.5 Calcium Sensitizers (Pimobendan)

Although pimobendan increases the myocardial contractility and dilates vessels to increase cardiac output and decrease pulmonary capillary pressure, no clear evidence has been obtained about the efficacy of this drug in the treatment of acute heart failure.

4.5 Myocardial Protective Agents

Survival should be prioritized in the treatment of acute heart failure. Once survival is ensured, then improvement of long-term prognosis and QOL should be aimed. Considering the fact that many cases of acute heart failure are acute worsening of chronic heart failure, physicians should try to protect the myocardium while taking into account the management during transition period from the acute to chronic phases.

For details, see Chapter “ VI. Drug Therapy ”.

5. Nonpharmacological Therapy

5.1 Mechanical Ventilation

5.1.1 Pathophysiology of Pulmonary Edema and Oxygen Therapy

Patients with acute left-sided heart failure have high pulmonary capillary pressure, severe pulmonary congestion or pulmonary edema. In patients with normal plasma protein levels, an increase in pulmonary capillary pressure to ≥24 mmHg causes leakage of plasma components into alveoli. As pulmonary capillary pressure increases the severity of pulmonary edema increases in a linear manner. In patients in whom plasma protein levels decrease to half of the lower normal limit, pulmonary edema develops when pulmonary capillary pressure is 11 mmHg or higher.⁴⁸³ Treatment of pulmonary edema should prioritize the management of dyspnea and hypoxemia to improve oxygen supply to peripheral tissues.

5.1.2 Oxygen Therapy and Non-Invasive Positive-Pressure Ventilation (NPPV)

In patients with acute heart failure, oxygen administration should be started with a nasal cannula or face mask at 2 to 6 L/min. In patients with a PaO₂ of less than 80 mmHg (oxygen saturation [SpO₂] of less than 95%) or an arterial partial pressure of carbon dioxide (PaCO₂) of 50 mmHg or more, or patients in whom symptoms such as tachypnea, forced respiration, and orthopnea are not improved or are worsening, NPPV should be initiated promptly using a mask or bag-mask device (Table 59).

Table 59. Indications and Contraindications of Noninvasive Positive Pressure Ventilation (NPPV) in Patients With Acute Heart Failure and the Criteria for Conversion to Tracheal Intubation

General indications of NPPV

(1) Patient is alert and cooperative 　(2) The airway is patent 　(3) Patient can expectorate 　(4) Patient has no facial injuries 　(5) Patient can wear a mask

Contraindications of NPPV

(1) Patient has undrained pneumothorax 　(2) Patient has vomiting, intestinal occlusion, or active gastrointestinal bleeding 　(3) Patient has a large amount of airway secretions 　(4) Patient is at a high risk of aspiration

Criteria for conversion to tracheal intubation

(1) Patient’s condition worsened 　(2) Patient shows no improvement or even worsening of arterial blood gas levels 　(3) New symptoms/signs (e.g., pneumothorax, sputum retention, and nose erosion) or complications developed 　(4) Symptoms do not disappear 　(5) Patient’s level of consciousness has declined

Continuous positive airway pressure (CPAP) is the first-choice treatment for patients with acute heart failure, but patients who still have high CO₂ levels or dyspnea during CPAP should receive bi-level PAP. Patients who do not respond well to NPPV should be intubated promptly to receive artificial respiration. Table 59 summarize how switch from NPPV to endotracheal intubation. In order to ensure the success of ventilation in patients with acute cardiogenic pulmonary edema, oxygen therapy should not be continued aimlessly. Patients who still have hypoxemia and dyspnea despite oxygen therapy should start receiving NPPV without delay.^484,485

5.1.3 Mechanical Ventilation With Endotracheal Intubation

In patients with no improvement of respiratory condition or arterial blood gasses during NPPV, or patients who have a consciousness disorder, loss of cough reflex, or difficulty in expectoration, artificial respiration under endotracheal intubation is indicated (Table 59).

Patients with acute decompensated heart failure associated with pulmonary congestion or pulmonary edema should receive positive end-expiratory pressure (PEEP) at around 2 to 10 cmH₂O to maximize oxygen delivery to peripheral tissues unless contraindicated. Typical ventilation conditions include a tidal volume of 10 to 15 mL/kg, a respiratory rate of 10 to 20 breaths per minute (target PaCO₂: 30 to 40 mmHg), and an inhale: exhale ratio of 1 to 1.5:2. These settings should be individualized based on the results of arterial blood gas analysis. Immediately after intubation, the fraction of inspiratory oxygen (FiO₂) should be set at 1.0, and then should be adjusted to maintain a PaO₂ of ≥80 mmHg. It is desirable that FiO₂ be set at ≤0.5 to prevent oxygen toxicity.

5.1.4 Weaning From Artificial Respiration and Extubation

When the condition required artificial respiration has been corrected with a FiO₂ of <0.5, a PEEP of <5 to 10 cmH₂O, and a PaO₂ of ≥60 mmHg, weaning from artificial ventilation should be considered (Table 60).⁴⁸⁶ Recently, high-flow nasal cannula oxygen therapy has been tried after extubation.⁴⁸⁷

Table 60. Criteria for Weaning From Ventilatory Support to Patients With Acute Heart Failure

1. Resolution of acute phase disease 2. Adequate cough 3. Adequate oxygenation (FiO2 <0.5 and PaO2 ≥60 mmHg) 4. Stable hemodynamics (heart rate <140 bpm, stable blood pressure, and no or minimal treatment with vasopressors) 5. Afebrile (temperature ≤38℃) 6. No respiratory acidosis 7. Adequate hemoglobin (8 to 10 mg/dL or higher) 8. Adequate mentation 9. Acceptable electrolytes

FiO₂, fraction of inspiratory oxygen; PaO₂, arterial partial pressure of oxygen. (Source: Prepared based on MacIntyre NR, et al. 2001⁴⁸⁶)

5.2 Management With Pacing (Cardiac Resynchronization Therapy and Other Types of Pacing)

5.2.1 Cardiac Resynchronization Therapy (CRT)

No studies have investigated the effects of CRT during the acute phase of acute heart failure. Patients with acute heart failure should receive pharmacotherapy first, and should then be considered for the indication of CRT during the chronic phase of heart failure (See Section “ 2. Cardiac Resynchronization Therapy ” in Chapter “ VII. Nonpharmacologic Therapy ”).

5.2.2 Emergency Temporary Pacing

Emergency temporary pacing should be performed promptly in patients with bradycardia leading to compromised hemodynamics or transient cerebral ischemia who do not respond to atropine regardless of type of causative conditions (Table 61).

Table 61. Recommendations and Levels of Evidence for Pacing (Cardiac Resynchronization Therapy and Other Techniques) in Patients With Acute Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Prompt initiation of emergency temporary pacing in patients with bradycardia that worsens hemodynamics and causes transient cerebral ischemia, and who do not respond well to atropine	I	C	C1	VI
Cardiac resynchronization therapy in the very early phase of acute heart failure	IIb	C	C2	VI

5.3 Acute Hemofiltration

In patients with acute decompensated congestive heart failure, hepatic congestion and edema may develop in association with pulmonary congestion and excessive fluid retention. During the acute phase treatment, excessive fluid should be rapidly corrected. Patients with renal dysfunction in whom diuresis cannot be achieved require acute hemofiltration (Table 62).

Table 62. Recommendations and Levels of Evidence for Hemofiltration in Patients With Acute Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Hemofiltration
Extracorporeal ultrafiltration method (ECUM)	IIb	B	C2	II
Continuous venovenous hemofiltration (CVVH) for patients with volume overload and stable hemodynamics	IIb	B	C2	II
Hemodialysis
Hemodialysis	IIb	B	C2	II
Peritoneal dialysis	IIb	B	C2	II
Hemodiafiltration
Peritoneal dialysis	IIb	B	C2	II

At present, ultrafiltration should be reserved for patients in whom fluid removal is difficult or impossible with any drug therapies.

5.4 Indications and Methods of Surgical Treatment in Patients With Acute Heart Failure (Cardiac Tamponade and Acute Valvular Disease)

5.4.1 Cardiac Tamponade

Cardiac tamponade is a condition of elevated pericardial pressure caused by pericardial effusion, resulting in decreased venous return during the diastolic phase and impaired ventricular filling.

In cases of urgency, echocardiography-guided pericardiocentesis and drainage are conducted. Inotropes are not effective in urgent situations. In patients with hemorrhagic cardiac tamponade with hypovolemia, drainage is effective in maintaining hemodynamics on a temporary basis. In patients with unsuccessful pericardiocentesis or patients with recurrent pericardial effusion due to hemorrhagic cardiac tamponade, surgical drainage by pericardiotomy through a subxiphoid approach or pericardiotomy should be performed.

5.4.2 Acute Valvular Disease

a. Acute Aortic Regurgitation⁴⁸⁸

Acute aortic regurgitation is an emergent condition that may lead to cardiogenic shock unless prompt surgical intervention is undertaken. Causes of acute aortic regurgitation include aortic dissection, infective endocarditis, injuries, and iatrogenic aortic valve injury. Indication for surgery should be considered promptly for patients with acute aortic regurgitation. Echocardiography is essential for confirmatory diagnosis and severity assessment, and provides information that helps physicians specify the cause and assess the severity of pulmonary hypertension. IABP is contraindicated for patients with acute aortic regurgitation.

b. Acute Mitral Valve Insufficiency⁴⁸⁸

Acute mitral valve insufficiency (mitral valve regurgitation) causes acute volume overload of the left ventricle and left atrium, which results in pulmonary edema and cardiogenic shock. Patients with no improvement in hemodynamics after treatment with vasodilators and catecholamines are indicated for emergency surgery. IABP is used to maintain hemodynamics in patients who are waiting for surgery. Accurate color Doppler examination can be performed with transesophageal echocardiography. IABP may stabilize the hemodynamics of patients in preparation for surgery.

5.5 Treatment of Mechanical Complications Associated With Acute Myocardial Infarction

5.5.1 Left Ventricular Free Wall Rupture

Left ventricular free wall rupture develops in 4 to 24% of patients with acute myocardial infarction. Treatment often fails, and deaths due to this condition account for 20% of early deaths from acute myocardial infarction.⁴⁸⁹ Left ventricular free wall rupture often develops in 1 to 7 days after the onset of acute myocardial infarction. It is classified by mode of onset into oozing (slow rupture) type, which develops as cardiac tamponade caused by gradual accumulation of bloody pericardial effusion, and blow-out type, which develops as an abrupt rupture of the myocardial wall. Oozing cases can be diagnosed before shock develops, and should be treated with pericardial drainage followed by surgery. However, in blow-out cases, pulseless electrical activity develops rapidly, and leads to death. Patients should be diagnosed immediately after onset, receive percutaneous cardiopulmonary support (PCPS) promptly to maintain systemic circulation before undergoing emergency surgery.

5.5.2 Ventricular Septal Perforation

The incidence of ventricular septal perforation has been reported about half the incidence of free wall rupture. Ventricular septal perforation often develops on the third to fifth day after the onset of acute myocardial infarction. Patients with ventricular septal perforation often experience abrupt hemodynamic decompensation, hypotension, bilateral cardiac failure (right-sided heart failure is prominent in some cases), and newly developed holosystolic murmur. Patients with cardiogenic shock should undergo emergency surgery.

5.5.3 Mitral Papillary Muscle Dysfunction⁴⁹⁰( Table 63)

Table 63. Recommendations and Levels of Evidence for Invasive Treatment of Acute Mitral Regurgitation in Patients With Acute Myocardial Infarction

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Surgical repair through prompt IABP insertion	I	B	C1	IVa
Addition of CABG	I	B	C1	IVa

CABG, coronary artery bypass grafting; IABP, intra-aortic balloon pump.

