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Abstract

Aims

Rest echocardiography plays a role in hypertrophic cardiomyopathy (HCM) diagnosis and risk stratification because left atrial enlargement, severe left ventricle (LV) hypertrophy, and rest LV outflow tract (LVOT) gradients ≥50 mmHg are sudden cardiac death risk factors that have been highlighted in recent guidelines. Conversely, the lack of evidence makes that exercise-echocardiography findings play a limited role. In clinical practice, LVOT gradient, but also mitral regurgitation (MR) or pulmonary pressure, seems relevant parameters to look for, during the exercise. Therefore, we sought to determine whether exercise-induced changes in myocardial and valvular functions could improve HCM risk stratification.

Methods and results

Consecutive primitive HCM patients with a preserved LV ejection fraction underwent standardized exercise echocardiography (including the assessment of myocardial function, dynamic left intraventricular gradient, and valvular regurgitations) at baseline and were clinically followed for a median of 29.3 months. The primary endpoint was a composite criterion that included death from any cause, cardiorespiratory arrest, and hospitalization for a cardiovascular event. A total of 126 patients were included. Eighteen patients reached the primary endpoint. According to univariate Cox regression analysis, exercise LVOT gradient ≥50 mmHg [hazard ratio (HR) = 3.31, P = 0.01] and significant (≥2/4) exercise MR (HR = 3.64, P < 0.01) were associated with the primary endpoint. Patients with significant MR had significantly higher rest and exercise LVOT gradients (P = 0.001 and P = 0.001) and larger left atria volumes (P < 0.001).

Conclusion

Significant exercise-induced MR appears to significantly impact the prognoses of HCM patients, and it is also associated with higher LVOT rest and exercise gradients.

hypertrophic cardiomyopathy, prognosis, exercise echocardiography, exercise-induced mitral regurgitation

Introduction

Hypertrophic cardiomyopathy (HCM) is regarded as the most common genetic cardiovascular disorder1; it exhibits an autosomal dominant Mendelian pattern and age-related (and incomplete) penetrance. The pathophysiology of HCM is complex and continues to be a source of controversy in the literature.2 Echocardiography plays a major diagnostic role in this disease management.3

HCM is frequently compatible with a normal life expectancy.4,5 But, subgroups at risk for complications exist.1 Sudden cardiac death (SCD), which is the most worrisome and visible complication of HCM, but is not easily predictable. The following major features have been proposed for their value in distinguishing patients with an increased risk of SCD in adults: (i) age, (ii) non-sustained ventricular tachycardia (≥3 consecutive ventricular beats at ≥120 bpm lasting <30 s), (iii) maximum left ventricle (LV) wall thickness ≥30 mm, (iv) family history of SCD at a young age, (v) unexplained syncope, (vi) left atrium diameter (LAD), and (vii) left ventricle outflow tract obstruction (LVOTO) at rest.6 According to latest guidelines, calculation of the SCD risk score using these seven features is recommended.7

Exercise-echocardiography findings play only a limited role in recommendations certainly because of the lack of evidence.8 Interestingly, in the current European Society of Cardiology (ESC) guidelines,6 an LVOTO gradient is ≤50 mmHg at rest justify an exercise echocardiography, only in symptomatic patients to evaluate LVOTO during exercise. The exam should thus focus on LVOTO but the interaction between the myocardium, the valves and the blood flows looks too complex for just looking for LVOTO. In clinical practice, LVOT gradient, but also mitral regurgitation (MR) or pulmonary pressures, seems relevant parameters to look for, during the exercise. Therefore, we sought to determine whether exercise-induced changes not only in myocardial but also in mitral valvular regurgitations could improve HCM risk stratification.

Patients and methods

Patients

We prospectively included HCM patients who were admitted to our regional HCM Competence Center, from October 2009 to May 2013. Patients were prospectively evaluated at baseline using clinical parameters, as well as echocardiography at rest and during a standardized exercise. The following inclusion criteria were applied: patients suffering from HCM with LV hypertrophy, as defined by the current American College of Cardiology Foundation/American Heart Association,9 in the absence of another cardiac or systemic disease capable of producing the magnitude of LV hypertrophy observed. Patients with (i) permanent atrial fibrillation (AF), (ii) a history of coronary artery disease, (iii) a history of cardiac surgery (myomectomy or alcohol septal ablation), or (iv) inadequate acoustic windows (n = 4) were excluded from the analysis.

All patients provided informed consent to participate in this study, which was performed in accordance with the principles outlined in the Declaration of Helsinki on research in human subjects (CNIL declaration n°909378).

Exercise echocardiography

Medications were not withdrawn before the exams. Exercise echocardiography was conducted in accordance with EACVI recommendations.4 Following the clinical examination, arterial blood pressure measurements, and 12-lead electrocardiogram (ECG), the patients underwent exercise echocardiography in a standard semi-supine position with a slight left lateral tilt (bicycle tilted to ∼50°), on a tilting bicycle ergometer (Ergoline Gmbh, General Electric, Bitz, Germany). Using a Vivid 9 ultrasound system with an M4S transducer (GE Healthcare, Horten, Norway), an experienced (level 3) operator10 performed the exercise examination. Testing started with an initial workload of 30 W, and the workload increased in 30 W increments every 2 min. The pedalling rate was 60 rotations per minute. ECG results were recorded continuously, and blood pressure was measured every 2 min. Exercise was interrupted in case of significant arrhythmia, severe hypertension (systolic BP >240 mmHg or diastolic BP >110 mmHg), hypotensive response (decrease >20 mmHg from baseline), or limiting symptoms. Two-dimensional echocardiography was performed in standard parasternal and apical views at baseline and at peak exercise.

