Methods

We recruited consecutive patients with obstructive HC who were evaluated in Fuwai Hospital (Beijing, China) from November 2008 to June 2013. All subjects underwent a comprehensive cardiac evaluation, including complete medical history, physical examination, 12-lead electrocardiography, 24-hour ambulatory electrocardiographic monitoring, TTE, blood examination, CMR, and coronary angiography. The diagnosis of HC was based on a maximum LV wall thickness ≥15 mm (or ≥13 mm with an unequivocal family history of HC), as measured by echocardiography or CMR, in the absence of another cardiac or systemic disease capable of producing comparable magnitude of hypertrophy. The presence of LVOT obstruction was defined as an instantaneous peak Doppler LVOT pressure gradient ≥30 mm Hg at rest or during physiological provocation, such as Valsalva maneuver, standing, and exercise. Patients with established coronary artery disease, valvular heart disease, left ventricular ejection fraction (LVEF) <50% as measured by echocardiography or CMR, renal dysfunction (defined as an estimated glomerular filtration rate <60 ml/min/1.73 m ² ), concomitant neoplasm, infection, or connective tissue disease were excluded. Subjects who had a history of alcohol septal ablation, septal myectomy, or permanent mechanical device implantation were also excluded. Finally, 149 patients were recruited in the present study. This study was approved by the Ethics Committee of Fuwai Hospital. All participants provided their written informed consent in accordance with the Declaration of Helsinki.

TTE was performed using the Phillips iE33 Color Doppler Ultrasound System (Philips Healthcare, Andover, Massachusetts). M-mode, 2-dimensional, and pulsewave and continuous-wave Doppler study were used in the standard evaluation in accordance with recommendations of the American Society of Echocardiography. The LVOT gradient at rest was determined in all patients using continuous-wave Doppler echocardiography, whereas provoked LVOT gradient was only measured in patients with a LVOT gradient <50 mm Hg at rest.

A 1.5-T scanner (Magnetom Avanto; Siemens Medical Solutions, Erlangen, Germany) was used to perform all CMR studies, under electrocardiographic gating and breath holding. The imaging protocol and analysis have been described previously. Briefly, a true fast imaging with steady-state precession (TrueFisp) sequence was used to obtain cine images, which included LV 2-chamber and 4-chamber long-axis view, LVOT view, and LV short-axis views (contiguous slices from atrioventricular ring to apex).

All CMR images were transferred to workstation (Siemens Medical Systems, Erlangen, Germany) and was analyzed by an experienced radiologist. The dedicated software (version VE36 A; ARGUS; Siemens, Germany) was used for image analysis off-line. Endocardial and epicardial contours of the LV myocardium (excluding papillary muscles) were manually traced at end-diastole and end-systole on each LV short-axis cine image. LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LVEF, stroke volume, cardiac output, and LV mass (LVM) were then calculated in a standard fashion. LVM was derived by multiplying LV myocardial volume measured at end-diastole with the specific gravity of myocardium (1.05 g/ml). Furthermore, all those parameters were indexed to body surface area, except LVEF. The LVED diameter and maximal septal and LV wall thickness were traced and measured from the short-axis views at end-diastole.

Venous blood samples were collected at rest within 2 days of TTE and 1 week of CMR examination. Serum cTnI were measured within 4 hours of blood collection as routine sample analysis in our hospital laboratory, by medical technologists who were unaware of any clinical information about the studied patients. Serum cTnI was detected using an immunochemiluminometric assay (Access AccuTnI; Beckman Coulter, Brea, California) on a Beckman Coulter Access 2 analyzer. The lower limit of detection is 0.01 ng/ml, and the upper limit of normal (the 99th percentile of normal population) was 0.04 ng/ml. The inter-assay and intra-assay coefficients of variation were <6.07% and 4.42%, respectively. Plasma levels of N-terminal pro-B–type natriuretic peptide (NT-proBNP) were also measured, with an electrochemiluminescent immunoassay (Elecsys proBNP II assay; Roche Diagnostics, Mannheim, Germany).