Acute mitral regurgitation in patients with acute myocardial infarction is mainly caused by rupture of papillary muscle or chordae. Mitral regurgitation develops in about 14% of patients after acute myocardial infarction as mild to moderate in severity in almost all cases. Severe mitral regurgitation develops in 3% of patients after acute myocardial infarction, and the mortality is high. The prognosis depends on whether patients are diagnosed, and start receiving medical treatment without delay and promptly undergo emergency surgery. Effective medical treatment includes afterload reduction through intense vasodilation and diuresis. IABP is effective as well. Patients should receive medical treatment to stabilize hemodynamics, and undergo surgical treatment as soon as it is ready.

5.6. Cardiac Rehabilitation in Patients With Acute Heart Failure

5.6.1 Significance of Cardiac Rehabilitation in Patients With Acute Heart Failure

The goals of cardiac rehabilitation in patients with acute heart failure are

(1) facilitating early ambulation to prevent consequences of prolonged bed rest (e.g., physical/mental deconditioning, bedsores, and pulmonary embolism);

(2) establishing/sharing plans for prompt and safe discharge from hospital and return to society;

(3) improving QOL by increasing exercise capacity; and

(4) preventing recurrent heart failure and rehospitalization through comprehensive patient education and disease management.

As patients with heart failure are prone to have physical/mental deconditioning or disuse syndrome due to prolonged bed rest, and skeletal muscle atrophy due to malnutrition or increased proinflammatory cytokine levels (“cardiac cachexia”), it is important to start cardiac rehabilitation, consisting of physical therapy, exercise therapy and education/counseling, in the early phase of acute heart failure.

After the disease is stabilized, a comprehensive cardiac rehabilitation program should be initiated. The program should be shifted to an ambulatory cardiac rehabilitation program to continue disease management.¹⁴⁸

Cardiac rehabilitation only during hospitalization has not been demonstrated to improve long-term prognosis in patients with acute heart failure. However, comprehensive ambulatory cardiac rehabilitation programs have been reported to be effective in preventing rehospitalizations of patients with heart failure. In-hospital cardiac rehabilitation programs should aim for not only early ambulation and early discharge but also encouraging patients to participate and continue ambulatory cardiac rehabilitation after discharge.

Patients hospitalized in the ICU for the treatment of acute heart failure tend to have strong anxiety and unstable mental state because they are often overwhelmed with the abrupt onset of the disease, emergency hospitalization, invasive treatment procedures, fear of death, anxiety about the future, and unfamiliar environment apart from the family. They also have physical stress caused by invasive procedures and prolonged bed rest as well as mental stress and shame of receiving nursing care. Therefore, mental support for patients in the early stage of acute heart failure is important to alleviate patients’ mental stress and improve the QOL of patients during hospital stay. Healthcare professionals should try to detect mental health problems early, provide appropriate mental counseling, prescribe drug therapy, and consider for cognitive behavioral therapy, if necessary.¹⁴⁸

5.6.2 Early-Phase Cardiac Rehabilitation in Patients With Severe Heart Failure in the ICU ( Table 64)

Table 64. Recommendations and Levels of Evidence on Rehabilitation for Patients With Acute Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Educational programs on the prevention of recurrence and self-management for all patients	I	C	C1	VI
Rehabilitation for patients with heart failure who are treated with intravenous inotropic drugs and have stable hemodynamics, including low-intensity resistance training under strict supervision	IIb	C	C1	V
Comprehensive cardiac rehabilitation programs for all patients with heart failure after stabilization	IIa	C	C1	VI

Exercise therapy is not recommended for patients with unstable hemodynamics due to acute heart failure or severe heart failure and patients with dyspnea at rest due to pulmonary congestion or fever. However, it has been reported that even patients with severe heart failure on mechanical ventilation, IABP or CHDF or those who are receiving continuous infusion of cardiovascular drugs can safely receive early-phase cardiac rehabilitation including low-strength physical or exercise therapy when they have stable hemodynamics and no symptoms at rest.⁴⁹¹ For example, rhythmic low-strength resistance training using a rubber tube or ball can be conducted under the monitoring by ECG and vital signs in the bed or at the bedside. When unsupported sitting becomes possible, patients should prolong sitting time gradually, and then should try to stand. When standing at the bedside becomes possible, patients should try to stand on their tiptoes, among other training.

XI. Surgical Treatment

1. Surgical Procedures and TAVI

1.1 Left Ventricular Reconstruction

Left ventricular reconstruction was initially introduced as a surgical procedure for the treatment of left ventricular aneurysm in 1980 s. As the resection of left ventricular aneurysm, which increases in size during cardiac constriction, increases cardiac output by increasing the effective left ventricular volume and thereby improves cardiac function and symptoms. On the other hand, as prompt reperfusion therapy for the treatment of myocardial infarction has become a common procedure, cases of left ventricular aneurysm due to transmural infarction have become less common, while cases of ischemic cardiomyopathy with akinesis due to post-reperfusion extensive subendocardial infarction have become more common. Since Dor et al⁴⁹² have reported that left ventricular reconstruction may improve the long-term prognosis of patients with ischemic myocardiopathy and akinesis, diverse procedures have been developed. In 2009, the results of the Surgical Treatment for Ischemic Heart Failure (STICH) trial, a randomized controlled trial to assess the effects of adding left ventricular reconstruction to coronary-artery bypass grafting (CABG), were published.⁴⁹³ This study had unexpected results that adding left ventricular restoration to CABG are not effective in exercise capacity, symptoms, or prognosis in patients with ischemic cardiomyopathy and LVEF ≤35%. A considerable number of objections have been published, but it is still unclear how surgical left ventricular resizing decreases wall tension against the remodeling myocardium, and thereby reverse the remodeling process. In a study in Japan, adding left ventricular reconstruction to mitral annuloplasty was beneficial in patients with ischemic cardiomyopathy with a left ventricular end-systolic volume index (LVESVI) of 105 to 150 mL/m².⁴⁹⁴ While in the J-STICH registry in patients undergoing left ventricular reconstruction, the one-year survival of patients with ischemic cardiomyopathy and severe mitral regurgitation was 60%.⁴⁹⁵ Myocardial viability should be considered to determine whether surgery is indicated or not. The efficacy of Batista procedure and other left ventricular reconstructive procedures for the treatment of non-ischemic cardiomyopathy has not been established. In 2005, the ACC/AHA guidelines for the diagnosis and treatment of chronic heart failure dropped the use of left ventricular reconstruction for this patient population to a Class III recommendation.⁴ In Japan, these procedures are conducted only in limited cases.

1.2 Transcatheter Aortic Valve Implantation (TAVI)

At present, transcatheter aortic valve implantation (TAVI) or transcatheter aortic valve replacement (TAVR) are indicated for the treatment of severe aortic stenosis. The indications and timing of these procedures are in accordance of those of aortic valve replacement (Table 65). For details, refer to latest guidelines for the treatment of valvular heart diseases.^370,371,496

Table 65. Recommendations and Levels of Evidence for Transcatheter Aortic Valve Implantation (TAVI) as a Treatment of Aortic Valve Stenosis

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
TAVI conducted by the multidisciplinary heart team	I	C	C1	VI
TAVI conducted only at medical institutions which have a department of cardiovascular surgery	I	C	C1	VI
TAVI for patients with aortic valve stenosis who cannot undergo cardiotomy and are expected to survive for at least 12 months after the procedure	I	A	A	II
TAVI as an alternative procedure for patients who are indicated for aortic valve replacement but in whom surgery risk is high	IIa	A	B	II
TAVI for patients with aortic valve stenosis in whom treatment is not expected to improve QOL or prognosis	III	A	D	II
TIVI for patients with aortic valve stenosis and low LVEF	III	C	C2	IVa

LVEF, left ventricular ejection fraction; QOL, quality of life; TAVI, transcatheter aortic valve implantation.

TAVI is recommended for patients with severe aortic stenosis who are not indicated for surgery and are expected to live more than 1 year after surgery by the heart team.^497–500 TAVI should also be considered for high-risk patients who are indicated for surgery when the heart team considers that TAVI is a more preferable treatment option according to the patient’s risk factors and anatomical conditions.^499–502 Patients in whom TAVI is not expected to improve symptoms and QOL are not indicated for the procedure.^{497,500–503}

Among patients with severe aortic stenosis and left ventricular dysfunction, those with low-flow/low-gradient aortic stenosis (defined as a valve area of <1 cm², LVEF <40%, and a mean aortic transvalvular gradient of <40 mmHg) are known to be associated with worse outcomes, and dobutamine stress echocardiography is useful in identifying such patients.^504,505 When the cause of left ventricular dysfunction cannot be determined to be excessive afterload, TAVI may not substantially improve left ventricular function or clinical symptoms, but does improve life expectancy.⁵⁰⁶ In patients with low cardiac function, some studies have reported favorable early postoperative results,^507,508 while other studies have pointed out that low cardiac function predicts poor prognosis after TAVI.^509,510 No consensus has been achieved regarding the efficacy of TAVI in patients with cardiac dysfunction. Careful consideration should be given to determine whether TAVI should be conducted or not in patients with cardiac dysfunction.

2. Mechanical Circulatory Support

2.1 Classification of Advanced Heart Failure

Advanced heart failure is classified by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles⁵¹¹ or the Japanese registry for Mechanically Assisted Circulatory Support (J-MACS) profiles⁵¹² (Table 66). In the INTERMACS profile, modifier A (arrhythmia) is defined as recurrent appropriate ICD shocks due to life-threatening ventricular arrhythmias.

Table 66. The INTERMACS and J-MACS Classifications and Options of Device Therapy

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. (Source: Prepared based on Stevenson LW, et al. 2009⁵¹¹ and the Japanese Association for Thoracic Surgery⁵¹²)

2.2 Percutaneous Circulatory Support for Patients With Acute Heart Failure

2.2.1 Intra-Aortic Balloon Pump (IABP)

IABP has been traditionally indicated for patients with acute myocardial infarction/complex coronary lesions who need hemodynamic support during reperfusion/revascularization or until surgical repair of mechanical complications, although its routine use is not recommended. IABP also has become indicated for patients with advanced heart failure who are categorized as INTERMACS profile 1 or 2. IABP is contraindicated for patients with moderate or severe aortic regurgitation or patients with aortic dissection.

2.2.2 Peripheral Veno-Arterial Extracorporeal Membrane Oxygenation (VA-ECMO)

The use of peripheral VA-ECMO (also called percutaneous cardiopulmonary support [PCPS] in Japan) is considered for patients with INTERMACS profile 1 or 2 often in combination with IABP. VA-ECMO is used as a temporal flow support system aiming for hemodynamic stabilization or bailing out of multiple organ failure, which sometimes works as a bridging device towards listing for heart transplant or converting to durable ventricular assist devices (VADs). Since it does not unload left ventricle in itself, an improvement in pulmonary congestion may not be expected.

2.2.3 Percutaneous VAD

In Japan, catheter-based transaortic microaxial pumps (Impella^® 2.5 and 5.0) have been approved as percutaneous VADs for the treatment of cardiogenic shock. These devices are expected to improve pulmonary congestion through unloading left ventricle.

2.3 Mechanical Circulatory Support Requiring Thoracotomy

2.3.1 Centrifugal Pumps for Extracorporeal Circulation

VA-ECMO with central cannulation using centrifugal pumps for extracorporeal circulation can be used for patients who do not respond well to peripheral VA-ECMO and require stronger circulatory support, or who cannot continue peripheral VA-ECMO due to complications such as bleeding from the access site.

The reimbursement of these pumps as VADs is not covered by the Japanese National Health Insurance, and these pumps are often switched to durable VADs approved in patients who require longer circulatory support (see below).

2.3.2 Types and Features of VADs

Among VADs currently available in Japan, paracorporeal VADs are pulsatile pumps, while implantable VADs are non-pulsatile (continuous flow) pumps. As these devices support the left ventricle in most cases, they are called left ventricular assist devices (LVADs). Paracorporeal VADs that support the right ventricle are called right ventricular assist devices (RVADs). Implantable RVADs are not approved in Japan.

