Clinical Features of Heart Failure in Patients With Hypertrophic Cardiomyopathy in a Regional Japanese Cohort　― Results From the Kochi RYOMA Study ―

Abstract

Background: The clinical features of heart failure (HF) in patients with hypertrophic cardiomyopathy (HCM) in Japan have not been fully elucidated.

Methods and Results: In 293 patients with HCM (median age at registration, 65 (57–72) years) in a prospective cardiomyopathy registration network in Kochi Prefecture (Kochi RYOMA study), HF events (HF death or hospitalization for HF) occurred in 35 patients (11.9%) (median age, 76 (69–80) years), including 11 HF deaths during a median follow-up of 6.1 years. The 5-year HF events rate was 9.6%. Atrial fibrillation, low percentage of fractional shortening, and high B-type natriuretic peptide level at registration were predictors of HF events. The combination of these 3 factors had a relatively high positive predictive value (55%) for HF events and none of them had a high negative predictive value (99%). There were 4 types of HF profile: left ventricular (LV) systolic dysfunction (40%), severe LV diastolic dysfunction (34%), LV outflow tract obstruction (LVOTO) (20%), and primary mitral regurgitation (MR) (6%). HF deaths occurred in patients with LV systolic dysfunction or LV diastolic dysfunction, but none of patients with LVOTO or primary MR due to additional invasive therapies.

Conclusions: In a Japanese HCM cohort, HF was an important complication, requiring careful follow-up and appropriate treatment.

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder that is defined by an unexplained isolated myocardial hypertrophy.^1–6 The prevalence of HCM is relatively high, occurring in about 0.2% of the adult population, and the clinical spectrum and phenotypic expression are variable. Some patients have no symptoms for their entire lives, while others experience serious events. Heart failure (HF) seems to be as important as sudden cardiac death or stroke within the broad clinical presentation of HCM.^1–7 However, there have been few studies on the clinical profiles of HF in Japanese patients with HCM.

Editorial p 1941

In 2004, we established the Kochi Cardiomyopathy Network, named the Kochi RYOMA (registry of myocardial diseases) study, to provide detailed information on the clinical features of HCM in an unselected regional community-based Japanese population.^8,9 In the present study, we assessed the occurrence and clinical profiles of HF in a regional Japanese HCM cohort.

Methods

Subjects

The Kochi Cardiomyopathy Network comprises 9 hospitals that provide inpatient treatment for cardiovascular patients in Kochi Prefecture, Japan, which had approximately 800,000 inhabitants in 2004. The 9 institutions are scattered throughout the local secondary medical area in Kochi Prefecture; 1 is a university hospital, and 8 are regional core hospitals.

The diagnosis of HCM was based on echocardiographic demonstration of an unexplained left ventricular hypertrophy (LVH: maximum LV wall thickness ≥15 mm). Between February 2004 and December 2013, 305 patients with a diagnosis of HCM were registered in the Kochi Cardiomyopathy Network; 3 of these patients were diagnosed as having specific cardiomyopathies (1 patient with cardiac amyloidosis, 2 patients with cardiac involvement of Fabry disease) and were excluded from this study. The remaining 302 patients were registered. A further 9 patients without available follow-up data were excluded, so the final study population consisted of 293 patients.

This investigation followed the Declaration of Helsinki and was approved by the Ethics Committee on Medical Research of Kochi Medical School (reference number ERB-002382). Informed consent was given by all patients or their families.

Clinical Evaluation

Patient evaluation included a medical history, clinical examination, 12-lead electrocardiography (ECG), echocardiography, and ambulatory 24-h Holter ECG analysis. The severity and distribution of LVH were assessed in the parasternal short-axis plane at the mitral valve and papillary muscle levels. LV end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD) were measured from M-mode and 2D images obtained in the parasternal long-axis view. Fractional shortening (FS) was calculated as [(LVEDD − LVESD) / LVEDD] × 100. The LV outflow tract (LVOT) and midventricular pressure gradient were calculated from continuous-wave Doppler using the simplified Bernoulli equation.

