Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease with both variable penetrance and a wide spectrum of phenotypic expression. Although there are several established risk factors for sudden cardiac death and progression to heart failure, these markers individually have low positive predictive value and only modestly high negative predictive value. Although the exact mechanisms are incompletely understood as yet, underlying abnormalities of myocardial architecture are thought to play a role in arrhythmogenesis and left ventricular (LV) remodeling. Alterations in myocardial structure at both macroscopic and microscopic levels predispose to myocardial ischemia, which may be associated with such complications as LV remodeling and progression to systolic dysfunction and heart failure. Myocardial imaging both at rest and during stress provides the opportunity to study alterations in myocardial function resulting from ischemia and abnormal loading conditions and to identify markers of adverse prognosis in these patients.
The Current Role of Exercise Echocardiography in Hypertrophic Cardiomyopathy
Despite the issues raised regarding the safety of exercise testing in patients with HCM in the 2002 American College of Cardiology and American Heart Association guidelines for exercise testing (in which HCM is listed as a relative contraindication), several series have subsequently demonstrated the safety of exercise testing in this patient group. However, concern still exists regarding the safety of exercising patients with high resting LV outflow tract (LVOT) gradients, given that little incremental information would be obtained in such patients. In the recent American College of Cardiology and American Heart Association HCM guidelines, stress testing has a class IIa indication for the quantification of provocable LVOT gradients, for risk stratification for sudden cardiac death, and to assess functional capacity and response to therapy.
Exercise echocardiography may play a role in the detection of occult systolic LV dysfunction, which has been described in 22% to 44% of patients with HCM. The assessment of regional wall motion abnormalities (WMAs) is inherently problematic in patients with HCM who demonstrate heterogeneous patterns of hypertrophy. Systolic thickening has previously been shown to be reduced in hypertrophied segments on cardiac magnetic resonance (CMR) imaging, with an inverse correlation between end-diastolic wall thickness and both systolic thickening and circumferential shortening. Okeie et al. demonstrated exercise-induced systolic dysfunction on echocardiography in up to 50% of patients with HCM, with regional WMAs occurring more frequently in hypertrophied segments. In addition, the global hyperkinesis and small LV cavity volumes frequently seen in these patients with exercise make the detection of WMAs difficult. Interpretation of the wall motion response to stress may be further confounded by the presence of LVOT obstruction and altered loading conditions, which are present on exercise provocation in up to 75% of patients.
Upright treadmill exercise allows the achievement of a greater workload and heart rate response compared with upright bicycle or supine exercise but presents challenges in that data must be recorded within the first minute after exercise to obtain a true indication of peak stress parameters. Given that the indication for exercise echocardiography in HCM is predominantly aimed at documenting peak LVOT gradients with exercise, there is likely to have been a significant decrease in heart rate by the time all images can be obtained for detailed regional wall motion analysis, thereby limiting the sensitivity for detection of regional dysfunction.
The Potential Role of Exercise Echocardiography in Risk Stratification in Hypertrophic Cardiomyopathy
In this issue of JASE , Peteiro et al. report the correlation between exercise echocardiographic parameters and cardiac events in 255 consecutive patients with HCM undergoing exercise echocardiography for the assessment of LV function and LVOT obstruction. Patients with systolic dysfunction (defined as a resting LV ejection fraction < 50%) were excluded from further analysis, as were any patients with either histories of or documented angiographic coronary artery disease. Patients performed standard symptom-limited treadmill exercise, with echocardiography performed at baseline and during the immediate postexercise period. LVOT gradients, the severity of mitral regurgitation, LV ejection fraction, and the 16-segment wall motion score index at peak exercise were compared with baseline values. Cardiac events included cardiac death or transplantation, sustained ventricular tachycardia, an appropriate implantable cardioverter-defibrillator discharge, myocardial infarction, heart failure requiring hospitalization, or a stroke in the setting of atrial fibrillation or flutter. Soft events were defined as syncope or new-onset atrial fibrillation. The mean follow-up period was 4.1 years.
