Patient Selection

One hundred seventy-five patients evaluated at Kochi Medical School Hospital were recruited for this study. The diagnosis of HCM was based on echocardiographic demonstrations of a hypertrophied nondilated left ventricle (maximum wall thickness ≥ 15 mm) in the absence of systemic hypertension or other cardiac disease (e.g., aortic stenosis) capable of producing the magnitude of the evident hypertrophy. Thirty patients were excluded because the time interval between echocardiographic examination and measurement of plasma BNP levels was >28 days. Ten patients with LV systolic impairment (defined as <25% fractional shortening), three patients with renal dysfunction (creatinine ≥ 2.0 mg/dL), and two patients with myocardial infarction due to coronary artery disease were also excluded. Finally, the study group retrospectively comprised 130 patients, whose BNP levels and echocardiographic findings were retrospectively assessed. All patients provided written informed consent to participate.

Echocardiography and Subtypes of HCM

Echocardiographic studies were performed using a Sequoia 512 (Siemens Medical Solutions USA, Inc., Mountain View, CA) instrument in daily clinical practice. Images were taken with patients in the lateral decubitus position. The dimensions of the left ventricle and the left atrium were measured according to the guidelines of the American Society of Echocardiography. Left atrial volume was also calculated using the modified Simpson’s method with the previously recorded images. In one patient, left atrial volume could not be measured because of inadequate images. The magnitude and distribution of LV hypertrophy were also assessed in the parasternal short-axis plane by diving the ventricle into four equal segments (anterior septum, posterior septum, lateral wall, and posterior wall) at the level of the mitral valve, papillary muscles, and two segments (anterior and posterior) at the apical level, as previously reported. The greatest wall thickness in any of the 10 segments in the left ventricle was regarded as the maximum wall thickness. Peak instantaneous outflow pressure gradient was measured at rest using continuous-wave Doppler imaging, and an LV outflow gradient ≥ 30 mm Hg was considered significant.

The morphologic subtypes of HCM were defined on the basis of echocardiographic findings as nonobstructive HCM, apical HCM (defined as LV wall thickening confined to the most distal region at the apex below the papillary muscle level), obstructive HCM, and midventricular obstruction (midventricular hypertrophy with midventricular obstruction).

The peak velocity of the early (E) wave and deceleration time of the E wave were determined from transmitral flow velocity in the apical four-chamber view, obtained by positioning the sample volume at the tip of the mitral leaflets during diastole. Tissue Doppler velocity using spectral Doppler was measured during early diastole (e′) at the septal and lateral corners of the mitral annulus from the apical four-chamber view by positioning the sample volume at the septal and lateral margins of the mitral annulus. Filters were set to exclude high-frequency signals. Gain settings were adjusted carefully, and the direction of motion was aligned with the scan line direction. Signals were obtained from one end-expiratory cycle in patients in sinus rhythm, and averages from three end-expiratory cycles in patients with atrial fibrillation were obtained.

Although it is controversial whether septal or lateral E/e′ ratio is more accurate to predict LV filling pressure, Ommen et al. reported that septal Doppler tissue images were consistently equivalent to or better than those from the lateral annulus. Therefore, we calculated the septal E/e′ ratio in this study. In addition, the cutoff value for a high septal E/e′ ratio was defined as 15, according to the previous report.

Assessment of Plasma BNP Levels

Peripheral venous blood samples were collected during clinically stable periods from the antecubital veins of patients within 28 days of the echocardiographic study (mean interval, 0.1 ± 3.8 days). Drugs were continued throughout this procedure. Plasma BNP levels were measured using an enzyme immunoassay (TOSOH II; TOSOH, Tokyo, Japan).

Clinical End Points

The initial clinical evaluation was defined as the time when blood was withdrawn for BNP measurements and when clinical status and cardiovascular events were systematically assessed.

Combined end points were defined as HCM-related death, admission for heart failure (occurring in the context of pulmonary congestion on chest x-ray) or stroke (judged to be a direct consequence of embolic events proven by computed tomography or magnetic resonance, usually in the setting of paroxysmal or chronic atrial fibrillation), appropriate defibrillation shocks from an implanted cardioverter-defibrillator, and/or progression of heart failure symptoms to severe symptoms (from New York Heart Association class I or II at baseline to class III during follow-up). HCM-related death was defined as sudden cardiac death (unexpected death occurring <1 hour from the onset of symptoms in patients previously experiencing relatively stable or uneventful clinical courses) and heart failure death and stroke death.