Based on the morphologic and hemodynamic assessments by echocardiography, the patients were divided into the following 5 HCM subtypes: (1) hypertrophic obstructive cardiomyopathy (HOCM), defined as the presence of LVOT obstruction (gradient ≥30 mmHg at rest); (2) midventricular obstruction (MVO), defined as the presence of systolic LV cavity obliteration in the mid-ventricle creating MVO with a peak systolic gradient ≥30 mmHg at rest; (3) dilated phase of HCM (D-HCM), defined as LV systolic dysfunction with global ejection fraction (EF) <50% (global EF being determined by the modified Simpson’s method); (4) apical HCM, defined as hypertrophy confined to the LV apex, and (5) hypertrophic non-obstructive cardiomyopathy (HNCM), defined as non-obstructive HCM other than D-HCM and apical HCM.⁵

HF events were defined as HF death and hospitalization for HF. Data on the survival and clinical status of patients were obtained during serial clinic visits or from their clinical record, including information from other institutes.

Data Analysis

Categorical variables are expressed as numbers (percentages) and continuous variables are presented as median (interquartile range). To compare differences between groups, the Mann-Whitney U test for continuous variables and the chi-squared test or Fisher’s exact test for categorical variables were used. Event-free estimate curves were calculated by the Kaplan-Meier method, and the log-rank test was used for comparison. A multivariate Cox proportional hazards model was used to analyze the relationships between HF events and clinical parameters including some variables with P≤0.05 in the univariate analysis. Receiver-operator characteristic (ROC) analysis for predicting HF events was performed and the area under the curve for determining the cutoff value of each predictor was used. Survival rates were compared by the log-rank test. P<0.05 was considered significant for all statistical analyses, which were performed using IBM SPSS statistics, version 28.0.1 (IBM Corp., Armonk, NY, USA).

Results

Clinical Characteristics at Registration

Table 1 shows the clinical characteristics of the 293 patients with HCM at registration. The median ages at registration and diagnosis were 65 (57–72) (range: 7–88) years and 58 (46–66) (range: 6–87) years, respectively, and 197 (67%) of the patients were male. Most of the 293 patients were completely asymptomatic or mildly symptomatic at registration: 272 patients (93%) were less than New York Heart Association (NYHA) functional class II, only 21 patients (7%) were NYHA class III, and no patient was NYHA class IV.

Table 1. Clinical Characteristics of 293 Patients With HCM at Registration and Patients With and Without HF Events

	All patients	HF events		P value
		Yes (n=35)	No (n=258)
Age at registration, years	65 (57–72)	70 (65–78)	63 (57–71)	0.005
Sex: male, n (%)	197 (67)	21 (60)	176 (68)	0.342
Age at diagnosis, years	58 (46–66)	59 (42–66)	58 (47–67)	0.864
Family history of HCM, n (%)	76 (26)	13 (37)	63 (24)	0.148
NYHA class III at registration, n (%)	21 (7)	15 (43)	6 (2)	<0.001
Presence of AF at registration, n (%)	86 (29)	25 (71)	61 (24)	<0.001
BNP at registration, pg/mL	185 (88–377)	442 (213–649)	162 (81–307)	<0.001
Echocardiographic data at registration
Subtype, n (%)
HOCM	40 (14)	8 (23)	32 (12)	<0.001
MVO	8 (3)	0	8 (3)
D-HCM	13 (4)	8 (23)	5 (2)
Apical HCM	52 (18)	0	52 (20)
HNCM	180 (61)	19 (54)	161 (62)
Maximum LV wall thickness, mm	19.0 (16.0–22.0)	18.0 (15.0–20.0)	19.0 (16.8–22.0)	0.100
LV end-diastolic diameter, mm	46.0 (42.0–51.0)	49.0 (44.0–55.0)	46.0 (42.0–50.0)	0.079
FS, mm	41.0 (36.0–46.0)	33.0 (27.0–43.0)	41.0 (37.0–46.0)	<0.001
Left atrial diameter, mm	44.0 (39.0–50.0)	52.0 (49.0–57.0)	43.0 (38.8–48.0)	<0.001
D-HCM at registration, n (%)	13 (4)	8 (23)	5 (2)	<0.001
Medications at registration, n (%)
β-blocker	119 (41)	22 (63)	97 (38)	0.006
Calcium antagonist	79 (27)	12 (34)	67 (26)	0.313
ACEI or ARB	78 (27)	13 (37)	65 (25)	0.154
ICD implantation at registration, n (%)	4 (1)	1 (3)	3 (1)	0.400
Follow-up period (days)	2,240 (841–3,164)	1,431 (465–2,211)	2,380 (936–3,250)	<0.001