We calculated the number of metabolic equivalents (METs) for each patient (in terms of the METs achieved during exercise and the expected results based on age and sex). To predict METs, we used the Veterans Affairs cohort formula for men and the St James Take Heart Project formula for women. These formulas reportedly perform best in their ability to predict outcomes.11 We then calculated the achieved/predicted METs ratio as described by Desai et al.12

We also calculated the 5-year probability of SCD in our population as described in the latest ESC guidelines.6

Echocardiographic measurements

Two-dimensional echocardiographic analyses were performed offline at baseline and during exercise by two experienced physicians who were unaware of each patient's clinical status. All measurements were performed according to recommendations of chambers quantification13 and diastolic function assessment.14 MR, if present, was graded (0–4) using the proximal isovelocity surface area (PISA) method as described in the European Association of Cardiovascular Imaging recommendations.15 During exercise and at rest, outflow velocities were measured using continuous-wave Doppler. Outflow gradients were automatically calculated from the flow velocity using the modified Bernoulli equation.16 Care was taken not to confuse LV outflow and MR flow. Systolic anterior motion (SAM) of the mitral valve was defined as a paradoxical motion of the anterior mitral valve leaflet towards the LVOT during systole.4

Deformation imaging indices

Three consecutive cardiac cycles were recorded and averaged, and the frame rate was set to 60–80 frames/s. The analysis was performed offline using customized software (EchoPAC PC BT12; GE Healthcare). Global longitudinal strain (GLS) of the LV has been measured according to the previous report.17 The LA endocardial border was also manually traced on the apical four-chamber view. After manual adjustment of a region of interest covering the full thickness of the myocardium, the software divided the LA into six segments and automatically scored the segmental tracking quality. The software rejected segments with inadequate image quality and excluded them from the analysis. Longitudinal strain curves were generated for each of the six LA segments in the four chambers. Global peak LA longitudinal strain during ventricular systole (εs) was then measured by averaging the values obtained from the six LA segments. The same tracing method was used to calculate the strain rate and to analyse the LA systolic peak of strain rate. A cardiologist with a level 3 in echocardiography, who was unaware of the patients’ information, analysed all of the echocardiographic values (Figure 1).

Kaplan–Meier primary event survival curves (log-rank test) in patients with exercise MR ≥2 vs. <2 (A), exercise LVOT gradient ≥50 mmHg vs. <50 mmHg (B), and rest sPAP ≥35 mmHg vs. <35 mmHg (C). The small vertical lines in the survival curves indicate time points at which patients were censored.
Figure 1

Kaplan–Meier primary event survival curves (log-rank test) in patients with exercise MR ≥2 vs. <2 (A), exercise LVOT gradient ≥50 mmHg vs. <50 mmHg (B), and rest sPAP ≥35 mmHg vs. <35 mmHg (C). The small vertical lines in the survival curves indicate time points at which patients were censored.

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Follow-up

After the initial evaluation, follow-up data were obtained in summer 2014. Data were collected from our hospital computer database; in case of missing data, the patient's cardiologist or general practitioner was contacted by phone or, if necessary, the patients themselves were contacted. The mean duration follow-up was determined using the most recent evaluation or the patient's date of death.

Endpoints

The primary clinical endpoint was a composite criterion including death from any cause, cardiorespiratory arrest, and hospitalization related to a cardiac event.

The secondary endpoint was a cardiorespiratory arrest (resuscitated or not) event [or judge as equivalent: justified shock from an implantable cardioverter-defibrillator (ICD)].

Statistical analysis

Continuous variables are presented as the mean ± standard deviation or as the median [interquartile range] in case of skewness. Categorical data are summarized as frequency and percentages. We compared patients who reached endpoints and the others. The differences in baseline characteristics between the two groups were analysed with the Student's t-test, Mann–Whitney test, χ2 or Fisher's exact test, as appropriate. Survival analyses were performed with two different tests; a univariate Cox proportional hazard regression analysis was performed to assess relationship between the different variables and the endpoints. We did a multivariate Cox regression for primary endpoint with stepwise selection based on the Aikake Information Criteria. Exercise MR and rest echocardiographic parameters selected with P < 0.1. That multivariable analysis was only ‘informative’ but, was of limited value because of the low number of events. Ten events are usually required for each variable included in a multivariable analysis. The other survival analysis was the building of survival curves according to the Kaplan–Meier method.

A P-value <0.05 was considered statistically significant. All statistics were done with R (R Foundation for Statistical Computing, Vienna, Austria. http://www.R-project.org/).

Results

Patient population

A total of 126 patients were included in our study. The median follow-up time was 29.3 months, with an interquartile range of 24.3 months. The majority of patients was male (78%), with a mean age of 47 years. Eighteen patients reached the primary endpoint (14.2%). Seven patients presented with cardiorespiratory arrest: three died, two of an unknown cause, and one following a heart surgery for left-ventricular assistance device implantation. Three patients were successfully resuscitated following ventricular arrhythmia. One patient had an appropriate internal shock delivered by his ICD for ventricular fibrillation.

Eleven patients were hospitalized for cardiac-related events. Four patients were hospitalized for pulmonary oedema, two for a sinus node dysfunction requiring a pace maker, two for symptomatic AF, and one patient for chest pain. One patient presented a syncope and one patient suffered from a pulmonary embolism.

Echocardiography and primary endpoint

Significant exercise-induced MR (MR ≥ 2/4) was present in 22 patients (20.9%). Exercise-induced MR but not rest MR was associated with primary endpoint, P < 0.01 and P = 0.09, respectively. Rest SAM, rest, and exercise LVOT gradient ≥50 mmHg were determinant of primary endpoint (P = 0.02, P = 0.05 and P < 0.01, respectively). Exercise-induced tricuspid regurgitation (TR) was not linked to the primary endpoint (P = 0.41), whereas TR-based estimation of the systolic pulmonary artery pressure (sPAP) at rest was a determinant of primary endpoint when a cut-off of 35 mmHg was used (P = 0.04). Achieved/predicted METs ratio was not associated with the primary endpoint (P = 0.23).

Secondary endpoint: cardiorespiratory arrest

The variables linked with the hard point (i.e. cardiorespiratory arrest) were the probability of SCD at 5 years, which was calculated according to the formula in the ESC guidelines (P < 0.01), significant exercise-induced MR (P = 0.02), exercise left atrial volume indexed (LAVi) (P = 0.04), and an exercise LVOT gradient ≥50 mmHg (P = 0.04) (Table 1).

Table 1
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Univariable Cox regression