In Japan, paracorporeal VADs are available only for in-hospital setting. The use of paracorporeal VADs may increase the risk of serious complications such as cerebrovascular disorder and infections, and pump exchanges due to pump thrombosis or device malfunctions are common. Although implantable LVADs are superior to paracorporeal ones in terms of QOL improvement and the risk of complications, the implantable LVADs are reimbursed only in patients listed (or being listed) for heart transplantation.

2.3.3 Therapeutic Strategies With VADs

As indicated in the algorithms (Figure 13) and strategies (Table 67) in the VAD therapy, indications should be carefully evaluated to achieve the goal of an individual patient.⁵¹³

Figure 13.

Algorithm of VAD therapy for patients with advanced heart failure. AMI, acute myocardial infarction; BSC, best supportive care; BTB, bridge to bridge; BTD, bridge to decision; BTR, bridge to recover; BTT, bridge to transplant; HF, heart failure; IABP, intra-aortic balloon pump; IV, intravenous; LVAD, left ventricular assist device; VA-ECMO, veno-arterial extracorporeal membrane oxygenation; VAD, ventricular assist device.

Table 67. Various Strategies for VAD Therapy

Abbreviation	Strategy	Definition
BTD	Bridge to decision	Temporal use of VADs for the treatment of acute-onset cardiogenic shock before deciding the next treatment options
BTR	Bridge to recovery	Use of VADs to support circulation and thereby promote the recovery of cardiac function aiming for removal of VADs
BTB	Bridge to bridge	Conversion from a paracorporeal LVAD to an implantable LVAD
BTC	Bridge to candidacy	LVAD therapy to reverse organ dysfunction to obtain the eligibility for heart transplantation
BTT	Bridge to transplant	LVAD therapy as a bridge to transplant in patients who have been listed for heart transplantation but cannot maintain hemodynamics with medical treatment
DT	Destination therapy	Permanent LVAD therapy as an alternative to heart transplantation in patients who are ineligible for transplantation

LVAD, left ventricular assist device; VAD, ventricular assist device.

2.3.4 Indications and Outcomes of Paracorporeal VADs

Paracorporeal VADs are used as “bridge to decision” (BTD) in patients with INTERMACS profile 1 who cannot maintain hemodynamics even under mechanical circulatory support such as peripheral VA-ECMO, and as “bridge to candidacy” (BTC) in patients with INTERMACS profile 2 who are not immediate candidates for heart transplantation. Studies have reported that one-year survival rate in patients who received paracorporeal VADs implantation at high volume centers in Japan ranged between about 50 to 80%.^514–516

2.3.5 Indications and Outcomes of Implantable LVADs

Table 68 outlines the indication/exclusion criteria for implantable LVADs in Japan.⁵¹⁷ According to the J-MACS registry, one-year and two-year survival rates of patients with implantable LVADs were 93.6% and 89.8%, respectively, which were higher than the corresponding rates in patients with paracorporeal LVADs.⁵¹⁸ Complications requiring re-hospitalizations reported in patients with implantable LVADs include cerebrovascular disorder, device thrombosis, and drive-line infection.⁵¹⁹ Several complications such as gastrointestinal arteriovenous malformation, gastrointestinal bleeding, late-onset right-sided heart failure, and aortic regurgitation are rare among patients using pulsatile LVADs but have been known to be more common in patients using continuous-flow LVADs.

Table 68. Criteria for Implantable LVAD Under the Bridge-to-Transplant Policy

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.

2.3.6 Recommendations for and Evidence of LVADs ( Table 69)

Table 69. Recommendations and Levels of Evidence on the Use of Implantable Left Ventricular Assist Devices (LVADs)

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (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

HFrEF, heart failure with reduced ejection fraction; LVAD, left ventricular assist device; QOL, quality of life.

No controlled clinical studies of paracorporeal LVADs have been conducted. The use of implantable LVADs for bridge to transplant (BTT) is recommended, although their benefits have not been proven in randomized clinical trials. For the purpose of destination therapy (DT), the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial, a randomized controlled trial of a pulsatile implantable LVAD vs. medical therapy has concluded that the device has a survival benefit.⁵²⁰ Combined with the result of another randomized clinical trial that reported the superiority of continuous-flow device over the pulsatile device,⁵²¹ continuous-flow implantable LVADs are most effective to improve prognosis and is widely recommended.

3. Heart Transplantation

Heart transplantation is performed for patients with underlying cardiovascular disease such as dilated cardiomyopathy or dilated-phase hypertrophic cardiomyopathy, ischemic myocardial disease, and congenital heart disease. Criteria for indication of heart transplantation include lack of effective treatment other than heart transplantation; understanding of heart transplantation by patients and family; and ability to continue lifelong treatment such as immunosuppressive therapy and examinations such as myocardial biopsy (Table 70).⁵²² Additional conditions for application are patients with heart failure who require long-term or frequent hospitalizations and remain in NYHA Class III or IV despite conventional drug therapy including β-blockers and ACE inhibitors, and those with potentially fatal severe arrhythmia that does not respond to conventional treatment. Both types of patients are preferably under 65 years of age. Absolute exclusion criteria include severe irreversible organ failure, active infection, severe pulmonary hypertension, drug and substance abuse, including tobacco and alcohol, malignant tumor and positive results of human immunodeficiency virus (HIV) antibody test. Patients with irreversible pulmonary hypertension with pulmonary vessel resistance of >6 Wood units despite available treatments are not indicated for heart transplantation, and should be considered for heart-lung transplantation. When heart failure progresses during the waiting period, VAD implantation should be considered before other organ dysfunctions occur. By June 2016, a total of 284 patients underwent heart transplantation,⁵²³ and the survival rates at 5 and 10 years after the transplantation were 92.7% and 89.6%, respectively, which are among the highest in the world. According to an annual report of the heart and lung registries by the International Society for Heart and Lung Transplantation,⁵²⁴ heart transplantation is proved to be the most favorable for treatment of advanced heart failure compared to other treatment modalities. Table 71 summarizes recommendations and levels of evidence for heart transplantation in patients with heart failure.

Table 70. Indications for Heart Transplantation

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. (Excerpted from the Heart Transplantation Committee of the Japanese Circulation Society. 2013⁵²²)

Table 71. Recommendations and Levels of Evidence for Heart Transplantation

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Heart transplantation for patients with severe HFrEF resistant to appropriate drug therapies and device treatments	IIa	C	B	IVa

HFrEF, heart failure with reduced ejection fraction.

XII. Disease Management

1. Disease Management Programs (e.g., Educational Programs) and Team Medical Care

1.1 Disease Management Programs by Multidisciplinary Teams

Table 72 summarizes features and components of disease management for patients with heart failure. It is desirable that disease management for each patient should be operated by a multidisciplinary team of diverse healthcare professionals, including physicians, nurses, pharmacists and dieticians, and the team should contain two or more members who have expertise in the treatment, management and care of heart failure. In order to operate the disease management team efficiently, comprehensive cardiac rehabilitation programs should be utilized proactively. Disease management for patients with heart failure include guideline-based standard drug therapy, nonpharmacologic therapy and exercise therapy, patient education and counseling emphasizing the importance of treatment adherence and selfcare, symptom monitoring, preparation for and support of hospital discharge, appropriate use of social resources, follow-up examinations of patients, periodic assessment of physical, mental, and social functions, and mental support.

Table 72. Features and Components of Disease Management Programs for Patients With Heart Failure

Features

• Multidisciplinary team approaches by cardiologists, cardiovascular surgeons, nurses, pharmacists, physical therapists, nutritionists, social workers, and psychologists, etc. • Patient education, consultation and support by specially trained healthcare professionals • Implementation of comprehensive cardiac rehabilitation programs

Components

• Drug and nonpharmacologic therapy • Exercise therapy • Patient education focused on adherence and self-care • Symptoms monitoring by patients, family members, caregivers, or healthcare professionals • Discharge planning and support and utilization of social resources • Post-discharge follow-up • Continuous assessment of patients’ physical, mental and social functions (e.g., body weight, nutritional status, laboratory findings, ADL, mental status, and QOL changes) • Provide mental support to patients, family members, and caregivers

ADL, activities of daily living; QOL, quality of life.

1.2 Contents of Disease Management Programs for Patients With Heart Failure ( Tables 73 and 74)

Table 73. Contents of Treatment/Lifestyle Education and Support for Patients With Heart Failure, Family Members, and Caregivers

Contents of education	Specific education/support methods
Knowledge on heart failure
• Definition, causes, symptoms, and clinical course • Severity assessment (laboratory findings) • Factors of worsening heart failure • Comorbidities • Drug and nonpharmacologic therapy	• Provide information using appropriate materials suitable for individual patient’s comprehension and health literacy
Self-monitoring
• Necessity and importance of symptom monitoring by patients themselves • Self-monitoring skills • Utilizing patient diaries	• Encourage patients to recording in their diaries and utilize recorded information for better practice and patient education
Management of disease worsening
• Symptoms of worsening heart failure and assessment • How to contact healthcare professionals when disease worsens	• Instruct patients to visit clinic when symptoms of worsening heart failure (e.g., dyspnea, swelling, body weight gain by >2 kg in 3 days) develop, and explain how to contact the clinic
Adherence to treatment
• Name of drugs, expected effects, how to take drugs, adverse drug reactions • Importance of taking drugs as directed • Purpose of device therapy, and how to handle devices during daily life	• Provide information using appropriate materials suitable for individual patient’s comprehension and health literacy • Evaluate adherence to treatment periodically • Patients with poor adherence should be educated and supported by healthcare professionals
Infection control and vaccination
• Infections as factors worsening heart failure • Necessity of vaccinations against influenza and pneumonia	• Provide knowledge on how to prevent infections during daily life • Provide information on the timing of vaccinations
Salt and water management
• Risk of excessive water intake • Limit water intake in patients with severe heart failure • Appropriate salt intake (<6 g/day) • Importance of maintaining an appropriate body weight	• Explain how to measure water intake in detail • Explain how to reduce salt intake efficacy using educational materials • Observe patients for symptoms of decreased appetite due to salt restriction
Nutritional management
• Importance of well-balanced diet • Menus considering the nature of complications	• Observe patients periodically for nutritional status • Provide nutritional guidance based on the individual patient’s physical status (e.g. swallowing function) and life style • Explain that reduced meal size and appetite may be signs of worsening heart failure
Alcohol
• Risk of excessive alcohol consumption	• Suggest appropriate alcohol consumption based on the individual patient’s causes of heart failure
Smoking cessation
• Importance of quit smoking	• See the “Guidelines for Smoking Cessation (JCS 2010)”
Physical activity
• Importance of appropriate physical activity during stable conditions • Importance of bed rest and activity restrictions during worsening heart failure • Negative effects of excessive bed rest (e.g. decreased exercise capacity)	• Evaluate exercise capacity and skeletal muscles • Evaluate activities of daily living regularly • Considering the individual patient’s physical function and living environment, assess the risk of fall and provide detailed guidance on physical activities during daily life
Bath
• How to take a bath appropriately	• Instruct appropriate methods according to the severity of heart failure and living environment
Travel
• Precautions during travel (drug therapy, water intake, meals, and physical activity) • Risk of worsening heart failure during travel • How to manage worsening heart failure during travel	• Explain possible effects of changes in contents and timing of meals, weather and climates, and physical activities, etc. during travel on the condition of heart failure • Provide information on pre-travel preparation
Sex life
• Effects on sexual activity on heart failure • Relationship between heart failure mediations and sexual function • Precautions for using erectile dysfunction medications	• Explain that sexual activity may worsen heart failure • Refer to specialist physicians whenever necessary
Mental support
• Heart failure and mental/psychological changes • Stress management during daily life	• Evaluate psychiatric symptoms periodically • Explain the importance and methods of stress management during daily life • When worsening psychiatric symptoms are suspected, consult the patient to psychiatrists, psychosomatic medicine specialists, and clinical psychotherapists
Periodic hospital visits
• Importance of periodical clinic visits	• Before discharge, confirm appoints for out-patient clinic visits after discharge • Instruct patients to contact medical institutions promptly when symptoms worsen regardless of visit schedule • Ensure easy access to healthcare professionals (e.g., Telephone consultation, and utilization of social resources)