Data are presented as median (interquartile range) or number (%). ACEI, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; BNP, B-type natriuretic peptide; D-HCM, dilated phase of HCM; FS, fractional shortening; HCM, hypertrophic cardiomyopathy; HF, heart failure; HNCM, hypertrophic nonobstructive cardiomyopathy; HOCM, hypertrophic obstructive cardiomyopathy; ICD, implantable cardioverter-defibrillator; LV, left ventricular; MVO, midventricular obstruction; NYHA, New York Heart Association.

HF Events

During a median follow-up period of 6.1 (2.3–8.7) years from registration, 77 cardiovascular events occurred in 70 patients: HF events in 35 patients included 11 deaths, and thromboembolic events in 23 patients, and sudden cardiac death-related events in 19 patients, included 9 sudden deaths. Figure 1 shows the incidence of HF events. The 5-year HF events rate was 9.6%. The median age of the patients at the time of HF events was 76 (69–80) years and the median age at the time of HF deaths was 80 (71–81) years.

Figure 1.

Incidence of heart failure (HF) events in patients with hypertrophic cardiomyopathy (HCM). The 5-year HF event rate was 9.6%.

A comparison of patients with HF events and patients without HF events is shown in Table 1. Patients with HF events were older at registration and had higher frequencies of NYHA functional class III and presence of atrial fibrillation (AF). B-type natriuretic peptide (BNP) levels were higher in patients with HF events than in patients without HF events. Of the echocardiographic parameters, there was a significant difference between patients with and without HF events among the subtypes. Figure 2 shows the proportions of patients with HF events stratified by HCM subtype at registration. In the D-HCM group at registration, more than half of the patients had HF events, whereas in the MVO group and apical HCM group at registration, none of the patients developed HF. Regarding other echocardiographic parameters (Table 1), patients with HF events tended to have smaller maximum LV wall thicknesses than patients without HF events at registration. LVEDD and left atrial size were larger and %FS was lower in patients with HF events than in patients without HF events. As for the follow-up period, patients with HF events had a shorter follow-up than patients without HF events.

Figure 2.

Proportions of patients with progression to heart failure (HF) events stratified by HCM subtype at registration. Data are shown as number of patients with HF events per total number of patients in each subtype at registration (percent). D-HCM, dilated phase of HCM; HCM, hypertrophic cardiomyopathy; HNCM, hypertrophic nonobstructive cardiomyopathy; HOCM, hypertrophic obstructive cardiomyopathy; MVO, midventricular obstruction.

Predictors of HF Events

Using a multivariate Cox proportional hazards model, we analyzed the relationships between HF events and selected parameters at registration with statistical significance in the univariate analysis (Table 2). AF, %FS, and BNP were significant predictors of HF events in our patient cohort. By ROC analysis, we obtained the optimal cutoff values of %FS and BNP for predicting HF events: %FS <40% and BNP >300 pg/mL.