Primary endpoint
Cardiorespiratory arrest
HRPHRP
Clinical data
 Age1.00 (0.97–1.04)0.880.95 (0.90–1.01)0.08
 Men1.5 (0.43–5.2)0.520.60 (0.11–3.3)0.56
 Weight1.03 (0.99–1.06)0.091.01 (0.95–1.07)0.76
 Body surface area (m2)14.1 (1.13–176.5)0.041.44 (0.02–80.4)0.86
 Follow-up duration (months)1.00 (0.99–1)0.060.99 (0.98–1.00)0.03
 Family history of HCM0.31 (0.09–1.08)0.070.3 (0.03–2.6)0.27
 Implanted defibrillator0.77 (0.17–3.48)0.733.2 (0.51–20.1)0.21
 Caucasian0.40 (0.05–3)0.371.4 (0.16–11.9)0.77
 History of hypertension1.2 (0.43–3.2)0.750.48 (0.05–4.26)0.51
 Angina0.97 (0.27–3.51)0.960.76 (0.08–7.12)0.81
 NYHA class0.99 (0.44–2.3)0.990.93 (0.22–3.9)0.92
Medications
 VKA2.96 (1.09–8.05)0.032.13 (0.39–11.8)0.38
 Beta-blockers4.14 (0.55–31.3)0.17∞ (0–∞)0.99
 Calcium channel blockers2.26 (0.79–6.44)0.130.89 (0.10–7.7)0.91
 ACE inhibitors/ARBs3.13 (1.12–8.72)0.034.4 (0.70–27.5)0.11
Major risks factors for SCD
 Lipothymia/syncope1.93 (0.63–5.93)0.251.05 (0.12–9.07)0.97
 Familial SCD0.40 (0.09–1.77)0.230.64 (0.07–5.50)0.68
 LV hypertrophy (≥30 mm)0 (0–∞)0.990 (0–∞)0.99
 Non-sustained ventricular tachycardia1.14 (0.37–3.55)0.823.6 (0.73–18.3)0.12
 Left atrial diameter (mm)1.08 (1.01–1.15)0.021.05 (0.96–1.15)0.32
Exercise parameters
 Achieved/predicted METs0.99 (0.96–1.02)0.660.98 (0.93–1.025)0.37
LV function parameters
 Rest LVEF1.01 (0.95–1.07)0.741.05 (0.95–1.17)0.34
 Exercise LVEF1.03 (0.98–1.08)0.310.99 (0.92–1.07)0.92
 Rest SGL0.95 (0.83–1.08)0.480.93 (0.75–1.15)0.50
 Exercise SGL0.94 (0.86–1.03)0.200.98 (0.85–1.12)0.72
LVOT parameters
 Rest LVOT gradient ≥50 mmHg2.2 (0.72–6.8)0.163.5 (0.67–18.03)0.14
 Exercise LVOT gradient ≥50 mmHg3.31 (1.26–8.6)0.013 (0.62–14.4)0.17
Diastolic function
 LAVi rest1.02 (0.99–1.05)0.291.04 (0.99–1.09)0.1
 LAVi exercise1.02 (0.99–1.5)0.131.04 (0.99–1.08)0.1
Mitral regurgitation
 Rest MR ≥2/41.96 (0.64–6)0.231.05 (0.12–8.8)0.97
 Exercise MR ≥2/43.64 (1.4–9.3)<0.014.72 (1.04–21.63)0.04
RV parameters
 Rest sPAP ≥35 mmHg3.60 (1.34–9.68)0.011.8 (0.35–9.37)0.48
SCD ESC risk score
 SCD at 5 years ≥5%NANA1.9 (1.36–2.7)<0.01
Primary endpoint
Cardiorespiratory arrest
HRPHRP
Clinical data
 Age1.00 (0.97–1.04)0.880.95 (0.90–1.01)0.08
 Men1.5 (0.43–5.2)0.520.60 (0.11–3.3)0.56
 Weight1.03 (0.99–1.06)0.091.01 (0.95–1.07)0.76
 Body surface area (m2)14.1 (1.13–176.5)0.041.44 (0.02–80.4)0.86
 Follow-up duration (months)1.00 (0.99–1)0.060.99 (0.98–1.00)0.03
 Family history of HCM0.31 (0.09–1.08)0.070.3 (0.03–2.6)0.27
 Implanted defibrillator0.77 (0.17–3.48)0.733.2 (0.51–20.1)0.21
 Caucasian0.40 (0.05–3)0.371.4 (0.16–11.9)0.77
 History of hypertension1.2 (0.43–3.2)0.750.48 (0.05–4.26)0.51
 Angina0.97 (0.27–3.51)0.960.76 (0.08–7.12)0.81
 NYHA class0.99 (0.44–2.3)0.990.93 (0.22–3.9)0.92
Medications
 VKA2.96 (1.09–8.05)0.032.13 (0.39–11.8)0.38
 Beta-blockers4.14 (0.55–31.3)0.17∞ (0–∞)0.99
 Calcium channel blockers2.26 (0.79–6.44)0.130.89 (0.10–7.7)0.91
 ACE inhibitors/ARBs3.13 (1.12–8.72)0.034.4 (0.70–27.5)0.11
Major risks factors for SCD
 Lipothymia/syncope1.93 (0.63–5.93)0.251.05 (0.12–9.07)0.97
 Familial SCD0.40 (0.09–1.77)0.230.64 (0.07–5.50)0.68
 LV hypertrophy (≥30 mm)0 (0–∞)0.990 (0–∞)0.99
 Non-sustained ventricular tachycardia1.14 (0.37–3.55)0.823.6 (0.73–18.3)0.12
 Left atrial diameter (mm)1.08 (1.01–1.15)0.021.05 (0.96–1.15)0.32
Exercise parameters
 Achieved/predicted METs0.99 (0.96–1.02)0.660.98 (0.93–1.025)0.37
LV function parameters
 Rest LVEF1.01 (0.95–1.07)0.741.05 (0.95–1.17)0.34
 Exercise LVEF1.03 (0.98–1.08)0.310.99 (0.92–1.07)0.92
 Rest SGL0.95 (0.83–1.08)0.480.93 (0.75–1.15)0.50
 Exercise SGL0.94 (0.86–1.03)0.200.98 (0.85–1.12)0.72
LVOT parameters
 Rest LVOT gradient ≥50 mmHg2.2 (0.72–6.8)0.163.5 (0.67–18.03)0.14
 Exercise LVOT gradient ≥50 mmHg3.31 (1.26–8.6)0.013 (0.62–14.4)0.17
Diastolic function
 LAVi rest1.02 (0.99–1.05)0.291.04 (0.99–1.09)0.1
 LAVi exercise1.02 (0.99–1.5)0.131.04 (0.99–1.08)0.1
Mitral regurgitation
 Rest MR ≥2/41.96 (0.64–6)0.231.05 (0.12–8.8)0.97
 Exercise MR ≥2/43.64 (1.4–9.3)<0.014.72 (1.04–21.63)0.04
RV parameters
 Rest sPAP ≥35 mmHg3.60 (1.34–9.68)0.011.8 (0.35–9.37)0.48
SCD ESC risk score
 SCD at 5 years ≥5%NANA1.9 (1.36–2.7)<0.01

HCM, hypertrophic cardiomyopathy; NHYA, New York Heart Association; SCD, sudden cardiac death; VKA, vitamin K antagonist; ACE, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor antagonist; LV, left ventricle; METs, metabolic equivalents; LEVF, left ventricle ejection fraction; GLS, global longitudinal strain; LVOT, left ventricle outflow tract; SAM, sytolic anterior motion; LAVi, left atrial volume indexed; MR, mitral regurgitation; RV, right ventricle; sPAP, systolic pulmonary artery pressure.