Table 74. Recommendations and Levels of Evidence for Disease Management in Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Multidisciplinary team-based education and support to improve treatment adherence and self-care for patients, family members, and caregivers	I	A	A	I
Discharge support and continuous follow-up	I	A	B	I
Smoking cessation	I	C	B	IVb
Symptom monitoring	I	C	C1	VI
Monitoring and specialists’ treatment for psychiatric symptoms	I	B	B	II
Educational support for patients at a high risk of worsening heart failure and use of social resources for people living alone, elderly patients, and people who also have dementia	I	A	A	I
Low-salt diet (ca. 6 g/day)	IIa	C	C1	VI
Restriction of alcohol	IIa	C	C1	VI
Vaccinations to prevent infections	IIa	C	B	IVb

1.2.1 Patient Education Emphasizing the Importance of Adherence and Self-Care

Appropriate self-care behaviors play an important role in preventing worsening heart failure, and patient education to prove their self-care capabilities is expected to improve prognosis and QOL.^525–527 Healthcare professionals should evaluate appropriateness of patients’ self-care, and educate and consult patients and their family members to improve the quality of self-care behaviors.^528,529 In patient education, healthcare professionals should consider their health literacy, the ability to access, understand, and utilize appropriate information on the disease,⁵³⁰ and should provide materials suitable for individual patients according to the level of health literacy.⁵³¹ For patients with limited self-care capabilities such as elderly, people living alone, and patients also suffering from cognitive disorder, healthcare professionals should educate and support their family members, and utilize social resources such as sending home visiting physicians, nurses or caregivers in a more proactive way.

2. Comprehensive Cardiac Rehabilitation

2.1 Significance of Ambulatory Cardiac Rehabilitation in Disease Management Programs

The most common reasons for rehospitalization in patients with heart failure are 1) worsening congestion (fluid retention), 2) non-cardiac comorbidities, 3) poor adherence.⁵³² It has also been pointed out that sarcopenia and frailty predict the long-term prognosis of elderly patients with heart failure.¹⁴ Accordingly, out-patient and home-based interventions are essential for elderly patients with heart failure and noncardiac comorbidities with a high risk of rehospitalization to improve QOL and exercise capacity and prevent rehospitalization and conditions requiring nursing care. These interventions should include systemic disease management covering both heat failure and noncardiac comorbidities and exercise interventions to prevent sarcopenia and frailty.⁵³³

Although many studies have reported the efficacy of multidisciplinary intervention/disease management programs in patients with heart failure,⁵³⁴ and a systematic review⁵³⁵ has concluded that multidisciplinary interventions significantly reduce rehospitalization rates and all-cause mortality in patients with heart failure, there are many unsolved issues, such that the program contents have not been standardized.^536–539 In contrast, comprehensive ambulatory cardiac rehabilitation programs, which include lifestyle interventions to prevent recurrent heart failure and clinical monitoring of heart failure, are expected to serve as disease management programs for heart failure, and their benefits have been demonstrated.^540,541

2.2 Practical Examples of Ambulatory Cardiac Rehabilitation as a Disease Management Program ( Table 75)

Table 75. Recommendations and Levels of Evidence for Comprehensive Ambulatory Cardiac Rehabilitation for Patients with Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
For patients with HFrEF, conduct exercise therapy as ambulatory cardiac rehabilitation sessions to improve symptoms and exercise capacity	I	A	A	I
For patients with HFrEF, conduct exercise therapy as ambulatory cardiac rehabilitation sessions to improve QOL and prevent rehospitalization	IIa	B	B	II
For patients hospitalized for heart failure, conduct multidisciplinary disease management to facilitate ambulatory cardiac rehabilitation sessions to improve QOL and exercise capacity and prevent rehospitalization after discharge	IIa	B	B	II

HFrEF, heart failure with reduced ejection fraction; QOL, quality of life.

Figure 14 outlines a typical flowchart of exercise therapy and heart failure monitoring in an ambulatory cardiac rehabilitation program.⁵⁴² Every time when a patient visits the clinic for a rehabilitation session, he/she is checked for physical condition before, during and after the session, and periodically for improvement in exercise capacity (Table 76). When findings suggestive of worsening heart failure are observed, the patient is referred to his or her physician, who may modify the exercise prescription, limit water intake or increase the dose of diuretics, among other measures, to prevent worsening heart failure.⁵⁴³ Comprehensive ambulatory cardiac rehabilitation sessions as a disease management program for patients with heart failure is superior to medical consultations at clinic in terms of identifying early signs of worsening heart failure through symptoms, signs and ECG changes during exercise.

Figure 14.

Exercise therapy and disease management for heart failure in ambulatory cardiac rehabilitation programs. BP, blood pressure; CPX, cardiopulmonary exercise testing; HF, heart failure; HR, heart rate. (Adapted from Goto Y. 2014⁵⁴² with modifications)

Table 76. Points to Be Examined During Ambulatory Cardiac Rehabilitation Sessions for Patients With Heart Failure, and Signs of Worsening Heart Failure or Excessive Exercise

Items		Signs of worsening heart failure/excessive exercise
Before exercise	Symptoms	Persistent malaise, residual fatigue from previous day
	Body weight	Tendency of body weight gain (by ≥2 kg in 1 week)
	Heart rate	High heart rate at rest (≥100 bpm), increase by ≥10 bpm from last week
	Blood pressure	Systolic blood pressure increased or decreased by ≥20 mmHg from last week
	ECG monitor	Occurrence of arrhythmias (paroxysmal atrial fibrillation, complete atrioventricular block, frequent premature ventricular contractions, and ventricular tachycardia), abnormal ST segment, or new left bundle branch block
	BNP levels in the blood	Increase by ≥100 pg/mL from the preceding value (measure once a month)
During exercise	Symptoms	Borg’s scale during exercise of ≥14 or an increase in Borg’s scale by ≥2 from last week Respiratory symptoms (shortness of breath and dyspnea), anginal symptoms (chest compression and chest pain), low-cardiac-output symptoms (dizziness and malaise), and/or orthopedic symptoms (myalgia and arthralgia)
	Heart rate	High heart rate (≥130 bpm) during exercise, or an increase in heart rate by ≥10 bpm during same exercise load from last week
	Blood pressure	Increased or decreased systolic blood pressure during exercise by ≥20 mmHg from last week
	ECG monitor	Occurrence of arrhythmias (paroxysmal atrial fibrillation, complete atrioventricular block, frequent premature ventricular contractions, and ventricular tachycardia), abnormal ST segment, or new left bundle branch block
	Respiration, SpO2 monitor	Substantial increase in respiratory rate during exercise, low SpO2 (<90%)
After exercise	Symptoms	Persistent symptoms after exercise
	ECG monitor	Arrhythmia at rest after exercise (paroxysmal atrial fibrillation, frequent premature ventricular contractions, and ventricular tachycardia)
	Exercise capacity	Decreased exercise capacity (peak oxygen uptake, 6-minute walk distance), and reduced ventilation efficiency (V̇E/V̇CO2 slope) from the last session

ECG, electrocardiogram; SpO₂, oxygen saturation

XIII. Palliative Care

The World Health Organization (WHO) describes palliative care as services that must be considered for all patients with life-threatening conditions such as cardiovascular diseases and respiratory diseases. Many patients with heart failure are suffering from total pain and healthcare professionals should support patients with heart failure and their family members from early stages of the disease in a multidisciplinary setting to improve their QOL. In 2014, WHO has reported that nearly 40% of adults who need palliative care has cardiovascular diseases.⁵⁴⁴

1. Advance Care Planning and Decision-Making Support

Although the number of elderly patients with heart failure, are increasing year by year, their recognition about prognosis is substantially more optimistic than the real situation.⁵⁴⁵ Also, it is often difficult to introduce palliative care in a timely manner. Advance care planning (ACP) is an important step to help individual patients prepare for future changes in their disease condition. ACP is a process to share decisions what the patient and his or her family members decided about what treatment they want and what way of life they want to lead in advance, before the patient becomes difficult to make his or her own decisions. It has been recommended that ACP should be conducted at an annual heart failure review and at the end of hospitalization during which clinical milestones that trigger review of treatment strategies occurred (Table 77).⁵⁴⁶ The aim of ACP is to avoid unwanted, invasive treatments near death and improve the quality of death. A randomized controlled in ACP in non-cancer patients has reported its benefits.⁵⁴⁷

Table 77. Triggers for Formally Assessing Prognosis and Having Conversations About Goals of Care and Voluntary Advance Care Planning (ACP)

Routine • “Annual Heart Failure Review” with a scheduled clinic visit Event-driven “milestones” that should prompt reassessment • Increased symptom burden and/or decreased quality of life • Significant decrease in functional capacity 　Loss of ADLs 　Falls 　Transition in living situation (independent to assisted or LTC) • Worsening heart failure prompting hospitalization, particularly if recurrent • Serial increases of maintenance diuretic dose • Symptomatic hypotension, azotemia, or refractory fluid retention necessitating neurohormonal medication underdosing or withdrawal 　Circulatory-renal limitations to ACEI/ARB 　Decrease or discontinuation of β-blockers because of hypotension • First or recurrent ICD shock for VT/VF • Initiation of intravenous inotropic support • Consideration of renal replacement therapy • Other important comorbidities: new cancer, etc • Major “life events”: death of a spouse

ADL indicates activities of daily living; LTC, long-term care; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ICD, implantable cardioverter-defibrillator; VT, ventricular tachycardia; and VF, ventricular fibrillation. (Adapted from Allen LA, et al. 2012⁵⁴⁶)

ACP may include completion of an advance directive, a document that describes the patient’s preferences about end-of-life care. Specifically, the patient may make shared decision making, with support from a multidisciplinary team, about Do Not Attempt Resuscitation (DNAR) orders and policies on whether or not to discontinue device therapy such as implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT), and left ventricular assist device (LVADs), and prepare an advance directive. At this time, the patient should be informed that he or she can change the contents of the advance directive at any time. When necessary, the patient may designate another person to make health care decisions for him or her when the patient becomes unable to make health care decisions. In the guidelines for decision making with end-of-life care published by the Ministry of Health, Labor and Welfare in 2007, a flow process to determine medical and care policies at the end of life is described (Figure 15).⁵⁴⁸

Figure 15.

Process of end-of-life medical/care planning. (Adapted from The Ministry of Health, Labor and Welfare. 2017⁵⁴⁸)

“The statement on the treatment of elderly patients with heart failure” published by the Japanese Heart Failure Society in 2016 describes the importance of pain-relieving treatment in end-of-life care for elderly patients and the roles of multidisciplinary conferences and ACP.⁵⁴⁹ In 2016, the Japanese Society of Intensive Care Medicine published “Advice on Do Not Attempt Resuscitation (DNAR) Order”⁵⁵⁰ to describe that ACR is not a procedure just to determine DNAR policies but is an important process to share the patient’s values and philosophy on life and death with healthcare professionals.