Table 2. Predictors of HF Events (Multivariate Cox Proportional Hazards Model)

	Hazard ratio	P value
NYHA class III at registration	2.560	0.095
Presence of AF at registration	4.405	0.002
BNP at registration, pg/mL	1.002	0.006
Fractional shortening, %	0.947	0.007

Abbreviations as in Table 1.

Using these 3 risk factors of HF events at registration, we divided our patients into 4 groups by adding 1 point for each of the 3 risk factors at registration. Figure 3 shows the Kaplan-Meier curves for each score. Estimated event-free rates during a 10-year period in patients with scores of 0, 1, 2, and 3 were 98%, 87%, 52%, and 22%, respectively (P<0.001). In patients with a score of 3, HF events occurred gradually over time from registration, whereas most of the HF events in patients with scores of 0–2 occurred after 5 years from registration.

Figure 3.

Kaplan-Meier analysis of heart failure in patients with hypertrophic cardiomyopathy according to 4 risk categories (scores 0–3) stratified by the total number of risk factors (presence of atrial fibrillation at registration, B-type natriuretic peptide level >300 pg/mL, and % fractional shortening <40) at registration.

The upper bar graph in Figure 4 shows the incidence rate of HF events for each of the scores for risk factors. The higher the score, the greater the number of HF events. Of the 102 patients in the score 0 group, only 1 patient (1%) had a HF event and this score had a very high negative predictive value (99%) for HF events. On the other hand, of the 22 patients in the score 3 group, 12 (55%) had HF events. The incidence rates of HF events in the score 1 and 2 groups were lower than the incidence rate in the score 3 group. However, two-thirds of the HF events occurred in 169 patients in the score 1 and 2 groups.

Figure 4.

Distribution of scores and the number of HF events in each score (Upper). By the total number of the 3 risk factors, patients were stratified to 4 subgroups (scores 0–3). Data are shown as number of patients with HF events per total number of patients with each score (percent). Detailed number of HF events in each score group by the profile of HF (Lower). HF, heart failure; LV, left ventricular; LVOTO, LV outflow tract obstruction; MR, mitral regurgitation.

Detailed Profiles of HF Events

Next, we focused on the detailed profiles of HF events (Table 3), of which there were 4: (1) LV systolic dysfunction (D-HCM) (hospitalization: n=14, death: n=5), (2) LVOT obstruction (LVOTO) (hospitalization: n=7), (3) primary mitral regurgitation (MR) due to mitral valve chordal rupture (hospitalization: n=2), and (4) severe LV diastolic dysfunction (hospitalization: n=12, death: n=6).

Table 3. Clinical Profiles of HF and Treatment

Profile of HF	Clinical characteristics at registration				HF events				Treatment for HF
					Hospitalization for HF		HF death
	Subtype	N	Age at diagnosis (years)	Age at registration (years)	Age at hospitalization for HF (years)	N	Age at death (years)	N		N
LV systolic dysfunction (D-HCM)	D-HCM	8	56 (38–62)	71 (58–78)	72 (61–80)	8	78 (68–81)	5	Medical	10
	HNCM	6	60 (47–64)	70 (57–78)	75 (61–82)	6		0	Medical & CRT	4
LVOTO	HOCM	7	66 (62–68)	69 (66–78)	77 (72–82)	7		0	Medical Medical & PTSMA Medical & DDD PM	4 1 2
Primary MR	HOCM	1	70	70	74	1		0	MV replacement	2
	HNCM	1	35	52	59	1
Severe LV diastolic dysfunction	HNCM	12	59 (51–69)	74 (68–76)	79 (74–81)	12	81 (75–86)	6	Medical	12

Data are presented as median (interquartile range) or number. CRT, cardiac resynchronized therapy; LVOTO, LV outflow tract obstruction; MR, mitral regurgitation; MV, mitral valve; N, number; PM, pacemaker; PTSMA, percutaneous transluminal septal myocardial ablation. Other abbreviations as in Table 1.

