Study Protocol

From October 2009 to September 2012, patients with HCM referred to the regional HCM Competence Center at the University Cardiologic Hospital Haut-Leveque of Bordeaux-Pessac (France) were prospectively evaluated at baseline, using clinical parameters as well as two-dimensional (2D) echocardiography, both at rest and during exercise, to compare the predictive value of these two conditions as indicators of outcomes.

The study inclusion criteria were (1) previous formal diagnosis of HCM on the basis of morphologic hypertrophy, genetic tests, or familial history; (2) sinus rhythm; and (3) ability to perform bicycle exercise testing.

Morphologic HCM diagnoses were based on the presence, according to 2D echocardiography, of a hypertrophied, nondilated left ventricle (wall thickness ≥ 15 mm) in the absence of other cardiac or systemic diseases susceptible to produce similar degree of hypertrophy. We excluded all patients presenting with long-standing hypertension, severe uncontrolled and stage 2 hypertension (blood pressure > 159/99 mm Hg on at least two measurements performed at two different times).

Exclusion criteria were (1) poor ultrasound window quality, (2) recent history of syncope or severe arrhythmia, (3) persistent atrial fibrillation at the time of investigation, and (4) New York Heart Association (NYHA) functional class IV.

Medications were not withdrawn before echocardiography. Information concerning the study and data collection was provided to all patients, and the institutional review board approved the study protocol.

Resting Echocardiography

Resting 2D echocardiography was performed according to American Society of Echocardiography guidelines, with ultrasound recordings obtained on a Vivid 9 (GE Vingmed Ultrasound AS, Horten, Norway) by an experienced (level 3) operator. Recordings in standardized views were acquired in 2D, pulsed, continuous, and color Doppler modalities and stored for subsequent analysis. Pulsed Doppler tissue imaging (DTI) analysis was carried out in the apical four-chamber view at the lateral and septal sides of the mitral annulus and at the lateral free side of the right ventricle. M-mode acquisition was performed in the parasternal long-axis view on the left ventricle and the mitral valve to examine systolic anterior motion (SAM) and in the apical four-chamber view on the lateral side of the tricuspid annulus, after zooming in on the area. Particular attention was paid to the LVOT area to identify and analyze SAM of the mitral valve in both the parasternal long-axis and apical three- and five-chamber views. The LVOT was scanned with continuous Doppler to measure maximal outflow velocity.

Exercise Echocardiography

Exercise echocardiography was conducted in accordance with European Association of Echocardiography guidelines. Exercise consisted of bicycle exertion in a semisupine position (50 ^o ) with a slight left lateral tilt to enable simultaneous transthoracic echocardiography. Exercise examination was performed with the Vivid 9 (GE Vingmed Ultrasound AS) by an experienced (level 3) operator. Starting at 25 W, the workload was increased by 25 W every 2 min, up to the maximum tolerated effort. At each stage from rest to recovery, conventional recordings were acquired in 2D views and continuous and color Doppler modalities and were stored for offline analysis. Systolic and diastolic blood pressures, in addition to the electrocardiogram, were recorded from rest to recovery at each stage. Blood pressure was measured using a cuff sphygmomanometer at rest and at 1-min intervals during exercise. Inadequate blood pressure response to exercise was defined by an increase in systolic blood pressure of <25 mm Hg or a drop in systolic blood pressure at peak of ≥15 mm Hg.

Echocardiographic Measurements

An independent observer, blinded to patient history, analyzed all cases retrospectively, applying standard measurements according to European Association of Echocardiography and American Society of Echocardiography guidelines and using the system’s internal quantitation package. Hypertrophy localization was performed according to the classification of Maron et al . Maximal end-diastolic wall thickness was measured on 2D imaging. LV diameters, volumes, and LVEF were calculated from the apical two- and four-chamber views using Simpson’s rule. Biplane maximal left atrial volume was calculated using the area-length method and indexed to body surface area. Mitral pulsed Doppler velocities were also measured. LV filling pressures were estimated using the ratio of mitral orifice E and septal and lateral annular E′ peak velocities (E/E′ ratio). S′ and A′ peaks, per DTI, were also estimated at both the septal/lateral mitral annular side and on the free side of the right ventricle. Systolic pulmonary artery pressure was calculated from the measured tricuspid gradient (as 4 [tricuspid velocity in m/sec] ² ) plus an estimate of right atrial pressure from the excursion of the inferior vena cava. Mitral regurgitation (MR), if present, was graded (0–4) using the proximal isovelocity surface area method. In case of noncentral jets, the extension of the color jet in the three main apical views and the peak velocity of the E mitral wave (grade 3 or 4 if >130 cm/sec) were also taken into account to optimize the grading of MR severity. For the right ventricle, systolic function was assessed using DTI (peak S′ at the lateral free wall), and tricuspid annular plane systolic excursion using M-mode imaging.