2. End-Stage Heart Failure and Indication for Palliative Care

End-stage heart failure is defined as a heart condition that doesn’t respond to maximal medical or on-pharmaceutical treatments. End of life is defined as the period in which death is imminent due to repeated or rapid worsening of an illness and there is little likelihood of cure.⁵⁵¹ However, patients with advanced chronic heart failure show a clinical course different from that of patients with cancer. If is often difficult to know the end of life is approaching in patients with advanced heart failure (Figure 16).⁵⁵² The 2013 ACCF/AHA guideline for the management of heart failure described end-stage heart failure as Stage D heart failure, defined as “patients with truly refractory heart failure who might be eligible for specialized, advanced treatment strategies, such as mechanical circulatory support, procedures to facilitate fluid removal, continuous inotropic infusions, or cardiac transplantation or other innovative or experimental surgical procedures, or for end-of-life care, such as hospice”.⁵⁵³ The 2016 ESC guidelines for the diagnosis of treatment of acute and chronic heart failure defined heart failure requiring end-of-life care as the conditions, including:

Figure 16.

Models of end-stage treatment in chronic heart failure and cancer. ADL, activities of daily livings. (Adopted from: Lynn J. 2001⁵⁵² with modification)

• progressive functional decline (physical and mental) and dependence in most activities of daily living

• severe heart failure symptoms with poor quality of life despite optimal pharmacological and nonpharmacologic therapies

• frequent admissions to hospital or other serious episodes of decompensation despite optimal treatment

• heart transplantation and mechanical circulatory support ruled out

• cardiac cachexia

• clinically judged to be close to end of life.¹⁴

In Japan, the Japanese Circulation Society published the “Statement for End-stage Cardiovascular Care” in 2010.⁵⁵⁴ All of these guidelines assume that patients with heart failure receive appropriate treatment throughout the disease course, which clearly differs from the situation of cancer treatment where end-stage patients often do not receive aggressive treatment. To alleviate their signs and symptoms, patients should be treated for heart failure and its complications throughout the life. Moreover, palliative care is not the same as end-of-life care, and is not indicated only for patients nearing the end of life (Figure 17).⁵⁵⁵ Palliative care should be initiated in the early phase of heart failure where symptoms begin. ACP should be conducted in the early phase as well, and a multidisciplinary team should repeatedly assess the physical, psychological, and mental needs of patients (Table 78).

Figure 17.

Models of palliative care in heart failure. (Adopted from: Gibbs JS, et al. 2002⁵⁵⁵ with modification)

Table 78. Recommendations and Levels of Evidence for Palliative Care for Patients With End-Stage Heart Failure

	Class of Recommendation	Level of Evidence	Grade of Recommendation (MINDS)	Level of Evidence (MINDS)
Conduct advance care planning (ACP) in which physicians share decisions with the patient and his/her family members about treatment and care before the patient becomes difficult to make his or her own decisions	I	B	B	II
Continued treatment to manage heart failure and complications and relieve symptoms	I	C	B	II
Multidisciplinary team-based frequent assessment for the patient’s physical, mental and spiritual needs	II	C	C1	VI

3. Importance of Multidisciplinary Approaches

In order to prevent and remove total pain in patients with heart failure, a multidisciplinary approach is essential. A team of physicians, nurses, pharmacists, clinical psychotherapists, physical therapists, registered dieticians, medical social workers, clinical engineers and other health care experts should address this issue.

4. Symptoms and Treatment of End-Stage Heart Failure

Typical symptoms of end-stage heart failure include dyspnea, generalized malaise, pain, anorexia, and depression. It has been reported that 60 to 88% of patients with end-stage heart failure have dyspnea, 69 to 92% have generalized malaise, and 35 to 68% have pain.^556–558 It has also been reported that 70% of patients hospitalized for end-stage heart failure have depression.⁵⁵⁹ As heart failure itself is considered to lease these problems through causing fluid retention and low cardiac output, heart failure treatment in Stage D should be continued in combination with the following treatments to control these symptoms.

4.1 Dyspnea

It has been reported that low-dose morphine and other opioids are safe and effective in releasing intractable dyspnea.^560,561 However, opioids may cause adverse drug reactions such as nausea, vomiting and constipation. Careful dose adjustment is required especially in elderly patients and patients with renal dysfunction to prevent overdosage, which may lead to respiratory depression in some patients.

4.2 Pain

A study has reported that the prevalence of pain increases as NYHA functional class worsens.⁵⁶² Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided whenever possible as they may worsen renal dysfunction and fluid retention in patients with end-stage heart failure. It is recommended that acetaminophen, a non-opioid analgesic, should be tried first and then opioids should be added if pain in difficult to control.

4.3 Generalized Malaise

Patients should be examined not only for low cardiac output but also for depression, hypothyroidism, anemia, overuse of diuretics, electrolyte imbalance, sleep apnea, and occult infections, and should be treated accordingly. As pharmacotherapy is often ineffective in alleviating this condition, and nonpharmacologic therapy such as energy-conservation techniques may work in some patients.⁵⁶³

4.4 Depression and Anxiety

In patients with heart failure, depression predicts poor prognosis and is also associated with poor QOL.⁵⁶⁴ Depression is commonly treated with selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants, but it has been recently reported that concomitant use of β-blockers and SSRIs may increase the risk of death,⁵⁶⁵ and antidepressants may not always improve the prognosis of patients with heart failure.^566–568 Tricyclic antidepressants should be used with caution as they may prolong QT intervals and cause anticholinergic effects. Benzodiazepines are the first-line treatment for anxiety. Nonpharmacologic therapy such as cardiac rehabilitation and expert counseling are beneficial as well.^569,570

4.5 Delirium

Delirium often develops in patients with end-stage heart failure, especially in elderly. Delirium should be differentiated from dementia and depression, and early intervention should be offered to prevent severe delirium. When delirium develops in a patient with heart failure, the physician should review his/her treatment and environment for whether or not he/she uses drugs that may induce or worsen delirium (e.g. antihypertensives, β-blockers, antiarrhythmics, sympathomimetics, anticholinergics, hypnotics, and antianxiety drugs), take appropriate safety measures, and, if the condition is severe, consult him/her to a psychiatrist and consider for antipsychotic therapy.

4.6 End-of-Life Pain

As the final measure for patients suffering from uncontrollable pain, an appropriate amount of midazolam, a benzodiazepine drug, may be administered.

4.7 Deactivation of Medical Devices

When the patient’s clinical status reaches the end-of-life stage, the patient, his/her family members and the palliative care team should discuss fully to determine whether to deactivate his/her ICD, pacemaker or CRT.⁵⁷¹ In the “Concept of optimizing the indications for ventricular assist devices in Japan: Destination therapy (DT),”⁵⁷² the Japan VAD Council has recommended that the physician should explain about end-stage cardiovascular care to the patient and his or her family members before implanting cardiac devices, inform that he/she has an option to deactivate his/her implantable LVAD at the end-of-life stage, and recommend him/her to describe his/her preferences in an advance directive. Healthcare professionals should explain to patients about potential problems of DT (e.g., device malfunction, serious LVAD-related complications, status of comorbidities, and poor QOL after LVAD implantation) fully in advance, and help them plan how to address such problems in future according to the patients’ own life philosophy and values. This process is called “preparedness planning.”⁵⁷³ The guidelines on the use of implantable LVADs proposed by the Japanese Circulation Society and the Japanese Society for Cardiovascular Surgery in 2013,⁵¹⁷ and the guidelines on end-stage care for patients in emergency room or ICU proposed by the Japanese Association for Acute Medicine, the Japanese Society of Intensive Care Medicine, and the Japanese Circulation Society in 2014⁵⁷⁴ recommend multidisciplinary process-oriented approaches based on the advance directives and family’s wishes.

5. Early Introduction of Palliative Care for Heart Failure

The introduction of palliative care for heart failure does not mean abandoning hope for cure. Palliative care is conducted to improve the QOL of the patient and his or her family members, and is continued together with standard heart failure treatment. Accordingly, palliative care should be initiated in the early phase of the disease rather than considering near the end of life.

XIV. Future Treatment

1. Ivabradine (If-Channel Blocker)

Ivabradine decreases heart rate by blocking If channels of sinus node cells. It is indicated only for patients with sinus rhythm. In a randomized, double-blind, placebo-controlled trial of ivabradine in patients who had HFrEF (LVEF <35%), were in sinus rhythm with a heart rate ≥70 bpm, had been admitted to hospital for heart failure within the previous year, and were receiving a β-blocker at the recommended or maximum tolerated dose, an angiotensin converting enzyme (ACE) inhibitor (or an ARB), and/or a mineralocorticoid receptor antagonist, ivabradine significantly reduced the composite of cardiovascular death or hospital admission for worsening heart failure.⁵⁷⁵ This study revealed that increased heart rate is a risk factor in patients with HFrEF in sinus rhythm, and lowering heart rate is an important target for treatment of heart failure.⁵⁷⁶

2. Sacubitril/Valsartan (ARNI)

Sacubitril/valsartan (LCZ696) is a new class of drug named as an angiotensin receptor neprilysin inhibitor (ARNI), and consists of valsartan, an ARB, and sacubitril (AHU-377), a prodrug of a neprilysin inhibitor, in a 1:1 mixture. Sacubitril is converted to the active form LBQ657, which exerts an inhibitory effect on neprilysin 3 to 4 hours after absorption. LBQ657 mainly inhibits the degradation of endogenous natriuretic peptide but does not inhibit ACE or aminopeptidase P. Therefore, it does not enhance the degradation of bradykinin, and the risk of angioedema is expected to be low. The half-life of LBQ657 is 12 hours and that of valsartan is 14 hours. Sacubitril/valsartan is administered twice daily.

The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial has revealed that sacubitril/valsartan is superior to ACE inhibitor enalapril in improving prognosis.⁵⁷⁷ ESC and ACC/AHA Guidelines recommended the replacement from ACE inhibitor to ARNI for HFrEF and the inhibition of the renin-angiotensin system with ACE inhibitors, ARBs, or ARNI in patients with HFrEF as Class I recommendations with Level of Evidence B.^14,578

In Japan, the Prospective comparison of ARNI with ACE inhibitor to determine the novel beneficial treatment value in Japanese Heart Failure patients (PARALLEL-HF), a phase III randomized double-blind trial to obtain the approval from the government, is underway.⁵⁷⁹ Sacubitril/valsartan reduced plasma NT-proBNP levels to a greater extent than did valsartan at 12 weeks in heart failure with preserved ejection fraction (HFpEF) in the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction (PARAMOUNT) trial.⁵⁸⁰ The Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial, a large-scale clinical trial to investigate the effects of sacubitril/valsartan on clinical outcomes is underway in countries including Japan. These large-scale clinical trials are expected to provide further evidence on the benefits of ARNI in patients with heart failure.

3. Vericiguat (cGS Activator)

In patients with heart failure, endothelial dysfunction and increased production of reactive oxygen species (ROS) reduce the production and bioavailability of nitric oxide (NO) and activity of the NO receptor, soluble guanylate cyclase (sGC), resulting in decreased activation of cyclic guanosine monophosphate (cGMP), as well as conversion to the NO-insensitive (inactive) sGC by ROS. Accordingly, cGMP-mediated intracellular signaling has attracted attention as a potential treatment target in HFrEF and HFpEF.^581–583

Vericiguat is a novel sGC stimulator that directly stimulates sGC to promote NO production in a NO-independent manner via a site other than the NO binding site and also synergizes with NO.^581,583

In a dose-finding phase II randomized controlled study of vericiguat in patients with HFrEF with a LVEF of <45% (the SOCRATES-REDUCED trial in the Soluble guanylate Cyclase stimulator in heart failure Study [SOCRATES] program),⁵⁸⁴ patients who were clinically stable with LVEF <45% within 4 weeks of a worsening chronic heart failure event received placebo (n=92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg, 2.5 mg, 5 mg, or 10 mg; n=91 for each dose) for 12 weeks. The primary endpoint, change from baseline to week 12 in log-transformed NT-proBNP level, was not significantly different between the pooled 3-highest-dose vericiguat group and placebo group, but a secondary analysis revealed that higher vericiguat doses were significantly associated with greater reductions in NT-proBNP level.⁵⁸⁵

As vericiguat was shown to tolerable in patients with HFrEF in phase II studies, the drug is currently being evaluated in a global phase III placebo-controlled randomized clinical trial called the Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTRIA) trial.⁵⁸⁶ The VICTRIA trial plans to enroll a total of 4,872 patients with NYHA class II to IV heart failure and LVEF >45% by the end of 2020, and will follow them for approximately 3.5 years. The primary endpoint is time to first occurrence of composite endpoint of cardiovascular death or heart failure hospitalization. The trial is conducted in many countries including Japan.