LV Systolic Dysfunction (D-HCM) The most common form of HF in our cohort was D-HCM. Based on its prevalence by subtype at registration, 13 patients were in the D-HCM group at registration and an additional 21 patients in the HNCM group at registration (Table 1) developed D-HCM during the follow-up period. Finally, 34 patients were in the D-HCM group, with the annual incidence of D-HCM being 1.2%. Of the 34 patients in the D-HCM group, 14 patients had HF hospitalization events (8 patients in the D-HCM group, 6 patients in the HNCM group at registration). In both groups of patients, HF events occurred over a period of about 20 years from the diagnosis of HCM. Although all patients received optimal medical therapy, 5 patients died of HF.

LVOTO HF hospitalization due to LVOTO occurred in 7 patients and all were in the HOCM group at registration. All received medical therapy, and 3 patients with medically refractory HOCM underwent percutaneous transluminal septal myocardial ablation or DDD pacemaker implantation, resulting in reduction of the outflow gradient. None of the patients died of HF.

Primary MR HF hospitalization due to MR occurred in 2 patients: a 73-year-old woman in the HOCM group at registration and a 58-year-old man in the HNCM group at registration. The 73-year-old woman with HOCM was complicated with MR due to systolic anterior motion of the mitral valve at registration. Both patients developed rapidly congestive HF with severe acute MR due to rupture of mitral chordae tendineae and required emergency surgical treatment. MV replacement was performed in both patients and their HF symptoms improved.

Severe LV Diastolic Dysfunction Not Involving LVOTO 12 patients had HF hospitalization mainly related to severe LV diastolic dysfunction. All were in the HNCM group at registration and developed progressive HF over a period of about 20 years from the diagnosis of HCM. All received medical therapy and 6 patients died of HF.

Using these profiles of HF, we analyzed the detailed number of HF events in each of the scores for risk factors (Figure 4). No difference was found between the scores and profiles of HF.

Discussion

We carried out a prospective multicenter investigation of the clinical profiles of HF in a regional Japanese HCM cohort and the main findings were (1) HF is a relatively frequent and important complication of HCM, (2) AF, FS <40% and BNP >300 pg/mL at registration were predictors of HF events, (3) there were 4 profiles of HF events comprising LV systolic dysfunction (D-HCM), LVOTO, acute primary MR, and severe LV diastolic dysfunction, and (4) there were no HF deaths of patients with LVOTO or acute primary MR who received appropriate treatment.

Incidence of HF Events in Patients With HCM in the Kochi RYOMA Study Cohort

For the overall study group, HF events including 11 deaths occurred in 35 patients (11.9%) with a 5-year HF event rate of 9.6%. The incidence rates of HF in patients with HCM in previous studies have been between 5.3 and 14/1,000 patient years.^10–13 The incidence in our cohort was slightly higher at 19/1,000 patient years. Because the patients in our regional cohort from the Kochi RYOMA study were relatively older than patients in HCM cohorts in previous studies,^4,14,15 the difference in ages is likely to be the reason for the difference in incidence rates of HF.

Risk Factors of HF Events

Our study results revealed that the presence of AF, FS <40%, and BNP >300 pg/mL at registration were predictors of HF events. Each of these determinants had been reported as a predictive marker of HF in patients with HCM. Firstly, AF is the most frequent arrhythmia in patients with HCM and is associated with a substantial risk for HF-related death, stroke, and severe functional disability in HCM patients.^16–18 Secondly, we have already reported that lower %FS at initial assessment was associated with progression of LV systolic dysfunction and HF death in a different HCM cohort.¹⁹ Finally, it was reported that BNP was independently related to the presence and magnitude of HF symptoms in patients with HCM.^20–22

Collectively, the results indicated that the combination of the presence of AF, low %FS, and high BNP level is reasonable for predicting HF events. According to our results, there was a high possibility for the occurrence of HF events in patients with the 3 risk factors and a high negative predictive value for HF events in patients with no risk factors. For patients with 0 or 3 risk factors, this scoring system may be useful to predict HF events. However, two-thirds of the HF events occurred in patients with 1 or 2 risk factors. Furthermore, the HF events in patients with 1 or 2 risk factors often occurred after 5 years from registration. For patients with 1 or 2 risk factors, it seems to be difficult to predict HF events based on this scoring system, and we should therefore follow the patients over a long period with attention to the possibility of subsequent HF events if patients have any 1 of the 3 risk factors.