Longitudinal LV deformation with contraction was measured using the 2D speckle-tracking echocardiographic method. Once three endocardial markers were placed in an end-diastolic frame, the software automatically tracked the contour over subsequent frames. Adequate tracking could be verified in real time and corrected by adjusting the region of interest or by manually correcting the contour to ensure optimal tracking. Longitudinal strain was assessed in apical views. Average longitudinal strains were calculated for the 17 segments in relation to the strain magnitude at aortic valve closure, and LV GLS was also obtained. GLS is usually expressed using negative numbers, because longitudinal shortening leads to a smaller segment length in systole compared with baseline, but to avoid any confusion induced by the “minus” sign and the cutoff values, we present GLS in terms of magnitude (absolute value) in this report.

The length of the anterior mitral leaflet was measured from the parasternal long-axis view during mid-diastole, with the leaflet maximally extended, as the distance from the junction between the anterior leaflet and the posterior aortic wall to the tip of the leaflet. Mitral annular diameter was measured in diastole in the parasternal long-axis view. SAM was considered present only in the case of complete systolic apposition of the mitral valve on the septal wall. Outflow gradients were measured and automatically calculated from the flow velocities using the modified Bernoulli equation. Outflow velocities were measured using continuous-wave Doppler during exercise, with the same direction and angle as recorded at rest. Specific attention was paid so as not to confuse MR flow, when present.

Follow-Up

Patients were followed up clinically and with Holter electrocardiography every 6 months. At the end of follow-up, all patients were telephoned to record the occurrence of any new cardiac events. The mean duration of follow-up was determined using the most recent evaluation as of April 1, 2013, or the patient’s death. For severely symptomatic patients who underwent major therapeutic interventions known to relieve outflow tract gradient (septal myectomy, mitral valve surgery, alcohol septal ablation, or DDD stimulation), the follow-up period was terminated at the time of the procedure.

Composite Cardiac Event

Similarly to Maron et al . in 2003, we defined a composite cardiac event including death related to HCM (sudden cardiac death, death as a consequence of heart failure, or stroke related to atrial fibrillation occurrence), sustained ventricular tachycardia, appropriate cardiac shock or resuscitated cardiac arrest, and progression of symptoms to NYHA functional class III or IV (for patients in NYHA class I or II only). Sudden cardiac death was defined as a sudden and unexpected collapse in patients who had previously had relatively uneventful clinical courses. Death related to heart failure was defined as occurring in the context of cardiac decompensation and a progressive course with limiting symptoms, particularly when it was complicated by pulmonary edema, required hospitalization for treatment, or both. Potentially lethal events in which patients were resuscitated from cardiac arrest or sustained ventricular tachycardia or received appropriate shocks from implanted defibrillators were regarded as serious events and included as cardiac events. Nonsustained ventricular tachycardia and atrial fibrillation occurrence was not considered in the composite cardiac event.

Statistical Analysis

All statistical analyses were performed using SPSS version 17.0 (SPSS, Inc., Chicago, IL). Data are expressed as mean ± SD. Unpaired Student t tests and one-way analysis of variance were used to compare normally distributed data. Pearson χ ² and Fisher exact tests were used to compare noncontinuous variables expressed as proportions. Univariate Cox regression analysis was performed for all clinically relevant echocardiographic variables. To highlight independent indicators of outcomes, we used a Cox automated backward-entry selection model integrating major covariates ( P < .05) on univariate analysis. Hazard ratio (HR) and 95% confidence intervals were calculated. The HR indicates the risk for a given outcome per unit change in an explanatory variable. Survival curves were constructed according to the Kaplan-Meier method and using the log-rank test to compare the differences between the groups of interest. P values ≤ .05 were considered statistically significant.

Study Population

Over 160 consecutive patients followed at the HCM Competence Center from October 2009 to September 2012, the study enrolled and included finally prospectively 115 patients with HCM for both rest and exercise echocardiography. Excluded from the study analysis were six patients with permanent atrial fibrillation, six further patients with poor acoustic windows, seven patients with recent histories of syncope or severe arrhythmia, 15 patients with NYHA class IV symptoms, six patients with maximal septal wall thickness between 13.0 and 14.9 mm, and five patients for inability to perform exercise. The mean age at initial evaluation was 51.9 ± 15.2 years (66% men), and the mean follow-up duration was 19 ± 11 months. Two patients were censored at the time of alcohol septal ablation and one patient at the time of pacemaker implantation (with short atrioventricular delay settings). According to our definition, 18 patients (16%) exhibited cardiac events: one patient died of heart failure, four had sustained ventricular tachycardia, three were hospitalized for heart failure, and 10 had progression of NYHA class from I or II to III or IV.