Phase III trials of vericiguat are expected to generate evidence that help position this drug in the treatment of heart failure, which will be described in the relevant guidelines including Western guidelines in the future.

4. Omecamtiv Mecarbil (Cardiac Myosin Activator)

As omecamtiv mecarbil increase the transition rate of myosin from weakly to strongly actin-bound force-generating state and thereby increase myocardial contractility,⁵⁸⁷ this drug is expected to increase cardiac function without increasing intracellular calcium concentration and worsening prognosis.

In phase II clinical trial of intravenous omecamtiv mecarbil in patients with HFrEF,⁵⁸⁸ left ventricular ejection time and stroke volume increased proportionally with plasma concentration of omecamtiv mecarbil, and higher plasma concentrations were also associated with reductions in left ventricular end-systolic and end-diastolic volumes. Heart rate decreased slightly but significantly. Cardiac ischemia developed in some patients receiving higher doses of the drug.

In a following large-scale randomized controlled trial, the Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure (ATOMIC-AHF),⁵⁸⁹ 606 patients with acute heart failure who had LVEF ≤40%, elevated natriuretic peptide level, and persistent dyspnea received omecamtiv mecarbil at 3 escalating intravenous doses. Omecamtiv mecarbil resulted in significantly greater dyspnea relief in the higher-dose group as compared with the control group, but plasma troponin levels were significantly higher in patients treated with omecamtiv mecarbil compared with placebo.

In the Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF) trial,⁵⁹⁰ a clinical study of oral omecamtiv mecarbil in 448 patients with HFrEF, patients receiving the drug at 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics had longer systolic ejection time, larger cardiac output, smaller left ventricular end-systolic diameter, and lower heart rate than the control group.

A phase III study in about 8,000 patients with HFrEF to evaluate the effect of omecamtiv mecarbil on the risk of cardiovascular death or heart failure events, the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, is currently ongoing.⁵⁹¹

5. Percutaneous Mitral Valve Repair System (MitraClip^®)

Percutaneous mitral valve repair should be considered for patients with mitral valve insufficiency for whom mitral repair is expected to reduce symptoms and improve QOL but surgical risk is high. In Japan, MitraClip^® has become available recently (Figure 18). This system facilitates early ambulation after surgery. Symptomatic improvement reported by patients receiving this procedure on day 30 after the procedure is better than those undergoing thoracotomy.

Figure 18.

Treatment of mitral valve insufficiency with MitraClip^®. (Figures courtesy of Abbott Vascular Japan Co., Ltd.)

6. Human (Autologous) Skeletal Muscle-Derived Cell Sheet (HeartSheet^®)

Myoblast sheet is a cell therapy technology for severe heart failure, and five sheets, each contains 6×10⁷ myoblasts, are applied on the epicardium to cover the anterior and lateral walls of the left ventricle through a left lateral thoracotomy. The implanted myoblast sheets secrete cytokines such as hepatocyte growth factor, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and stromal derived factor-1 that are considered to promote neovascularization, induce stem cells, and inhibit fibrosis, and thereby improve cardiac function.⁵⁹² In animal models of heart failure, the sheet improved cardiac function and prolonged survival.

It has been reported that among 4 patients with dilated cardiomyopathy supported by a LVAD who received the autologous myoblast sheet implantation, two patients showed an improvement in cardiac function and could remove the LVAD.⁵⁹³ Safety and efficacy of the myoblast sheet technology for treatment of ischemic cardiomyopathy were demonstrated in clinical research⁵⁹⁴ and a multi-center company-sponsored study,⁵⁹⁵ and the sheet was approved as the world’s first tissue-engineered medical product, HeartSheet^®, under the fast-track designation and reimbursed by the National health Insurance.

Investigator-initiated studies are now underway to assess the efficacy and safety of the product in the treatment of children and adults with dilated cardiomyopathy.

7. Waon Therapy

In Waon therapy,⁵⁹⁶ a thermal therapy developed in Japan, patients stay in a far-infrared dry sauna at 60℃ for 15 minutes, and then maintain body temperature for 30 minutes after sauna bath.

It has been reported that Waon therapy is beneficial in improving hemodynamics,⁵⁹⁷ left ventricular function,^598–601 heart failure symptoms,^598,600,602 QOL and exercise capacity,⁶⁰⁰ and peripheral vascular endothelial function,^600,602 and reducing heart rate variability in patients with heart failure.^603,604 A retrospective study has revealed that Waon therapy significantly reduced the risk of death and rehospitalization for worsening heart failure, and improved the prognosis of patients with chronic heart failure.⁶⁰⁵ In the WAON-CHF trial, a multicenter prospective randomized trial in 149 patients treated in 19 medical institutions,⁶⁰⁶ patients receiving Waon therapy once daily for 10 days showed improvement in BNP levels, NYHA functional class, 6-minute walk distance, and cardiothoracic ratio and a favorable safety profile. However, no significant difference between the Waon therapy group and the control group was found in the change in BNP from before and after treatment, which was the primary endpoint of the study.

At present, Waon therapy in the treatment of heart failure is not covered by the National Health Insurance in Japan.

Supplement 1. A Statement on Appropriate Use of Adaptive Servo-Ventilation (ASV) by the Japanese Circulation Society and the Japanese Heart Failure Society (the Second Statement)

1) Adaptive Servo-Ventilation (ASV) for patients whose conditions are similar to the participants in the SERVE-HF trial (patients with heart failure who have predominant central sleep apnea and stable left ventricular systolic dysfunction with left ventricular ejection fraction [LVEF] ≤45%)

The introduction and continuation of ASV in these patients are not contraindicated, but careful consideration is required. In the clinical practice, it is desirable that, as described in the relevant guidelines in Japan,1,2 patients should be first considered for continuous positive airway pressure (CPAP) and then ASV should be considered only for patients who still have sleep apnea despite CPAP or are intolerable to CPAP. After initiating ASV, patients should be observed carefully for clinical conditions, and should be considered for switching to CPAP whenever possible. Healthcare professional should fully inform patients and their family members of the advantages and disadvantages of ASV on the basis not only the relevant guidelines in Japan but also the results of small-scale clinical studies,3 the SERVE-HF study,4 and SAVIOR-C trial,5 Western guidelines, and regulations for use of ASV by regulatory authorities to obtain informed consent from patients to introduce and continue taking ASV.

2) ASV for patients who do not meet the above criteria 1 but have heart failure and sleep apnea (e.g. those with predominant obstructive sleep apnea, and those with sleep apnea and heart failure with preserved ejection fraction [LVEF <45%])

At present, there are no reasons to limit the introduction and continuation of ASV in these patients. However, patients should be observed carefully for their clinical course during the introduction and continuation of ASV to ensure safety of treatment. Patients should first be considered for CPAP, and receive ASV only when it is necessary (the coverage with the National Health Insurance should be reviewed individually).

3) ASV for patients with or without sleep apnea in whom ASV has been effective in the treatment of severe congestion

ASV may be continued in patients with heart failure in whom severe congestion was not alleviated with conventional medical treatment but was successfully treated with ASV when physicians consider that discontinuing ASV would worsen heart failure, regardless of whether sleep apnea is present or not. However, it should be considered whether patients can withdraw from ASV or switch from ASV to other procedures when they become clinically stable or when 6 months has passed since the introduction of ASV. At this time, patients should be assessed for sleep apnea and those with sleep apnea should be treated according to the criteria 1 and 2 above.

4) ASV for patients who do not meet any of the criteria 1 to 3

This statement does not describe the use or appropriateness of ASV for patients who do not meet any of the criteria 1 to 3.

5) ASV in clinical research

No restrictions are placed on the use of ASV in clinical research that is conducted according to the ethical standard at the medical institution even when participating patients have conditions similar to those in the SERVE-HF trial. However, investigators must fully explain to participants and their family members the usage of ASV in non-research settings, as well as the results of small-scale studies, the SERVE-HF trial, and the SAVIOR-C trial before obtaining informed consent. Investigators of ongoing clinical research of ASV must share the results of the SERVE-HF trial as new safety guidelines with all relevant healthcare professionals at participating medical institutions.

6) Other remarks

The above criteria 1 to 5 will be revised and updated when new information is available in the SERVE-HF trial or other studies.

1) The Japanese Circulation Society. Circ J 2010; 74 (suppl. II): 963–1051.

2) Guidelines on Positive Pressure Ventilation (NPPV), Second Revision Nankodo 2015.

3) Aurora RN, et al. J Clin Sleep Med 2016; 12: 757–761.

4) Cowie MR, et al. N Engl J Med 2015; 373: 1095–1105.

5) Momomura S, et al. Circ J 2015; 79: 981–990.

(Adapted from The Japanese Circulation Society²⁷¹)

Supplement 2. Effects of Exercise Therapy in Heart Failure

1) Exercise capacity: Improvement 2) Effects on the heart 　a) Left ventricular function: No change or slight improvement in LVEF at rest, increase in the increment of cardiac output during exercise, and improvement in left ventricular early diastolic function 　b) Coronary circulation: Improvement in coronary endothelial function, improvement in myocardial perfusion during exercise, and increase in coronary collateral flow 　c) Left ventricular remodeling: Prevention (or inhibition) of progression, decrease in BNP 3) Peripheral effects 　a) Skeletal muscle: Increase in muscle mass/strength, improvement in aerobic metabolism, and increase in expression of antioxidant enzymes 　b) Respiratory muscles: Improvement in respiratory muscle function 　c) Vascular endothelium: Improvement in endothelium-dependent vasodilation responses, and increase in expression of eNOS 4) Neurohumoral factors 　a) Autonomic nervous system function: Suppression of sympathetic nervous activity, increase in parasympathetic activity, and improvement in heart rate variability 　b) Ventilatory response: Improvement in ventilatory response and CO2 sensitivity of the respiratory center 　c) Inflammatory markers: Decreases in inflammatory cytokines (e.g., TNF-α) and CRP 5) QOL: Improvement in health-related QOL 6) Long-term prognosis: Decrease in hospitalizations due to heart failure

BNP: brain (B-type) natriuretic peptide; CRP, C-reactive protein; eNOS, endothelial nitric oxide synthase; LVEF, left ventricular ejection fraction; QOL, quality of life; TNF, tumor necrosis factor. (Adapted from The Japanese Circulation Society¹⁴⁸ with modification)

Supplement 3. Contraindications in Exercise Therapy for Patients With Heart Failure

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 Society¹⁴⁸ with modification)

Supplement 4. Exercise Prescriptions for Patients With Heart Failure

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 Society¹⁴⁸ with modification)

Supplement 5. CHADS₂ Score

	Clinical characteristics			Score
C	Heart Failure			1
H	Hypertension			1
A	Age ≥75 years			1
D	Diabetes mellitus			1
S	History of cerebral infarction or transient ischemic attack			2
CHADS2 Score		Stroke rate per 100 patient-years
0		1.9
1		2.8
2		4.0
3		5.9
4		8.5
5		12.5
6		18.2

(Source: Prepared based on Gage BF, et al. 2001³²⁸)

Appendix 1. JCS Joint Working Group

Chair:

• Hiroyuki Tsutsui, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences

Members:

• Yoichi Goto, Yoka Municipal Hospital

• Taiki Higo, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences

• Atsushi Hirayama, The Division of Cardiology, Department of Medicine, Nihon University Graduate School of Medicine