Table 1
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Univariable Cox regression

Primary endpoint
Cardiorespiratory arrest
HRPHRP
Clinical data
 Age1.00 (0.97–1.04)0.880.95 (0.90–1.01)0.08
 Men1.5 (0.43–5.2)0.520.60 (0.11–3.3)0.56
 Weight1.03 (0.99–1.06)0.091.01 (0.95–1.07)0.76
 Body surface area (m2)14.1 (1.13–176.5)0.041.44 (0.02–80.4)0.86
 Follow-up duration (months)1.00 (0.99–1)0.060.99 (0.98–1.00)0.03
 Family history of HCM0.31 (0.09–1.08)0.070.3 (0.03–2.6)0.27
 Implanted defibrillator0.77 (0.17–3.48)0.733.2 (0.51–20.1)0.21
 Caucasian0.40 (0.05–3)0.371.4 (0.16–11.9)0.77
 History of hypertension1.2 (0.43–3.2)0.750.48 (0.05–4.26)0.51
 Angina0.97 (0.27–3.51)0.960.76 (0.08–7.12)0.81
 NYHA class0.99 (0.44–2.3)0.990.93 (0.22–3.9)0.92
Medications
 VKA2.96 (1.09–8.05)0.032.13 (0.39–11.8)0.38
 Beta-blockers4.14 (0.55–31.3)0.17∞ (0–∞)0.99
 Calcium channel blockers2.26 (0.79–6.44)0.130.89 (0.10–7.7)0.91
 ACE inhibitors/ARBs3.13 (1.12–8.72)0.034.4 (0.70–27.5)0.11
Major risks factors for SCD
 Lipothymia/syncope1.93 (0.63–5.93)0.251.05 (0.12–9.07)0.97
 Familial SCD0.40 (0.09–1.77)0.230.64 (0.07–5.50)0.68
 LV hypertrophy (≥30 mm)0 (0–∞)0.990 (0–∞)0.99
 Non-sustained ventricular tachycardia1.14 (0.37–3.55)0.823.6 (0.73–18.3)0.12
 Left atrial diameter (mm)1.08 (1.01–1.15)0.021.05 (0.96–1.15)0.32
Exercise parameters
 Achieved/predicted METs0.99 (0.96–1.02)0.660.98 (0.93–1.025)0.37
LV function parameters
 Rest LVEF1.01 (0.95–1.07)0.741.05 (0.95–1.17)0.34
 Exercise LVEF1.03 (0.98–1.08)0.310.99 (0.92–1.07)0.92
 Rest SGL0.95 (0.83–1.08)0.480.93 (0.75–1.15)0.50
 Exercise SGL0.94 (0.86–1.03)0.200.98 (0.85–1.12)0.72
LVOT parameters
 Rest LVOT gradient ≥50 mmHg2.2 (0.72–6.8)0.163.5 (0.67–18.03)0.14
 Exercise LVOT gradient ≥50 mmHg3.31 (1.26–8.6)0.013 (0.62–14.4)0.17
Diastolic function
 LAVi rest1.02 (0.99–1.05)0.291.04 (0.99–1.09)0.1
 LAVi exercise1.02 (0.99–1.5)0.131.04 (0.99–1.08)0.1
Mitral regurgitation
 Rest MR ≥2/41.96 (0.64–6)0.231.05 (0.12–8.8)0.97
 Exercise MR ≥2/43.64 (1.4–9.3)<0.014.72 (1.04–21.63)0.04
RV parameters
 Rest sPAP ≥35 mmHg3.60 (1.34–9.68)0.011.8 (0.35–9.37)0.48
SCD ESC risk score
 SCD at 5 years ≥5%NANA1.9 (1.36–2.7)<0.01
Primary endpoint
Cardiorespiratory arrest
HRPHRP
Clinical data
 Age1.00 (0.97–1.04)0.880.95 (0.90–1.01)0.08
 Men1.5 (0.43–5.2)0.520.60 (0.11–3.3)0.56
 Weight1.03 (0.99–1.06)0.091.01 (0.95–1.07)0.76
 Body surface area (m2)14.1 (1.13–176.5)0.041.44 (0.02–80.4)0.86
 Follow-up duration (months)1.00 (0.99–1)0.060.99 (0.98–1.00)0.03
 Family history of HCM0.31 (0.09–1.08)0.070.3 (0.03–2.6)0.27
 Implanted defibrillator0.77 (0.17–3.48)0.733.2 (0.51–20.1)0.21
 Caucasian0.40 (0.05–3)0.371.4 (0.16–11.9)0.77
 History of hypertension1.2 (0.43–3.2)0.750.48 (0.05–4.26)0.51
 Angina0.97 (0.27–3.51)0.960.76 (0.08–7.12)0.81
 NYHA class0.99 (0.44–2.3)0.990.93 (0.22–3.9)0.92
Medications
 VKA2.96 (1.09–8.05)0.032.13 (0.39–11.8)0.38
 Beta-blockers4.14 (0.55–31.3)0.17∞ (0–∞)0.99
 Calcium channel blockers2.26 (0.79–6.44)0.130.89 (0.10–7.7)0.91
 ACE inhibitors/ARBs3.13 (1.12–8.72)0.034.4 (0.70–27.5)0.11
Major risks factors for SCD
 Lipothymia/syncope1.93 (0.63–5.93)0.251.05 (0.12–9.07)0.97
 Familial SCD0.40 (0.09–1.77)0.230.64 (0.07–5.50)0.68
 LV hypertrophy (≥30 mm)0 (0–∞)0.990 (0–∞)0.99
 Non-sustained ventricular tachycardia1.14 (0.37–3.55)0.823.6 (0.73–18.3)0.12
 Left atrial diameter (mm)1.08 (1.01–1.15)0.021.05 (0.96–1.15)0.32
Exercise parameters
 Achieved/predicted METs0.99 (0.96–1.02)0.660.98 (0.93–1.025)0.37
LV function parameters
 Rest LVEF1.01 (0.95–1.07)0.741.05 (0.95–1.17)0.34
 Exercise LVEF1.03 (0.98–1.08)0.310.99 (0.92–1.07)0.92
 Rest SGL0.95 (0.83–1.08)0.480.93 (0.75–1.15)0.50
 Exercise SGL0.94 (0.86–1.03)0.200.98 (0.85–1.12)0.72
LVOT parameters
 Rest LVOT gradient ≥50 mmHg2.2 (0.72–6.8)0.163.5 (0.67–18.03)0.14
 Exercise LVOT gradient ≥50 mmHg3.31 (1.26–8.6)0.013 (0.62–14.4)0.17
Diastolic function
 LAVi rest1.02 (0.99–1.05)0.291.04 (0.99–1.09)0.1
 LAVi exercise1.02 (0.99–1.5)0.131.04 (0.99–1.08)0.1
Mitral regurgitation
 Rest MR ≥2/41.96 (0.64–6)0.231.05 (0.12–8.8)0.97
 Exercise MR ≥2/43.64 (1.4–9.3)<0.014.72 (1.04–21.63)0.04
RV parameters
 Rest sPAP ≥35 mmHg3.60 (1.34–9.68)0.011.8 (0.35–9.37)0.48
SCD ESC risk score
 SCD at 5 years ≥5%NANA1.9 (1.36–2.7)<0.01