The authors identified exercise-induced WMAs in 19 patients (7.9% of the study population), being global in nature in five and regional in 14 patients. Although both resting and exercise LV ejection fractions were lower in the patients with exercise WMAs, these patients still demonstrated an augmentation of systolic function with exercise. The presence of WMAs appeared unrelated to the degree of LVOT obstruction, blood pressure response to exercise, and degree of LV hypertrophy at baseline.
On multivariate analysis, the authors found four echocardiographic variables to be predictors of hard cardiac events, namely, maximal LV wall thickness, metabolic equivalents, resting wall motion score index, and change in wall motion score index with exercise.
Of note, there were no associations between any of the following parameters and cardiac events: LVOT obstruction, family history of sudden cardiac death, history of syncope, and exercise blood pressure response. The lack of association between LVOT obstruction and cardiac events, which is in contrast to previous studies, may simply be related to the smaller sample size and lower prevalence of provocable LVOT obstruction in the current series.
The authors make no comment on the number of segments excluded from analysis because of suboptimal image quality or the heart rate at which images for wall motion analysis were acquired. Given the difficulties of acquiring data for LVOT gradients, mitral regurgitation, and all apical and parasternal images for wall motion scoring, this may account for the lower prevalence of exercise-induced regional WMAs in the present study. However, bearing in mind that patients with obstructive physiology are prone to ischemia, as discussed in more detail below, the low prevalence of WMAs may be a reflection of the low prevalence of provocable LVOT obstruction in this patient population.
In terms of the markers of poor prognosis identified in the current study, maximal LV wall thickness, resting wall motion score index, and the functional capacity of the patients (as evidenced by workload and metabolic equivalents) can be obtained without the need for imaging at peak stress, which is inherently problematic.
The Potential Role of Exercise Echocardiography in Risk Stratification in Hypertrophic Cardiomyopathy
In this issue of JASE , Peteiro et al. report the correlation between exercise echocardiographic parameters and cardiac events in 255 consecutive patients with HCM undergoing exercise echocardiography for the assessment of LV function and LVOT obstruction. Patients with systolic dysfunction (defined as a resting LV ejection fraction < 50%) were excluded from further analysis, as were any patients with either histories of or documented angiographic coronary artery disease. Patients performed standard symptom-limited treadmill exercise, with echocardiography performed at baseline and during the immediate postexercise period. LVOT gradients, the severity of mitral regurgitation, LV ejection fraction, and the 16-segment wall motion score index at peak exercise were compared with baseline values. Cardiac events included cardiac death or transplantation, sustained ventricular tachycardia, an appropriate implantable cardioverter-defibrillator discharge, myocardial infarction, heart failure requiring hospitalization, or a stroke in the setting of atrial fibrillation or flutter. Soft events were defined as syncope or new-onset atrial fibrillation. The mean follow-up period was 4.1 years.
The authors identified exercise-induced WMAs in 19 patients (7.9% of the study population), being global in nature in five and regional in 14 patients. Although both resting and exercise LV ejection fractions were lower in the patients with exercise WMAs, these patients still demonstrated an augmentation of systolic function with exercise. The presence of WMAs appeared unrelated to the degree of LVOT obstruction, blood pressure response to exercise, and degree of LV hypertrophy at baseline.
On multivariate analysis, the authors found four echocardiographic variables to be predictors of hard cardiac events, namely, maximal LV wall thickness, metabolic equivalents, resting wall motion score index, and change in wall motion score index with exercise.
Of note, there were no associations between any of the following parameters and cardiac events: LVOT obstruction, family history of sudden cardiac death, history of syncope, and exercise blood pressure response. The lack of association between LVOT obstruction and cardiac events, which is in contrast to previous studies, may simply be related to the smaller sample size and lower prevalence of provocable LVOT obstruction in the current series.