Baseline Clinical Characteristics

As presented in Table 1 , only NYHA class approached a significant difference in the cardiac event group ( P = .053). There were no significant differences between patients with and without cardiac events with regard to age, sex, height, weight, body surface area, personal clinical history, or familial history of sudden cardiac death or HCM. The follow-up duration was similar. At the time of baseline echocardiographic (resting and exercise) evaluation, 70 patients (61%) were undergoing medical therapy with β-blockers and/or calcium inhibitors: 68 patients on β-blockers (11 [61%] in the cardiac event group vs 57 [59%]) and six on calcium inhibitors (two [11%] in the cardiac event group vs four [4%]).

Echocardiography at Rest

Morphologically, there were no significant differences between the two groups concerning LV maximal wall thickness and LV volume ( Table 2 ). Maron type II tended to be more frequent in the cardiac event group, but LV morphology revealed no significant difference between the groups. Patients with cardiac events more frequently exhibited resting LVOT gradients ≥30 mm Hg (67% vs 31%, P < .004) and complete SAM of the mitral valve (56% vs 21%, P = .002), and they also displayed a more severe mean LVOT peak gradient (52 ± 39 vs 27 ± 31 mm Hg, P = .004). Regarding LV systolic function, LVEF was significantly reduced in the cardiac event group ( P = .03). There were no significant differences concerning septal S′, but DTI revealed significantly lower lateral S′ and mean GLS values expressed in magnitude (14.0 ± 2.6% vs 17.0 ± 3.6%, P = .001) in the cardiac event group. Additionally, LV diastolic function alteration was significantly larger in patients with cardiac events: increases in maximal biplane left atrial volume index (43 ± 16 vs 34 ± 18 mL/m ² , P = .04) and lateral E/E′ ratio ( P = .02) were significantly higher than in patients without events, and peak A′ velocity at the lateral annulus was reduced (6.5 ± 2.1 vs 9.2 ± 3.4 cm/sec, P < .003). Patients with cardiac events tended to have longer anterior mitral valves ( P = .12), had larger mitral annular diameters ( P = .05), and more frequently had grade 2 MR (28% vs 6%). None of the patients exhibited grade 3 or 4 MR at rest.

Exercise Echocardiography

Because patients with recent histories of severe symptoms and those in NYHA functional class IV were excluded from analysis, all patients well tolerated exercise echocardiography, without sustained or nonsustained ventricular tachycardia, severe symptoms, or syncope or lipothymia, even in those with resting LVOT gradients ≥ 50 mm Hg (NYHA functional class I or II) ( Table 3 ). In the cardiac event group, we observed lower peak LVEFs (67 ± 8% vs 72 ± 6%, P < .05) at peak exercise and higher peak LVOT gradients (77 ± 55 vs 38 ± 38 mm Hg, P < .0005). In contrast, peak LVOT gradient during the 6-min recovery stage (after exercise) did not differ significantly between the two groups. There was no significant difference concerning MR grade. None of the patients presented regional wall motion abnormalities during exercise.

Table 3

Exercise echocardiographic characteristics

Echocardiographic measurement	All patients ( n = 115)	Patients without events ( n = 97)	Patients with cardiac events ( n = 18)	P
Under therapy	70 (61%)	57 (59%)	13 (72%)	.28
Maximal level (W)	122 ± 40	122 ± 42	119 ± 33	.75
Total exercise time (min)	9.9 ± 3.1	9.9 ± 3.2	9.8 ± 2.5	.90
Theoretical maximal heart rate (%)	77.0 ± 13.5	77.8 ± 13.4	72.9 ± 13.8	.16
Peak systolic BP (mm Hg)	168 ± 31	171 ± 31	154 ± 22	.04
Peak diastolic BP (mm Hg)	76 ± 23	77 ± 25	70 ± 12	.24
Peak heart rate (beats/min)	127 ± 23	128 ± 23	120 ± 25	.21
LVEDV (mL)	72.4 ± 21.6	72.3 ± 20.9	72.9 ± 25.8	.93
LVESV (mL)	21.2 ± 9.1	20.8 ± 8.9	23.3 ± 10.3	.32
Peak LVEF (Simpson) (%)	71.2 ± 6.8	71.7 ± 6.4	68.3 ± 8.1	.047
MR grade
0	64 (57%)	55 (58%)	9 (50%)	.81
1	39 (34%)	32 (34%)	7 (39%)
2	10 (9%)	8 (8%)	2 (11%)
LVOT gradient ≥50 mm Hg at peak	34 (30%)	23 (24%)	11 (61%)	.001
Peak LVOT gradient (mm Hg)	45.3 ± 44.5	39.6 ± 40.1	75.7 ± 55.1	.0013
Maximal LVOT gradient (mm Hg) during recovery phase	64.6 ± 58.4	61.0 ± 58.2	81.8 ± 57.7	.17
Nonsustained ventricular tachycardia	0 (0%)	0 (0%)	0 (0%)	NA
Inadequate BP response	17 (15%)	15 (15%)	2 (12%)	.69

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