HCM, hypertrophic cardiomyopathy; NHYA, New York Heart Association; SCD, sudden cardiac death; VKA, vitamin K antagonist; ACE, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor antagonist; LV, left ventricle; METs, metabolic equivalents; LEVF, left ventricle ejection fraction; GLS, global longitudinal strain; LVOT, left ventricle outflow tract; SAM, sytolic anterior motion; LAVi, left atrial volume indexed; MR, mitral regurgitation; RV, right ventricle; sPAP, systolic pulmonary artery pressure.

Univariable Cox regression analysis

The study results are shown in Table 1. Exercise-induced MR ≥2, rest sPAP ≥35 mmHg, and exercise LVOT gradient ≥50 mmHg were associated with the primary endpoint. Regarding cardiorespiratory arrest, exercise-induced MR was the only determining echocardiographic variable [hazard ratio (HR) = 4.7, P = 0.04]. Kaplan–Meier survival curves associated with primary endpoint and cardiorespiratory arrest are shown in Figures 1 and 2, respectively.

Kaplan–Meier cardiorespiratory arrest survival curves (log-rank test) in patients with patients with SCD risk score ≥5 vs. <5% (A) and with patients with exercise MR ≥2 vs. <2 (B). The small vertical lines in the survival curves indicate time points at which patients were censored.
Figure 2

Kaplan–Meier cardiorespiratory arrest survival curves (log-rank test) in patients with patients with SCD risk score ≥5 vs. <5% (A) and with patients with exercise MR ≥2 vs. <2 (B). The small vertical lines in the survival curves indicate time points at which patients were censored.

Open in new tabDownload slide

Exercise-induced MR and others echocardiographic parameters

Regarding the results of the prognosis importance of exercise-induced MR in our population, we studied the link between MR and others echocardiographic parameters. The results are shown in Table 2. There is a strong relationship between exercise-induced MR and LVOT obstruction during exercise and at rest (P = 0.001). Half of patients with exercise-induced MR (n = 12) had a LOVT gradient ≥50 mmHg, whereas 6.2% of patients (n = 7) without an exercise-induced MR had an LVOT gradient ≥50 mmHg (P < 0.001). Patients with exercise-induced MR had a larger LA (at rest and at exercise) and a reduced LA 2D strain (P = 0.02).