The authors make no comment on the number of segments excluded from analysis because of suboptimal image quality or the heart rate at which images for wall motion analysis were acquired. Given the difficulties of acquiring data for LVOT gradients, mitral regurgitation, and all apical and parasternal images for wall motion scoring, this may account for the lower prevalence of exercise-induced regional WMAs in the present study. However, bearing in mind that patients with obstructive physiology are prone to ischemia, as discussed in more detail below, the low prevalence of WMAs may be a reflection of the low prevalence of provocable LVOT obstruction in this patient population.
In terms of the markers of poor prognosis identified in the current study, maximal LV wall thickness, resting wall motion score index, and the functional capacity of the patients (as evidenced by workload and metabolic equivalents) can be obtained without the need for imaging at peak stress, which is inherently problematic.
Mechanisms for Wall Motion Abnormalities in Hypertrophic Cardiomyopathy
The underlying pathophysiology of WMAs in HCM is likely to be multifactorial in any individual patient.
Myocardial Ischemia
LV hypertrophy is known to compromise coronary blood flow reserve, occurring first in the subendocardial layer, and has been demonstrated as an underlying mechanism for angina in patients with aortic stenosis and normal coronary arteries. Impairment of myocardial blood flow in HCM is multifactorial, occurring as a result of the increased myocardial oxygen demand of the hypertrophied myocardium, in addition to structural abnormalities such as myocyte disarray, increased interstitial fibrosis, small-vessel narrowing, and reduced capillary density. Abnormalities of myocardial perfusion have been demonstrated to be common in HCM using 201 Tl scintigraphy, in positron emission tomographic studies using dipyridamole, and on CMR stress imaging. Using CMR imaging to assess perfusion, not only is there a greater reduction in myocardial blood flow in the subendocardial layer than the subepicardial layer, but also there is a relationship between the degree of abnormal perfusion and the magnitude of LV hypertrophy. In addition, the presence of myocardial bridging (tunneling of the coronary artery within the myocardium), particularly of the left anterior descending coronary artery, is a clinical feature of HCM that may be associated with myocardial ischemia in the absence of epicardial coronary artery disease. Myocardial bridging has been found to be present in 15% of patients in angiographic series and 40% at autopsy. Just as myocardial ischemia is responsible for stress-induced WMAs in coronary artery disease, it is likely that myocardial ischemia is the prominent underlying cause of WMAs on stress testing in HCM.
LVOT Obstruction
Numerous studies have assessed the effects of LVOT obstruction on hemodynamics and myocardial metabolic efficiency in patients with HCM. Compared with patients with nonobstructive HCM, the presence of LVOT obstruction has been shown to be associated with higher basal coronary flow and myocardial oxygen consumption, with transmural coronary flow reserve exhausted at heart rates of 130 beats/min. In addition, the markedly increased LV intracavitary pressures, oxygen requirements, and abnormal loading conditions lower the ischemic threshold further. Surgical relief of LVOT obstruction has been shown to result in improvement or normalization of myocardial perfusion in the majority of patients with reversible perfusion defects along with a decrease in intracavitary pressures.
Diastolic Dysfunction
The origin of diastolic dysfunction is multifactorial, with changes occurring at the molecular, myocardial tissue, and global LV levels. The hypertrophied left ventricle is markedly susceptible to ischemia-induced diastolic dysfunction. At increasing heart rates, the resultant decrease in diastolic filling period results in an increase in diastolic intracavitary pressure, which may result in subendocardial ischemia, creating a vicious cycle of worsening diastolic function. In addition, the reduction in preload reserve seen in these patients may also contribute to the onset of ischemia and stress-induced WMAs.
Late Gadolinium Enhancement
Late gadolinium enhancement (a surrogate marker for the presence of fibrosis) is an important phenotypic characteristic of HCM, with a prevalence of about 50% to 77% in unselected cohorts. The presence of late gadolinium enhancement on CMR imaging has been found to be associated with the presence of both perfusion abnormalities and resting and exercise induced WMAs.
There is a complex interplay of the above disturbances, many of which coexist within any individual patient. The presence of late gadolinium enhancement is likely to account for regional disturbances of myocardial function at rest, with the common pathway of myocardial ischemia accounting for the presence of stress-induced WMAs.
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