Clinical Profiles of HF and Treatment

Among the 4 profiles of HF events in our cohort, HF events occurred in 40% of the patients with D-HCM, in 34% of the patients with severe LV diastolic dysfunction, and in 20% of the patients with LVOTO. It was reported that HF symptoms progress along 3 predominant pathways: D-HCM, LVOTO, and absence of LVOTO with severe LV diastolic dysfunction.^6,10–13,16 In our patient cohort, in addition to the 3 profiles of HF, although the number of patients was small, acute primary MR was identified as one of the causes of HF. Acute HF is infrequent in patients with HCM; however, it can be precipitated by conditions such as tachyarrhythmia (e.g., AF), ischemia, and acute or worsening MR (e.g., chordal rupture), as occurred in our study patients.

In this study, HF death occurred in patients with HF due to LV systolic dysfunction and severe LV diastolic dysfunction, but no HF deaths occurred in patients with HF due to LVOTO or acute primary MR who were treated with additional invasive therapies. This suggested that HF death could be avoided in some HCM patients with HF by appropriate management and treatment according to their HF profile. In some cases, invasive treatments such as surgical myectomy or percutaneous septal alcohol ablation for LVOTO and cardiac resynchronization therapy for D-HCM are reasonable.^6,10,23–25 Heart transplantation is the only definitive treatment for D-HCM and severe diastolic dysfunction, although it was not performed in this study because many patients in our cohort were excluded from transplant consideration based on age. To date, no disease-modifying therapies for HCM have been established, although clinical trials of novel therapeutics are in progress.²⁶ Future therapies may effectively address the pathophysiology of HCM even for such elderly patients as in our cohort. Until then, we strongly suggest a continuity of careful follow-up for performing appropriate treatment at an appropriate timing for patients with HCM.

Study Limitations

First, the number of HF events was relatively small, which might have affected some of the statistical analyses. More data from a larger patient cohort are needed to validate our results. Second, in this study, we mainly analyzed the baseline characteristics at registration. Changes in the clinical features during follow-up might be more important for prediction of HF events. Third, this study did not include genetic data.

In 2015, we established a large-scale registration survey of patients with HCM throughout Japan, named the J-HCM Registry Study. This prospective registration study is ongoing, and we believe that this multicenter project will provide important information on the prognostic factors in HCM patients.

Conclusions

In our unselected registry from an aged Japanese community, a relatively large proportion of HCM patients had HF events. Recognition of the profiles of HF, careful follow-up and management, and appropriate treatment including invasive therapies for each patient are essential to improve survival and quality of life for patients with HCM.

Acknowledgments

Participating investigators from the study hospitals are Naohisa Hamashige, MD, Masahiko Fukatani, MD, Shoichi Kubokawa, MD, Yoko Nakaoka, MD (Chikamori Hospital), Takashi Yamasaki, MD (National Hospital Organization Kochi National Hospital), Yoko Hirakawa, MD (Tosa Municipal Hospital), Masanori Kuwabara, MD (Kochi Prefectural Aki General Hospital), Tatsuya Noguchi, MD, Kazuya Miyagawa, MD (Kochi Medical School). We thank all the physicians who made this study possible.

Disclosures

H.K. is a member of Circulation Journal’s Editorial Team.

Conflicts of Interest

None declared.

Grants

This study did not receive any specific funding.

IRB Information

Approved by the Ethics Committee on Medical Research of Kochi Medical School (reference no. ERB-002382).

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