Table 2
Open in new tab

Characteristics according to the presence of an MR or not

All patients (n = 126)Exercise MR <2 (n = 105)Exercise MR ≥2 (n = 21)P
Clinical data
 Age47.41 ± 15.4847.04 ± 15.6549.29 ± 14.830.55
 Men (%)99 (78.1%)85 (81%)14 (66.7%)0.15
 Weight (kg)75.6 ± 13.975.0 ± 12.978.8 ± 18.10.26
 Body surface area (m2)1.86 ± 0.191.86 ± 0.191.89 ± 0.230.45
 Follow-up duration (months)29.3 [24.3]28.6 [73.9]39.9 [69.2]0.08
 Family history of HCM42 (34.1%)37 (36.3%)5 (23.8%)0.32
 Implanted defibrillator16 (12.7%)11 (10.5%)5 (23.8%)0.14
 Caucasian109 (86.5%)89 (84.8%)20 (95.2)0.30
 History of hypertension39 (31.0%)37 (35.2%)2 (9.5%)0.02*
 Angina14 (10.4%)12 (11.4%)2 (9.5%)1
NYHA class0.02*
 I66 (52.4%)60 (57.1%)6 (28.6%)
 II55 (43.7%)42 (40%)13 (61.9%)
 III5 (4.0%)3 (2.9%)2 (9.5%)
Medications
 VKA17 (13.5%)10 (9.5%)7 (33.3%)0.01*
 Beta-blockers95 (75.4%)74 (70.5%)21 (100%)0.002*
 Calcium channel blockers17 (13.5%)13 (12.4%)4 (19%)0.48
 ACE inhibitors/ARBs34 (27.0%)27 (25.7%)7 (33.3%)0.59
Major risks factors for SCD
 Lipothymia/syncope16 (51.9%)13 (12.4%)2 (9.5%)1
 Familial SCD28 (20.7%)25 (23.8%)3 (14.3%)0.40
 LV hypertrophy (≥30 mm)7 (5.2%)5 (4.8%)2 (9.5%)0.33
 Non-sustained ventricular tachycardia18 (10.8%)13 (12.4%)5 (23.8%)0.18
 Left atrial diameter (mm)52 ± 852 ± 757 ± 80.002*
Exercise parameters
 Achieved/predicted METs (%)67 ± 2169 ± 2259 ± 160.05*
LV parameters
 Rest LVEF (%)66 ± 866 ± 964 ± 140.23
 Exercise LVEF (%)72 ± 1572 ± 1766 ± 130.08
 Rest GLS (%)−15.2 ± 3.9−15.70 ± 5.80−14.70 ± 3.20.35
 Exercise GLS (%)−18.1 ± 5.3−18.55 ± 7.58−15.50 ± 3.80.04*
LVOT parameters
 SAM at rest19 (15.1%)10 (9.5%)9 (42.9%)0.001*
 Rest LVOT gradient (mmHg)7 [8]7 [6]24 [56]0.001*
 Rest LVOT gradient ≥50 mmHg11 (8.7%)2 (1.9%)9 (42.9%)<0.001*
 Exercise LVOT gradient (mmHg)12 [22]10 [14]67 [111]0.001*
 Exercise LVOT gradient ≥50 mmHg16 (12.7%)5 (4.8%)11 (52.4%)<0.001*
LA parameters
 LA diameter (mm)52 ± 852 ± 757 ± 80.005*
 LA exercise 2DS (%)30.6 [69.5]32.2 [ 22.7]22.3 [9.7]0.02*
 LA rest 2DS (%)26.0 [49.5]26.8 [14.1]21.3 [7.5]0.13
 Exercise LAVi (mL/m2)28 [15]26 [15]42 [18]<0.001*
 Rest LAVi (mL/m2)25 [14]24 [13]37 [15]<0.001*
All patients (n = 126)Exercise MR <2 (n = 105)Exercise MR ≥2 (n = 21)P
Clinical data
 Age47.41 ± 15.4847.04 ± 15.6549.29 ± 14.830.55
 Men (%)99 (78.1%)85 (81%)14 (66.7%)0.15
 Weight (kg)75.6 ± 13.975.0 ± 12.978.8 ± 18.10.26
 Body surface area (m2)1.86 ± 0.191.86 ± 0.191.89 ± 0.230.45
 Follow-up duration (months)29.3 [24.3]28.6 [73.9]39.9 [69.2]0.08
 Family history of HCM42 (34.1%)37 (36.3%)5 (23.8%)0.32
 Implanted defibrillator16 (12.7%)11 (10.5%)5 (23.8%)0.14
 Caucasian109 (86.5%)89 (84.8%)20 (95.2)0.30
 History of hypertension39 (31.0%)37 (35.2%)2 (9.5%)0.02*
 Angina14 (10.4%)12 (11.4%)2 (9.5%)1
NYHA class0.02*
 I66 (52.4%)60 (57.1%)6 (28.6%)
 II55 (43.7%)42 (40%)13 (61.9%)
 III5 (4.0%)3 (2.9%)2 (9.5%)
Medications
 VKA17 (13.5%)10 (9.5%)7 (33.3%)0.01*
 Beta-blockers95 (75.4%)74 (70.5%)21 (100%)0.002*
 Calcium channel blockers17 (13.5%)13 (12.4%)4 (19%)0.48
 ACE inhibitors/ARBs34 (27.0%)27 (25.7%)7 (33.3%)0.59
Major risks factors for SCD
 Lipothymia/syncope16 (51.9%)13 (12.4%)2 (9.5%)1
 Familial SCD28 (20.7%)25 (23.8%)3 (14.3%)0.40
 LV hypertrophy (≥30 mm)7 (5.2%)5 (4.8%)2 (9.5%)0.33
 Non-sustained ventricular tachycardia18 (10.8%)13 (12.4%)5 (23.8%)0.18
 Left atrial diameter (mm)52 ± 852 ± 757 ± 80.002*
Exercise parameters
 Achieved/predicted METs (%)67 ± 2169 ± 2259 ± 160.05*
LV parameters
 Rest LVEF (%)66 ± 866 ± 964 ± 140.23
 Exercise LVEF (%)72 ± 1572 ± 1766 ± 130.08
 Rest GLS (%)−15.2 ± 3.9−15.70 ± 5.80−14.70 ± 3.20.35
 Exercise GLS (%)−18.1 ± 5.3−18.55 ± 7.58−15.50 ± 3.80.04*
LVOT parameters
 SAM at rest19 (15.1%)10 (9.5%)9 (42.9%)0.001*
 Rest LVOT gradient (mmHg)7 [8]7 [6]24 [56]0.001*
 Rest LVOT gradient ≥50 mmHg11 (8.7%)2 (1.9%)9 (42.9%)<0.001*
 Exercise LVOT gradient (mmHg)12 [22]10 [14]67 [111]0.001*
 Exercise LVOT gradient ≥50 mmHg16 (12.7%)5 (4.8%)11 (52.4%)<0.001*
LA parameters
 LA diameter (mm)52 ± 852 ± 757 ± 80.005*
 LA exercise 2DS (%)30.6 [69.5]32.2 [ 22.7]22.3 [9.7]0.02*
 LA rest 2DS (%)26.0 [49.5]26.8 [14.1]21.3 [7.5]0.13
 Exercise LAVi (mL/m2)28 [15]26 [15]42 [18]<0.001*
 Rest LAVi (mL/m2)25 [14]24 [13]37 [15]<0.001*

For abbreviations, see legend of Table 1.