Continuous variables are expressed as mean ± SD or median (interquartile range [IQR]), according to their normality. Categorical variables are shown as frequencies (percentages). Differences of continuous variables were evaluated with the independent Student’s t test, Mann-Whitney U test, or Kruskal-Wallis H test (as appropriate). Categorical variables were compared using the chi-square test or Fisher’s exact test (as appropriate). Pearson’s correlation test was used to examine correlations between 2 continuous variables. Logarithmic transformations were performed for the analysis of cTnI and NT-proBNP. Multivariate logistic regression analysis using backward elimination method was performed to detect independent predictors of the elevation of cTnI levels (≥0.04 ng/ml). Stepwise multiple linear regression analysis (p value threshold to enter ≤0.05; to remove, ≤0.10) was undertaken to identify independent variables that might determine cTnI levels. Variables with a p value <0.10 in the univariate analysis were included in the multiple regression analysis. A 2-tailed p value <0.05 was considered as statistically significant. Statistical analysis was performed with the statistical package SPSS 21.0 (SPSS Inc, Chicago, Illinois).

Results

One hundred forty-nine patients were included in the present study (92 men [62%]; age 47.4 ± 10.8 years; Table 1 ). The majority of them (85%) had severe dyspnea (New York Heart Association functional class III/IV). Syncope was present in 50 patients (34%). Forty-seven patients (32%) were complicated with hypertension. All subjects had significant LVOT obstruction (gradient ≥30 mm Hg), including 139 patients (93%) with obstruction at rest and the remaining 10 patients (7%) with latent obstruction. Calcium antagonists were taken in 45 patients (30%), whereas β blockers in 111 patients (75%). Of the 149 obstructive patients with HC studied, 63 (42%) had ≥2 risk factors for SCD.

The median level of serum cTnI was 0.019 ng/ml (0.009 to 0.044) in the overall cohort. The patients were divided into 2 groups by the upper limit of normal value of cTnI (the 99th percentile of normal population): the normal cTnI group (cTnI <0.04 ng/ml, n = 107 [72%]) and the elevated cTnI group (cTnI ≥0.04 ng/ml, n = 42 [28%]; Table 1 ). More patients with elevated cTnI had a maximum wall thickness (MWT) ≥30 mm than those with normal cTnI (p <0.001). Plasma NT-proBNP concentrations were significantly higher in patients with elevated cTnI compared with those with normal cTnI (p <0.001). The percentage of patients with hypertension in the elevated cTnI group was significantly lower than that in the normal cTnI group (p = 0.014). Correspondingly, patients with hypertension had a less frequent elevated cTnI than those without hypertension (15% vs 34%, p = 0.014; Figure 1 ). Compared with patients with normal cTnI, patients with elevated cTnI had a tendency of having more ≥2 risk factors for SCD (p = 0.053).

(A) Percentages of elevated cTnI (≥0.04 ng/ml) in patients with and without hypertension. (B) Percentages of elevated cTnI across teriles of LVMI. The thirty-third and sixty-seventh percentile cut-off values of LVMI were 73.2 and 98.7 g/m ² , respectively.

Associations of elevated cTnI with echocardiographic and CMR parameters are presented in Table 2 . There were less moderate/severe mitral regurgitation (MR) in patients with elevated cTnI than in those with normal cTnI (p = 0.022). LVOT gradient at rest and after provocation were comparable between the elevated and normal cTnI group (p = 0.243 and 0.188, respectively). More patients in the elevated cTnI group had an LA diameter ≥50 mm compared with those in the normal cTnI group (p = 0.020), although the means of LA diameter did not differ between the 2 groups (p = 0.327). Compared with patients with normal cTnI, those with elevated cTnI had greater MWT (p <0.001), septal wall thickness (SWT, p <0.001), and LVM index (LVMI, p <0.001). After allocated according to the tertiles of LVMI, patients in the upper tertile had a significantly higher proportion of elevated cTnI than those in the lower and middle tertiles (55% vs 14% and 16%, p <0.001 for both comparisons; Figure 1 ).