• Mitsuaki Isobe, Sakakibara Heart Institute

• Hiroshi Ito, Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine

• Hiroshi Ito, Department of Cardiovascular Medicine, Division of Biophysiological Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

• Yasuki Kihara, Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University

• Koichiro Kinugawa, Second Department of Internal Medicine, University of Toyama

• Masafumi Kitakaze, Department of Clinical Medicine and Development, National Cerebral and Cardiovascular Center

• Issei Komuro, Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo

• Miyuki Makaya, Kitasato University Graduate School of Nursing

• Tohru Masuyama, Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine

• Shin-ichi Momomura, Saitama Medical Center, Jichi Medical University

• Toyoaki Murohara, Department of Cardiology, Nagoya University Graduate School of Medicine

• Koichi Node, Department of Cardiovascular Medicine, Saga University

• Ken Okumura, Division of Cardiology, Saiseikai Kumamoto Hospital Cardiovascular Center

• Minoru Ono, Department of Cardiac Surgery, Graduate School of Medicine, The University of Tokyo

• Yoshikatsu Saiki, Department of Cardiovascular Surgery, Tohoku University Graduate School of Medicine

• Yoshihiko Saito, Department of Cardiovascular Medicine, Nara Medical University

• Yasushi Sakata, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine

• Naoki Sato, Department of Cardiovascular Medicine, Kawaguchi Cardiovascular and Respiratory Hospital

• Yoshiki Sawa, Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine

• Yoshihiko Seino, Nippon Medical School Chiba Hokusoh Hospital

• Wataru Shimizu, Department of Cardiovascular Medicine, Nippon Medical School

• Hiroaki Shimokawa, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine

• Akira Shiose, Department of Cardiovascular Surgery, Kyushu University Graduate School of Medical Sciences

• Kazuhiro Yamamoto, Department of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori University

• Kenji Yamazaki, Department of Cardiology Surgery, Tokyo Women’s Medical University

• Masafumi Yano, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine

• Tsutomu Yoshikawa, Department of Cardiology, Sakakibara Heart Institute

• Michihiro Yoshimura, Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine

Collaborators:

• Masatoshi Akiyama, Department of Cardiovascular Surgery, Tohoku University School of Medicine

• Toshihisa Anzai, Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine

• Takeo Fujino, Department of Advanced Cardiopulmonary Failure, Kyushu University Graduate School of Medical Sciences

• Masaru Hatano, Department of Cardiovascular Medicine, The University of Tokyo Hospital

• Takayuki Hidaka, Department of Cardiovascular Medicine, Hiroshima University

• Teruhiko Imamura, Department of Medicine, University of Chicago Medical Center

• Takayuki Inomata, Department of Cardiovascular Medicine, Kitasato University Kitasato Institute Hospital

• Shiro Ishihara, Department of Cardiology, Nippon Medical School Musashi-Kosugi Hospital

• Yu-ki Iwasaki, Department of Cardiovascular Medicine, Nippon Medical School

• Takatoshi Kasai, Cardiovascular Respiratory Sleep Medicine, Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine

• Mahoto Kato, Department of Cardiovascular Medicine, Nihon University Graduate School of Medicine

• Makoto Kawai, Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine

• Yoshiharu Kinugasa, Department of Cardiovascular Medicine, Tottori University Hospital

• Shintaro Kinugawa, Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine

• Shigeki Kobayashi, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine

• Toru Kuratani, Department of Minimally Invasive Cardiovascular Medicine, Osaka University Graduate School of Medicine

• Shigeru Makita, Department of Cardiac Rehabilitation, Saitama Medical University International Medical Center

• Kotaro Nochioka, Department of Cardiovascular Medicine, Tohoku University School of Medicine

• Takashi Noda, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center

• Tomohito Ohtani, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine

• Katsuya Onishi, Onishi Heart Clinic

• Yasuhiko Sakata, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine

• Atsushi Tanaka, Department of Cardiovascular Medicine, Saga University

• Koichi Toda, Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine

• Osamu Yamaguchi, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine

Independent Assessment Committee:

• Uichi Ikeda, Nagano Municipal Hospital

• Takeshi Kimura, Department of Cardiovascular Medicine, Graduate School of Medicine and Faculty of Medicine, Kyoto University

• Shun Kohsaka, Department of Cardiology, Keio University School of Medicine

• Masami Kosuge, Division of Cardiology, Yokohama City University Medical Center

• Masakazu Yamagishi, Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine

• Akira Yamashina, Medical Education Promotion Center, Tokyo Medical University

(The affiliations of the members are as of November 2017)

Appendix 2. Disclosure of Potential Conflicts of Interest (COI): JCS 2017/JHFS 2017 Guideline on Diagnosis and Treatment of Acute and Chronic Heart Failure