Table 2
Open in new tab

Characteristics according to the presence of an MR or not

All patients (n = 126)Exercise MR <2 (n = 105)Exercise MR ≥2 (n = 21)P
Clinical data
 Age47.41 ± 15.4847.04 ± 15.6549.29 ± 14.830.55
 Men (%)99 (78.1%)85 (81%)14 (66.7%)0.15
 Weight (kg)75.6 ± 13.975.0 ± 12.978.8 ± 18.10.26
 Body surface area (m2)1.86 ± 0.191.86 ± 0.191.89 ± 0.230.45
 Follow-up duration (months)29.3 [24.3]28.6 [73.9]39.9 [69.2]0.08
 Family history of HCM42 (34.1%)37 (36.3%)5 (23.8%)0.32
 Implanted defibrillator16 (12.7%)11 (10.5%)5 (23.8%)0.14
 Caucasian109 (86.5%)89 (84.8%)20 (95.2)0.30
 History of hypertension39 (31.0%)37 (35.2%)2 (9.5%)0.02*
 Angina14 (10.4%)12 (11.4%)2 (9.5%)1
NYHA class0.02*
 I66 (52.4%)60 (57.1%)6 (28.6%)
 II55 (43.7%)42 (40%)13 (61.9%)
 III5 (4.0%)3 (2.9%)2 (9.5%)
Medications
 VKA17 (13.5%)10 (9.5%)7 (33.3%)0.01*
 Beta-blockers95 (75.4%)74 (70.5%)21 (100%)0.002*
 Calcium channel blockers17 (13.5%)13 (12.4%)4 (19%)0.48
 ACE inhibitors/ARBs34 (27.0%)27 (25.7%)7 (33.3%)0.59
Major risks factors for SCD
 Lipothymia/syncope16 (51.9%)13 (12.4%)2 (9.5%)1
 Familial SCD28 (20.7%)25 (23.8%)3 (14.3%)0.40
 LV hypertrophy (≥30 mm)7 (5.2%)5 (4.8%)2 (9.5%)0.33
 Non-sustained ventricular tachycardia18 (10.8%)13 (12.4%)5 (23.8%)0.18
 Left atrial diameter (mm)52 ± 852 ± 757 ± 80.002*
Exercise parameters
 Achieved/predicted METs (%)67 ± 2169 ± 2259 ± 160.05*
LV parameters
 Rest LVEF (%)66 ± 866 ± 964 ± 140.23
 Exercise LVEF (%)72 ± 1572 ± 1766 ± 130.08
 Rest GLS (%)−15.2 ± 3.9−15.70 ± 5.80−14.70 ± 3.20.35
 Exercise GLS (%)−18.1 ± 5.3−18.55 ± 7.58−15.50 ± 3.80.04*
LVOT parameters
 SAM at rest19 (15.1%)10 (9.5%)9 (42.9%)0.001*
 Rest LVOT gradient (mmHg)7 [8]7 [6]24 [56]0.001*
 Rest LVOT gradient ≥50 mmHg11 (8.7%)2 (1.9%)9 (42.9%)<0.001*
 Exercise LVOT gradient (mmHg)12 [22]10 [14]67 [111]0.001*
 Exercise LVOT gradient ≥50 mmHg16 (12.7%)5 (4.8%)11 (52.4%)<0.001*
LA parameters
 LA diameter (mm)52 ± 852 ± 757 ± 80.005*
 LA exercise 2DS (%)30.6 [69.5]32.2 [ 22.7]22.3 [9.7]0.02*
 LA rest 2DS (%)26.0 [49.5]26.8 [14.1]21.3 [7.5]0.13
 Exercise LAVi (mL/m2)28 [15]26 [15]42 [18]<0.001*
 Rest LAVi (mL/m2)25 [14]24 [13]37 [15]<0.001*
All patients (n = 126)Exercise MR <2 (n = 105)Exercise MR ≥2 (n = 21)P
Clinical data
 Age47.41 ± 15.4847.04 ± 15.6549.29 ± 14.830.55
 Men (%)99 (78.1%)85 (81%)14 (66.7%)0.15
 Weight (kg)75.6 ± 13.975.0 ± 12.978.8 ± 18.10.26
 Body surface area (m2)1.86 ± 0.191.86 ± 0.191.89 ± 0.230.45
 Follow-up duration (months)29.3 [24.3]28.6 [73.9]39.9 [69.2]0.08
 Family history of HCM42 (34.1%)37 (36.3%)5 (23.8%)0.32
 Implanted defibrillator16 (12.7%)11 (10.5%)5 (23.8%)0.14
 Caucasian109 (86.5%)89 (84.8%)20 (95.2)0.30
 History of hypertension39 (31.0%)37 (35.2%)2 (9.5%)0.02*
 Angina14 (10.4%)12 (11.4%)2 (9.5%)1
NYHA class0.02*
 I66 (52.4%)60 (57.1%)6 (28.6%)
 II55 (43.7%)42 (40%)13 (61.9%)
 III5 (4.0%)3 (2.9%)2 (9.5%)
Medications
 VKA17 (13.5%)10 (9.5%)7 (33.3%)0.01*
 Beta-blockers95 (75.4%)74 (70.5%)21 (100%)0.002*
 Calcium channel blockers17 (13.5%)13 (12.4%)4 (19%)0.48
 ACE inhibitors/ARBs34 (27.0%)27 (25.7%)7 (33.3%)0.59
Major risks factors for SCD
 Lipothymia/syncope16 (51.9%)13 (12.4%)2 (9.5%)1
 Familial SCD28 (20.7%)25 (23.8%)3 (14.3%)0.40
 LV hypertrophy (≥30 mm)7 (5.2%)5 (4.8%)2 (9.5%)0.33
 Non-sustained ventricular tachycardia18 (10.8%)13 (12.4%)5 (23.8%)0.18
 Left atrial diameter (mm)52 ± 852 ± 757 ± 80.002*
Exercise parameters
 Achieved/predicted METs (%)67 ± 2169 ± 2259 ± 160.05*
LV parameters
 Rest LVEF (%)66 ± 866 ± 964 ± 140.23
 Exercise LVEF (%)72 ± 1572 ± 1766 ± 130.08
 Rest GLS (%)−15.2 ± 3.9−15.70 ± 5.80−14.70 ± 3.20.35
 Exercise GLS (%)−18.1 ± 5.3−18.55 ± 7.58−15.50 ± 3.80.04*
LVOT parameters
 SAM at rest19 (15.1%)10 (9.5%)9 (42.9%)0.001*
 Rest LVOT gradient (mmHg)7 [8]7 [6]24 [56]0.001*
 Rest LVOT gradient ≥50 mmHg11 (8.7%)2 (1.9%)9 (42.9%)<0.001*
 Exercise LVOT gradient (mmHg)12 [22]10 [14]67 [111]0.001*
 Exercise LVOT gradient ≥50 mmHg16 (12.7%)5 (4.8%)11 (52.4%)<0.001*
LA parameters
 LA diameter (mm)52 ± 852 ± 757 ± 80.005*
 LA exercise 2DS (%)30.6 [69.5]32.2 [ 22.7]22.3 [9.7]0.02*
 LA rest 2DS (%)26.0 [49.5]26.8 [14.1]21.3 [7.5]0.13
 Exercise LAVi (mL/m2)28 [15]26 [15]42 [18]<0.001*
 Rest LAVi (mL/m2)25 [14]24 [13]37 [15]<0.001*

For abbreviations, see legend of Table 1.

Multivariable analysis

Table 3 is providing the result of a multivariable analysis supporting the prognostic value of the exercise-induced MR even if the number of event is low.

Table 3
Open in new tab

Multivariate Cox regression for primary endpoint with stepwise selection

HRP
Exercise MR ≥23.24 (1.22–8.5)0.02
Rest PAPs ≥35 mmHg1.03 (0.98–1.08)0.18
Rest LVOT gradient ≥50 mmHg0.45 (0.08–2.55)0.37
HRP
Exercise MR ≥23.24 (1.22–8.5)0.02
Rest PAPs ≥35 mmHg1.03 (0.98–1.08)0.18
Rest LVOT gradient ≥50 mmHg0.45 (0.08–2.55)0.37

For abbreviations, see legend of Table 1.

Table 3
Open in new tab

Multivariate Cox regression for primary endpoint with stepwise selection

HRP
Exercise MR ≥23.24 (1.22–8.5)0.02
Rest PAPs ≥35 mmHg1.03 (0.98–1.08)0.18
Rest LVOT gradient ≥50 mmHg0.45 (0.08–2.55)0.37
HRP
Exercise MR ≥23.24 (1.22–8.5)0.02
Rest PAPs ≥35 mmHg1.03 (0.98–1.08)0.18
Rest LVOT gradient ≥50 mmHg0.45 (0.08–2.55)0.37

For abbreviations, see legend of Table 1.

Discussion

Main results

Exercise echocardiography, actually used for a better assessment of the functional status of our patients, appeared to provide valuable prognostic information in HCM patients.