Statistical Analysis

Data are expressed as mean ± SD. Two groups were compared using Wilcoxon’s test. Correlations between two continuous variables were evaluated using linear regression analysis. Noncontinuous variables, expressed as proportions, were compared using the χ ² test or Fisher’s exact test. Multivariate logistic regression analysis including parameters that were associated with events at the level of P < .10 on univariate analysis was done to test whether the factors were useful for the prediction of combined end points. P values < .05 were considered significant. Data were analyzed using JMP version 7.0 (SAS Institute Inc., Cary, NC).

Incidence of Combined End Points

During a follow-up period of 3.7 ± 1.7 years, one patient succumbed to sudden death; nine were admitted for heart failure and five for stroke, respectively; heart failure symptoms progressed to New York Heart Association class III in four; and an implanted cardioverter-defibrillator appropriately discharged in one. Consequently, 20 patients reached the combined end points.

Basic Characteristics

Table 1 shows the basic clinical characteristics of all patients as well as a comparison of these features between patients with and without events. In the whole cohort, male gender predominated, and most of the patients were asymptomatic ( n = 70) or had mild symptoms ( n = 57). Table 1 also shows that women predominated among patients who developed events, and patients who had events had more severe symptoms, unexplained syncope, and atrial fibrillation compared with those without events. Differences in disease severity at the initial evaluation were reflected in more intensive medical therapy, such as a higher prevalence of the use of amiodarone and warfarin to prevent thromboembolic events. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were used for complicated mild systemic hypertension in patients without obstruction.

Echocardiographic Findings and Events

Table 2 compares the echocardiographic findings of patients with and without events. Among the subtypes, no patients with apical HCM were complicated with events. There were no significant differences in LV size, maximum LV wall thickness, and LV systolic function between patients with events and those without events. Two patients among patients with heart failure admission related to deterioration of LV systolic function. Left atrial volumes were larger and septal E/e′ ratios were higher in patients with than those without events. The prevalence of a septal E/e′ ratio > 15 was also higher in patients with events, and the prognoses of patients with septal E/e′ ratios > 15 were poorer than in those with lower septal E/e′ ratios ( Figure 1 , left ). Typical echocardiographic images in two patients with events and without events are shown in Figure 2 .

Table 2

Echocardiographic findings of patients with and without events

Variable	All patients ( n = 130)	With events ( n = 20)	Without events ( n = 110)	P ∗
Subtypes of HCM
Nonobstructive HCM	80 (61%)	15 (75%)	65 (59%)
Apical HCM	26 (20%)	0 (0%)	26 (24%)
Obstructive HCM	20 (15%)	5 (25%)	15 (14%)	.06
MVO	4 (4%)	0 (0%)	4 (4%)
LVDd (mm)	45 ± 5.7	45.6 ± 4.5	44.9 ± 6	.67
LVDs (mm)	26 ± 5.1	27.8 ± 5	25.7 ± 5	.14
Maximum LV wall thickness (mm)	20.7 ± 4.7	19.6 ± 3.9	20.9 ± 4.8	.23
Fractional shortening (%)	43.7 ± 9.5	42.2 ± 12.9	43.9 ± 8.8	.12
Left atrial volume (mm 3 )	75.4 ± 38.8	97.5 ± 42.7	71.3 ± 36.9	.005
E wave (mm)	74.9 ± 22.8	94.6 ± 22.7	71.3 ± 21.1	<.0001
Deceleration time (msec)	232.3 ± 73.5	185.6 ± 66.4	240 ± 71.9	.0003
Septal e′ (mm)	8.2 ± 2.0	6 ± 2.1	7.2 ± 2.2	.01
Septal E/e′ ratio	11.7 ± 5.2	17.4 ± 6.3	10.6 ± 4.3	<.0001
Septal E/e′ ratio > 15	24 (18%)	11 (54%)	13 (11%)	<.0001

LVDd , LV end-diastolic dimension; LVDs , LV end-systolic dimension; LVOT , LV outflow tract; MVO , midventricular obstruction.

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