Author	Employer/ leadership position (private company)	Stakeholder	Patent royalty	Honorarium	Payment for manuscripts	Research grant	Scholarship (educational) grant/endowed chair	Other rewards	Potential COI of the marital partner, first-degree family members, or those who share income and property
Group leader: Hiroyuki Tsutsui				·MSD K.K. ·Otsuka Pharmaceutical Co., Ltd. ·Takeda Pharmaceutical Company Limited ·Mitsubishi Tanabe Pharma Corporation ·Daiichi Sankyo Company, Limited ·Boehringer Ingelheim Japan, Inc. ·Novartis Pharma K.K. ·Bayer Yakuhin, Ltd. ·Pfizer Japan Inc.		·Japan Tobacco Inc. ·Boehringer Ingelheim Japan, Inc. ·Actelion Pharmaceuticals Japan Ltd.	·MSD K.K. ·Daiichi Sankyo Company, Limited ·Mitsubishi Tanabe Pharma Corporation
Member: Mitsuaki Isobe				·Daiichi Sankyo Company, Limited		·Chugai Pharmaceutical Co.,Ltd. ·Ono Pharmaceutical Co., Ltd.	·Teijin Pharma Limited ·Otsuka Pharmaceutical Co., Ltd. ·Daiichi Sankyo Company, Limited ·Ono Pharmaceutical Co., Ltd. ·Mitsubishi Tanabe Pharma Corporation
Member: Hiroshi Ito				·Daiichi Sankyo Company, Limited ·Mitsubishi Tanabe Pharma Corporation ·MSD K.K. ·Bayer Yakuhin, Ltd. ·Boehringer Ingelheim Japan, Inc. ·Kowa Pharmaceutical Co., Ltd.		·Novartis Pharma K.K. ·Kowa Pharmaceutical Co., Ltd.	·Daiichi Sankyo Company, Limited ·Takeda Pharmaceutical Company Limited ·Mitsubishi Tanabe Pharma Corporation ·MSD K.K. ·Bayer Yakuhin, Ltd. ·Boehringer Ingelheim Japan, Inc. ·Kowa Pharmaceutical Co., Ltd. ·Otsuka Pharmaceutical Co., Ltd. ·Sanofi K.K. ·Mochida Pharmaceutical Co.,Ltd. ·Actelion Pharmaceuticals Japan Ltd. ·Boston Scientific Corporation ·BIOTRONIK Japan, Inc. ·Fukuda Denshi Co., Ltd. ·St. Jude Medical Japan Co., Ltd. ·Medtronic Japan Co., Ltd.
Member: Ken Okumura				·Daiichi Sankyo Company, Limited ·Boehringer Ingelheim Japan, Inc. ·Johnson & Johnson K.K.
Member: Minoru Ono							·Edwards Lifesciences Corporation ·TERUMO CORPORATION ·Astellas Pharma Inc. ·Abbott Vascular Japan Co., Ltd. ·Kono Seisakusho Co., Ltd.
Member: Masafumi Kitakaze				·AstraZeneca K.K. ·Mitsubishi Tanabe Pharma Corporation ·Takeda Pharmaceutical Company Limited ·Ono Pharmaceutical Co., Ltd.		·KUREHA CORPORATION ·Boehringer Ingelheim Japan, Inc. ·Takeda Pharmaceutical Company Limited ·AstraZeneca K.K.	·Takeda Pharmaceutical Company Limited
Member: Koichiro Kinugawa				·Otsuka Pharmaceutical Co., Ltd. ·TERUMO CORPORATION ·Astellas Pharma Inc. ·Daiichi Sankyo Company, Limited ·Ono Pharmaceutical Co., Ltd. ·Boehringer Ingelheim Japan, Inc. ·Mitsubishi Tanabe Pharma Corporation ·Nipro Corporation			·Otsuka Pharmaceutical Co., Ltd.
Member: Yasuki Kihara				·Medical Corporation Ichiyokai ·Medical Corporation Kenkou Club ·Medical Corporation Keiseikai ·Shobara Redcross Hospital		·EP-CRSU Co., Ltd. ·HuBit genomix	·Shionogi & Co., Ltd. ·Otsuka Pharmaceutical Co., Ltd. ·Kowa Pharmaceutical Co., Ltd. ·Fukuda Lifetech Chugoku Co., Ltd. ·BIOTRONIK Japan, Inc. ·Pfizer Japan Inc. ·MSD K.K. ·Astellas Pharma Inc. ·Bayer Yakuhin, Ltd. ·Takeda Pharmaceutical Company Limited ·Teijin Pharma Limited ·Boehringer Ingelheim Japan, Inc.
Member: Issei Komuro				·Actelion Pharmaceuticals Japan Ltd. ·MSD K.K. ·Daiichi Sankyo Company, Limited ·Takeda Pharmaceutical Company Limited ·Mitsubishi Tanabe Pharma Corporation ·Boehringer Ingelheim Japan, Inc. ·Ono Pharmaceutical Co., Ltd. ·TOA EIYO LTD.		·Ono Pharmaceutical Co., Ltd.	·Astellas Pharma Inc. ·Edwards Lifesciences Corporation ·Otsuka Pharmaceutical Co., Ltd. ·Kowa Pharmaceutical Co., Ltd. ·Daiichi Sankyo Company, Limited ·Sumitomo Dainippon Pharma Co., Ltd. ·Takeda Pharmaceutical Company Limited ·Mitsubishi Tanabe Pharma Corporation ·Teijin Pharma Limited ·Nipro Corporation ·TERUMO CORPORATION
Member: Yoshikatsu Saiki							·SENKO MEDICAL INSTRUMENT Mfg. Co., Ltd. ·Century Medical,Inc. ·Terumo Corporation Cardiac & Vascular Company
Member: Yoshihiko Saito				·Novartis Pharma K.K. ·Mitsubishi Tanabe Pharma Corporation ·Otsuka Pharmaceutical Co., Ltd. ·Kowa Pharmaceutical Co., Ltd. ·Daiichi Sankyo Company, Limited ·Pfizer Japan Inc.		·Novartis Pharma K.K. ·Ono Pharmaceutical Co., Ltd. ·TERUMO CORPORATION ·St. Jude Medical Japan Co., Ltd. ·Bayer Yakuhin, Ltd.	·Daiichi Sankyo Company, Limited ·Otsuka Pharmaceutical Co., Ltd. ·Kyowa Hakko Kirin Co., Ltd. ·Sumitomo Dainippon Pharma Co., Ltd. ·Astellas Pharma Inc. ·Takeda Pharmaceutical Company Limited ·Ono Pharmaceutical Co., Ltd. ·Teijin Pharma Limited ·Mitsubishi Tanabe Pharma Corporation ·Eisai Co., Ltd. ·ZERIA Pharmaceutical Co.,Ltd. ·Boston Scientific Corporation ·Shionogi & Co., Ltd. ·MSD K.K.
Member: Yasushi Sakata				·Otsuka Pharmaceutical Co., Ltd. ·Daiichi Sankyo Company, Limited ·Takeda Pharmaceutical Company Limited ·Mitsubishi Tanabe Pharma Corporation ·Medtronic Japan Co., Ltd. ·Boehringer Ingelheim Japan, Inc.		·Edwards Lifesciences Corporation ·FUJIFILM RI Pharma Co., Ltd. ·REGiMMUNE Co., Ltd. ·Roche Diagnostics K.K.	·Otsuka Pharmaceutical Co., Ltd. ·Johnson & Johnson K.K. ·St. Jude Medical Japan Co., Ltd. ·Daiichi Sankyo Company, Limited ·Takeda Pharmaceutical Company Limited ·Mitsubishi Tanabe Pharma Corporation ·Teijin Pharma Limited ·Boehringer Ingelheim Japan, Inc. ·Bayer Yakuhin, Ltd. ·BIOTRONIK Japan, Inc. ·Boston Scientific Corporation ·Medtronic Japan Co., Ltd.
Member: Naoki Sato				·Otsuka Pharmaceutical Co., Ltd. ·Novartis Pharma K.K. ·Ono Pharmaceutical Co., Ltd. ·Daiichi Sankyo Company, Limited	·Otsuka Pharmaceutical Co., Ltd.	·Novartis Pharma K.K.	·Bayer Yakuhin, Ltd.
Member: Yoshiki Sawa		·Cuorips Inc.	·TERUMO CORPORATION			·TERUMO CORPORATION ·Asubio Pharma Co., Ltd. ·Daikin Industries, Ltd. ·Astellas Pharma Inc. ·JTEC Corporation ·Nacalai Tesque, Inc. ·Edwards Lifesciences Corporation ·Novartis Pharma K.K. ·Sun Medical Technology Research Corp. ·Nipro Corporation ·Johnson & Johnson K.K. ·Medtronic Japan Co., Ltd. ·W. L. Gore & Associates, Inc. ·Boston Scientific Corporation	·Edwards Lifesciences Corporation ·Konishi Medical Instruments Co., Ltd. ·Medtronic Japan Co., Ltd.
Member: Akira Shiose							·Edwards Lifesciences Corporation. ·Kanaya Ikakikai ·St. Jude Medical Japan Co., Ltd. ·Terumo Corporation Cardiac & Vascular Company ·BIOTRONIK Japan, Inc. ·LivaNova Japan K.K. ·KISHIYA INC ·SENKO MEDICAL INSTRUMENT Mfg. Co., Ltd. ·Japan Lifeline Co., Ltd. ·HEIWA BUSSAN Co., Ltd.
Member: Wataru Shimizu				·Daiichi Sankyo Company, Limited ·Bristol-Myers Squibb ·Boehringer Ingelheim Japan, Inc. ·Bayer Yakuhin, Ltd. ·Pfizer Japan Inc. ·Mitsubishi Tanabe Pharma Corporation ·Ono Pharmaceutical Co., Ltd.			·Daiichi Sankyo Company, Limited ·Bristol-Myers Squibb ·Boehringer Ingelheim Japan, Inc. ·Pfizer Japan Inc. ·Mitsubishi Tanabe Pharma Corporation ·Otsuka Pharmaceutical Co., Ltd. ·Ono Pharmaceutical Co., Ltd. ·Abbott Vascular Japan Co., Ltd. ·Bayer Yakuhin, Ltd.
Member: Hiroaki Shimokawa				·Bayer Yakuhin, Ltd. ·Boehringer Ingelheim Japan, Inc. ·Daiichi Sankyo Company, Limited		·Bayer Yakuhin, Ltd.	·MSD K.K. ·Nippon Shinyaku Co., Ltd. ·Daiichi Sankyo Company, Limited ·Mitsubishi Tanabe Pharma Corporation ·AstraZeneca K.K. ·Kyowa Hakko Kirin Co., Ltd. ·Boehringer Ingelheim Japan, Inc. ·Sumitomo Dainippon Pharma Co., Ltd. ·Novartis Pharma K.K. ·Bayer Yakuhin, Ltd. ·Astellas Pharma Inc. ·Otsuka Pharmaceutical Co., Ltd. ·GlaxoSmithKline K.K. ·Kowa Pharmaceutical Co., Ltd. ·Shionogi & Co., Ltd. ·Takeda Pharmaceutical Company Limited ·Chugai Pharmaceutical Co.,Ltd. ·Mochida Pharmaceutical Co.,Ltd. ·Nihon Kohden Corp. ·Asahi Kasei Pharma Corp. ·TERUMO CORPORATION ·Tesco ·Medtronic Japan Co., Ltd. ·Japan Lifeline Co.,Ltd. ·Abbott Vascular Japan Co., Ltd. ·St. Jude Medical Japan Co., Ltd. ·Hitachi, Ltd.
Member: Koichi Node						·Teijin Pharma Limited ·Mitsubishi Tanabe Pharma Corporation ·Boehringer Ingelheim Japan, Inc. ·Eli Lilly and Company. ·Astellas Pharma Inc.
Member: Atsushi Hirayama				·TOA EIYO LTD. ·Boehringer Ingelheim Japan, Inc. ·Sanofi K.K. ·Astellas Pharma Inc. ·Sumitomo Dainippon Pharma Co., Ltd. ·Bristol-Myers Squibb ·Amgen Astellas BioPharma K.K. ·AstraZeneca K.K. ·Daiichi Sankyo Company, Limited ·Bayer Yakuhin, Ltd.			·Boston Scientific Corporation ·Otsuka Pharmaceutical Co., Ltd. ·Fukuda Denshi Co., Ltd. ·St. Jude Medical Japan Co., Ltd. ·Medtronic Japan Co., Ltd. ·Japan Lifeline Co.,Ltd.
Member: Tohru Masuyama							·Actelion Pharmaceuticals Japan Ltd. ·Astellas Pharma Inc. ·MSD K.K. ·Otsuka Pharmaceutical Co., Ltd. ·Kowa Pharmaceutical Co., Ltd. ·Daiichi Sankyo Company, Limited ·Takeda Pharmaceutical Company Limited ·Mitsubishi Tanabe Pharma Corporation ·Teijin Pharma Limited ·Nippon Shinyaku Co., Ltd. ·Boehringer Ingelheim Japan, Inc. ·Novartis Pharma K.K. ·Bayer Yakuhin, Ltd. ·Pfizer Japan Inc. ·Fukuda Denshi Co., Ltd. ·St. Jude Medical Japan Co., Ltd. ·Medtronic Japan Co., Ltd.
Member: Toyoaki Murohara				·AstraZeneca K.K. ·MSD K.K. ·Daiichi Sankyo Company, Limited ·Takeda Pharmaceutical Company Limited ·Mitsubishi Tanabe Pharma Corporation ·Bayer Yakuhin, Ltd. ·Pfizer Japan Inc.			·Boehringer Ingelheim Japan, Inc. ·Pfizer Japan Inc. ·Otsuka Pharmaceutical Co., Ltd. ·Bayer Yakuhin, Ltd. ·Astellas Pharma Inc. ·MSD K.K. ·Sanofi K.K. ·Daiichi Sankyo Company, Limited ·Sumitomo Dainippon Pharma Co., Ltd. ·BIOTRONIK Japan, Inc. ·Takeda Pharmaceutical Company Limited ·Teijin Pharma Limited ·Mitsubishi Tanabe Pharma Corporation
Member: Shin-ichi Momomura				·Novartis Pharma K.K. ·Boehringer Ingelheim Japan, Inc. ·Bayer Yakuhin, Ltd. ·Daiichi Sankyo Company, Limited ·Bristol-Myers Squibb			·Roche Diagnostics K.K.
Member: Masafumi Yano				·Ono Pharmaceutical Co., Ltd.			·Otsuka Pharmaceutical Co., Ltd. ·MSD K.K. ·Boston Scientific Corporation ·Ono Pharmaceutical Co., Ltd. ·Daiichi Sankyo Company, Limited ·Takeda Pharmaceutical Company Limited ·Pfizer Japan Inc. ·Astellas Pharma Inc. ·Bristol-Myers Squibb ·Novartis Pharma K.K.
Member: Kenji Yamazaki	·Sun Medical Technology Research Corp.						·Edwards Lifesciences Corporation ·Century Medical, Inc. ·Luana Traum FrontierMedic Co., Ltd
Member: Kazuhiro Yamamoto				·Otsuka Pharmaceutical Co., Ltd. ·Novartis Pharma K.K.			·BIOTRONIK Japan, Inc. ·Johnson & Johnson K.K. ·Japan Lifeline Co.,Ltd. ·Otsuka Pharmaceutical Co., Ltd. ·Boehringer Ingelheim Japan, Inc. ·Mitsubishi Tanabe Pharma Corporation ·Takeda Pharmaceutical Company Limited ·Pfizer Japan Inc. ·Daiichi Sankyo Company, Limited ·Teijin Pharma Limited ·St. Jude Medical Japan Co., Ltd.
Member: Michihiro Yoshimura				·Pfizer Japan Inc. ·Mitsubishi Tanabe Pharma Corporation ·Daiichi Sankyo Company, Limited ·Mochida Pharmaceutical Co.,Ltd. ·Kowa Pharmaceutical Co., Ltd.			·Shionogi & Co., Ltd. ·Teijin Pharma Limited ·Astellas Pharma Inc.
Collaborator: Toshihisa Anzai				·Otsuka Pharmaceutical Co., Ltd.			·Bayer Yakuhin, Ltd.
Collaborator: Shiro Ishihara				·BIOTRONIK Japan, Inc.
Collaborator: Takayuki Inomata				·Daiichi Sankyo Company, Limited ·Otsuka Pharmaceutical Co., Ltd. ·Boehringer Ingelheim Japan, Inc.
Collaborator: Teruhiko Imamura	·Teijin Pharma Limited
Collaborator: Tomohito Ohtani	·Takeda Pharmaceutical Company Limited
Collaborator: Katsuya Onishi				·Takeda Pharmaceutical Company Limited ·Mitsubishi Tanabe Pharma Corporation ·Daiichi Sankyo Company, Limited ·Boehringer Ingelheim Japan, Inc. ·AstraZeneca K.K. ·Otsuka Pharmaceutical Co., Ltd.
Collaborator: Takatoshi Kasai						·Sanwa Kagaku Kenkyusho Co., Ltd. ·Asahi Kasei Pharma Corp.	·Koninklijke Philips N.V. ·Fukuda Denshi Co., Ltd. ·ResMed
Collaborator: Makoto Kawai							·Daiichi Sankyo Company, Limited
Collaborator: Shigeki Kobayashi				·Ono Pharmaceutical Co., Ltd.
Collaborator: Takashi Noda				·Medtronic Japan Co., Ltd. ·BIOTRONIK Japan, Inc.		·Medtronic Japan Co., Ltd. ·Boston Scientific Corporation
Collaborator: Masaru Hatano							·Otsuka Pharmaceutical Co., Ltd. ·Daiichi Sankyo Company, Limited
Collaborator: Takeo Fujino							·Medtronic Japan Co., Ltd. ·Social Medical Corporation Chiyukai ·St. Jude Medical Japan Co., Ltd. ·Nipro Corporation

Companies are listed only by name. The members and the collaborators other than the above have no relevant COIs.

Member: Hiroshi Ito, none

Member: Yoichi Goto, none

Member: Yoshihiko Seino, none

Member: Taiki Higo, none

Member: Miyuki Makaya, none

Member: Tsutomu Yoshikawa, none

Collaborator: Masatoshi Akiyama, none

Collaborator: Yu-ki Iwasaki, none

Collaborator: Mahoto Kato, none

Collaborator: Yoshiharu Kinugasa, none

Collaborator: Shintaro Kinugawa, none

Collaborator: Toru Kuratani, none

Collaborator: Yasuhiko Sakata, none

Collaborator: Atsushi Tanaka, none

Collaborator: Koichi Toda, none

Collaborator: Kotaro Nochioka, none

Collaborator: Takayuki Hidaka, none

Collaborator: Shigeru Makita, none

Collaborator: Osamu Yamaguchi, none

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