Serum cTnI values according to clinical variables are depicted in Table 3 . Higher cTnI levels were found in patients with MWT ≥30 mm compared with those with MWT <30 mm (p <0.001). Serum cTnI levels were also significantly higher in patients with LA diameter ≥50 mm than in those with LA diameter <50 mm (p = 0.022). In contrast, both the presence of syncope and moderate/severe MR were associated with lower serum cTnI (p = 0.030 and 0.041, respectively). Patients taking statins had significantly lower levels of cTnI (p = 0.010). There was a trend toward lower cTnI values in patients with hypertension than in those without hypertension (p = 0.082, Figure 2 ). In comparison with patients with LVOT gradient <30 mm Hg at rest, those with LVOT gradient ≥30 mm Hg at rest had borderline increased serum cTnI (p = 0.073).

Table 3

Serum cardiac troponin I levels according to clinical variables of 149 patients with obstructive hypertrophic cardiomyopathy

Variable	Cardiac Troponin I (ng/ml)				p Value
	Present		Absent
Men	n=92	0.021 (0.010-0.047)	n=57	0.017 (0.007-0.041)	0.130
Hypertension	n=47	0.015 (0.008-0.030)	n=102	0.021 (0.009-0.049)	0.082
Diabetes mellitus	n=6	0.022 (0.012-0.025)	n=143	0.019 (0.009-0.045)	0.787
Hypercholesterolemia	n=43	0.019 (0.007-0.045)	n=106	0.019 (0.010-0.043)	0.405
Current smokers	n=54	0.018 (0.010-0.044)	n=95	0.019 (0.008-0.044)	0.624
NYHA functional class III or IV	n=127	0.019 (0.008-0.043)	n=22	0.021 (0.011-0.047)	0.529
Chest pain	n=49	0.017 (0.008-0.036)	n=100	0.022 (0.009-0.045)	0.330
Palpitation	n=28	0.018 (0.009-0.036)	n=121	0.019 (0.009-0.045)	0.853
Family history of HC	n=35	0.021 (0.010-0.056)	n=114	0.018 (0.009-0.040)	0.203
Atrial fibrillation	n=13	0.021 (0.015-0.037)	n=136	0.019 (0.009-0.045)	0.590
Family history of SCD	n=16	0.016 (0.006-0.071)	n=133	0.019 (0.010-0.042)	0.978
Syncope	n=50	0.015 (0.007-0.031)	n=99	0.021 (0.010-0.047)	0.030
Maximum wall thickness ≥ 30mm	n=14	0.061 (0.043-0.066)	n=135	0.016 (0.008-0.034)	<0.001
Resting LVOTG ≥ 30mmHg	n=139	0.019 (0.010-0.044)	n=10	0.008 (0.005-0.037)	0.073
Non-sustained VT ∗	n=6	0.032 (0.007-0.060)	n=110	0.017 (0.009-0.038)	0.649
≥2 risk factors for SCD	n=63	0.022 (0.008-0.056)	n=86	0.019 (0.009-0.036)	0.276
Beta-blockers	n=111	0.017 (0.009-0.044)	n=38	0.022 (0.010-0.044)	0.752
Calcium antagonists	n=45	0.016 (0.010-0.037)	n=104	0.020 (0.009-0.046)	0.454
Amiodarone	n=7	0.056 (0.009-0.472)	n=142	0.019 (0.009-0.042)	0.146
ACEI/ARB	n=22	0.020 (0.006-0.030)	n=127	0.019 (0.010-0.045)	0.198
Statins	n=16	0.010 (0.007-0.017)	n=133	0.021 (0.010-0.046)	0.010
Aspirin	n=33	0.019 (0.010-0.052)	n=116	0.017 (0.009-0.043)	0.292
Diuretics	n=8	0.031 (0.008-0.069)	n=141	0.019 (0.009-0.042)	0.575
Systolic anterior motion	n=140	0.019 (0.010-0.045)	n=9	0.008 (0.007-0.030)	0.132
Moderate or Severe mitral regurgitation	n=61	0.016 (0.008-0.031)	n=88	0.023 (0.010-0.049)	0.041
Combined with mid-ventricular obstruction	n=9	0.024 (0.013-0.046)	n=140	0.019 (0.008-0.043)	0.345
Left atrium diameter ≥ 50mm	n=20	0.038 (0.018-0.054)	n=129	0.016 (0.008-0.039)	0.022

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