Exercise-induced LVOT gradient ≥50 mmHg and significant exercise-induced MR are strong predictors of cardiovascular events. Furthermore, exercise-induced MR was the only echocardiographic parameter associated with hard events such as cardiorespiratory arrests (or equivalent). The other predictor of this hard event in our population was the probability of SCD at 5 years calculated according to the latest ESC guidelines.6

Prognosis value of exercise echocardiography in the literature

In 2006, Maron et al.18 were the first to demonstrate the value of exercise echocardiography in studying LVOTO during exercise. Since, few studies have been published.

In a group of 426 HCM patients, using a composite endpoint of death, appropriate defibrillator discharge and hospitalization for heart failure, Desai et al.,12 showed that the per cent of age–sex–predicted METs (the ratio achieved/predicted) and AF was predictive of outcome. But the authors did not find that any exercise echocardiographic variable was linked to patient outcomes. Following 239 HCM patients for 4 years, Peteiro et al.19 found that in baseline echocardiography, LAD predicted hard events. This relationship between LAD and prognosis has been found in numerous studies before,7,20–22 thus LAD is now included in the recent ESC SCD risk calculation guidelines.6 Our study confirms the predictive value of the LAD. Regarding exercise echocardiography, they found that moderate or greater exercise-induced MR was present in 28% of patients during exercise and was linked to exercise LVOTO. Patients reaching primary endpoints had more significant exercise-induced MR (47 vs. 26%) but this result was not significant (P = 0.05). Wall motion abnormalities (WMAs) were significantly more frequent in patients with hard events (31 vs. 5%, P < 0.01). Myocardial ischaemia could be the explanation of WMAs, as suggested in some studies.23,24 This has been confirmed by this latest study published in 2015 with a similar protocol.25 Following 148 patients for a mean of 7.1 years, Peteiro et al. found that 23% of patients with events had WMA at exercise vs. 6% (P = 0.005) for patients without events. Perfusion defect area and late gadolinium enhancement in CMR were also associated with events. Exercise MR was not linked to events but again, exercise echocardiography was in fact post-exercise as images were acquired immediately after the exercise.

We performed images acquisition during exercise in a semi-supine bicycle and not in the post-exercise of a treadmill test. Indeed, workload tended to be higher with treadmill exercise in comparison with supine bicycle,26 but sensitivity to the detection of ischaemia appeared to be better with peak exercise imaging than with post-exercise imaging.27 Furthermore, when additional Doppler information is desired, supine bicycle exercise offers the advantage that information can be evaluated during exercise. Modesto et al.28 demonstrated that compared with post-exercise image analysis, peak exercise images acquisition was superior in recognizing patients with exercise-induced pulmonary hypertension and MR. In fact, as soon as the exercise is stopped, while inotropism continued for a while, afterload decreases immediately, inducing rapid changes in left and right side heart pressure. These differences between the two exercise-echocardiography protocols can explain the different results. When looking for the highest METs achieved, standard treadmill testing with post-exercise image acquisition should be preferred, but when studying pressure, gradients, and regurgitation, peak imaging should probably be favoured. In the latest ESC HCM guidelines, exercise echocardiography during exercise is recommended.6

In our work, we did not found significant WMAs during exercise and, using recent 2D strain speckle tracking techniques,29 we did not observe that patients with events demonstrated decreased LV systolic function at rest or during exercise. Recently, Reant et al.,30 in 119 HCM patients followed for 19 months, showed that peak exercise LVOT gradient and rest GLS <15% predicted outcomes (mainly dyspnoea or increase in NYHA class). Here, we did not found the independent prognostic value of GLS probably because of the difference in censured events during follow-up. GLS is probably more predictive of heart failure than of rhythmic events.

HCM and MR

MR has been described in patients with HCM since the condition was first described in the 1960s. In 1969, Wigle et al.31 showed that the degree of MR varied directly with the severity of LVOTO and primarily occurred secondary to the LVOTO.

If prognosis significance of exercise-induced MR in secondary MR is noted in the latest ESC guidelines,32 as an increase in MR severity and sPAP that occurs during exercise indicates mitral surgery, there is no dedicated work published, to the best of our knowledge, regarding exercise-induced MR and HCM. Of note, quantitative assessment of MR is challenging in patients with HCM. The PISA-method is highly challenging with a mix between MR and the LVOT aliasing. We thus used only an observer independent and expert careful semi-quantitative assessment of the MR in our study. By the way, this study is the first to show a potential relationship between prognosis and exercise-induced MR. MR, which is a common phenomenon in HCM, has two main aetiologies. SAM and severe LVOT obstruction may result in failure of normal leaflet coaptation and, thus MR. This phenomenon is dynamic in nature and its severity varies with the degree of LVOT obstruction.33 These findings may explain why it is important to evaluate MR at exercise and not only at rest. They also explain the strong association that we found between exercise-induced MR and exercise-induced LVOT gradient. Mitral leaflet morphological abnormalities (such as elongation) or papillary muscle abnormalities also cause MR in HCM.34 Regarding mitral valve morphological abnormalities, Sriram et al.35 showed that bileaflet mitral valve prolapse was associated with life-threatening ventricular arrhythmia.

Thus significant exercise-induced MR may define a group of patient with either a severe LVOT obstruction or morphologic abnormalities who have a higher risk of cardiovascular events.

Limitations

First, this study is limited by the size of the studied population and the fact that the study was performed by only one team. Unfortunately, we observed only a limited number of events during the follow-up. Larger studies with longer follow-up periods are thus needed. As medications were not withdrawn before test, LVOT gradient may have been blunted by the 75.4% of patients who were receiving beta-blockers (interrupting the treatment was judged un-ethical). Exercise-echocardiography protocols are not currently standardized-enough. It is thus, difficult to compare our study and published works. Precise evaluation of exercise-induced MR is challenging because PISA is usually merged with the LVOTO aliasing.

Clinical perspectives

Exercise echocardiography, with patients on their medications, should be considered in the routine implication of HCM, because several recent studies found that peak LVOT gradient ≥50 mmHg is an indicator of worse outcome. Also exercise-induced MR should probably be looked for especially for a best prediction of rhythmic events.

Conclusion

Exercise-induced MR and exercise LVOT gradient ≥50 mmHg may impact outcomes in HCM patients. Exercise-induced MR was the only echocardiographic parameter linked to SCD in our study. MR has several causes in HCM but the strong relationship between exercise-induced MR and LVOTO is confirmed as important.

Acknowledgements

We thank deeply the ‘ligue contre la cardiomyopathie’ for the grant we got to perform the study. Thanks also to Patricia Bouillet for her assistance in following the patients.

Conflict of interest: none declared.

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