Author + information
- Harry Rakowski, MD∗ ( and )
- Qin Li, MD
- Division of Cardiology, Peter Munk Cardiac Center, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- ↵∗Reprint requests and correspondence:
Dr. Harry Rakowski, Division of Cardiology, Toronto General Hospital, Peter Munk Cardiac Center, 4N-504, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada.
Hypertrophic cardiomyopathy (HCM) is a heterogeneous inherited cardiac condition that affects 0.2% of the general population (1). It is typified by a hypertrophied nondilated left ventricle (LV) with resting or provocable LV outflow tract (OT) obstruction, observed in up to two-thirds of patients (2). Significant efforts have been made in the past 2 decades to identify predictors of adverse clinical outcomes such as sudden cardiac death, heart failure, and stroke. These have included advanced imaging to quantitate the location and degree of hypertrophy and myocardial fibrosis, genetic testing, detection of ventricular and atrial arrhythmias, and assessment of blood pressure response to exercise. Despite the value of conventional risk stratification, we continue to be humbled by patients who appear to have a low-risk profile and few cardiac symptoms yet present with devastating outcomes.
Exercise Intolerance in HCM
Although many patients with HCM have minimal symptoms with near-normal life expectancy, many experience exercise limitations due to dyspnea, chest pain, pre-syncope or syncope, which may be debilitating. Symptoms may be due to myocardial ischemia, diastolic or systolic dysfunction, LVOT obstruction, atrial fibrillation (AF), or mitral regurgitation. Histologically, HCM is characterized by myocyte hypertrophy and disarray, interstitial fibrosis, as well as small vessel narrowing along with reduced capillary density (3). Such changes, coupled with increased myocardial oxygen demand due to LV hypertrophy, can result in a supply–demand mismatch, compromising endocardial blood flow and leading to ischemic symptoms. This is supported by studies in myocardial perfusion using 201Tl scintigraphy, positron emission tomography using dipyridamole, and cardiac magnetic resonance stress testing.
Diastolic dysfunction is a well-recognized cause of symptoms in HCM patients, regardless of the presence of obstruction, and likely reflects increased myocardial stiffness. Echocardiographic Doppler indices and myocardial mechanics are often abnormal, including increased E/E′ ratio, elevated left atrial volume, as well as prolonged time for LV untwisting and lower apical reverse rotation fraction on diastolic strain analysis (4). Markers of diastolic dysfunction correlated with lower peak Vo2 on exercise testing and worse New York Heart Association functional class (4,5). Increased heart rate in response to exercise can further shorten diastole, impairing LV filling. Resting LVOT obstruction occurs in 25% to 30% of patients, and up to two-thirds of all HCM patients have significant LVOT obstruction after provocation with Valsalva and/or exercise. However, some patients with very high LVOT gradients may be relatively asymptomatic, whereas others with lower gradients can be quite symptomatic. Thus, there is a complex interplay of factors causing symptoms in HCM patients.
Current Evidence for Using Stress Echocardiography in HCM Patients
The number of metabolic equivalents (METs) achieved and abnormal heart rate recovery (HRR) were predictive of survival in large population studies in non-HCM patients (6–8). In patients with HCM, exercise testing is useful for provoking latent obstruction by reduction of preload in the upright position and augmentation of LV contractility, detecting abnormal blood pressure response during exercise and exercise-induced ventricular arrhythmias (2). Thus, stress testing is a Class IIa indication for the quantification of provocable LVOT gradient, risk stratification of sudden cardiac death, and assessment of functional capacity and response to therapy (2).
Exercise Capacity and Outcome in HCM Patients
In this issue of iJACC, Desai et al. (9) report that in asymptomatic or minimally symptomatic HCM patients, the percent of predicted METs, abnormal HRR, and AF independently predicted adverse clinical outcomes. They studied a total of 426 patients over a 10-year period in a large HCM referral center, with a mean follow-up period of 8.7 ± 3.0 years. Patients with reduced ejection fraction <50%, valvular heart disease, those undergoing invasive therapies, and those with HCM of the elderly were excluded. Overall, there were 116 (27%) nonobstructive patients, 280 (66%) obstructive patients, and 30 (7%) patients with apical HCM. There were only 52 outcome events, which represents a linear rate of <1.5%/year, confirming that this was a relatively healthy cohort. There were no significant endpoint differences due to LVOT obstruction, but only relatively healthy patients were studied and the event rate was low. Thus, despite a good sample size, the study may be underpowered to draw this conclusion. However, importantly, there was a significant difference in combined outcome (death, appropriate implantable cardioverter-defibrillator discharges, congestive heart failure requiring hospital stay) between groups of patients who, on exercise testing, achieved different levels of METs (>100%: n = 76 [18%]; 85%–100%: n = 82 [19%]; and <85%: n = 268 [63%]). Despite being asymptomatic or minimally symptomatic, 82% of patients failed to achieve age-sex predicted METs, suggesting that over time, many patients accepted a lower functional status without fully appreciating their limitations. The event rates were 1% for patients achieving >100% predicted METs and remarkably 12% for those achieving <85% of predicted METs. In addition, abnormal HRR and AF were also independent predictors of adverse clinical outcome (p < 0.001). Potentially important information such as scar burden quantified by cardiac magnetic resonance and more sophisticated measures of diastolic function were not available, which is an important study limitation. The findings by Desai et al. (9) are in agreement with previous stress echocardiographic studies. Sorajia et al. (10) demonstrated that in minimally symptomatic patients with obstructive HCM, a <60% predicted peak myocardial O2 consumption was associated with only a 59% 4-year survival free of death and severe symptoms. Peteiro et al. (11) demonstrated that neither resting nor exercise-induced LVOT gradients correlated with the combined endpoints of cardiac death, transplantation, appropriate implantable cardioverter-defibrillator discharge, stroke, myocardial infarction, or heart failure. Interestingly, exercise-induced wall motion abnormalities and METs achieved were predictive of adverse outcomes, suggesting that myocardial ischemia may be an important factor in determining functional capacity and clinical outcome. In the current study (9), AF was also a predictor of adverse clinical outcome, underscoring the importance of educating patients about recognizing AF and treating it with anticoagulation to prevent embolic stroke. There may also be intrinsic abnormalities in the way patients with HCM respond to exercise, as evidenced by the abnormal vagal reactivation and abnormal HRR.
The cause of reduced exercise capacity in HCM patients is multifactorial and likely involves the interplay of myocyte hypertrophy and disarray, interstitial fibrosis, microvascular ischemia, diastolic dysfunction, and reduced systolic reserve. As we continue to search for therapies that may delay or arrest the development of hypertrophy and fibrosis, it is important to identify patients at higher risk of devastating adverse clinical outcomes. Exercise testing is a safe and effective way to assess patients' true functional status and provides incremental information about long-term prognosis even when patients are minimally symptomatic. As we evaluate more complex testing to determine prognosis in HCM, simple stress testing remains a very important predictor of both functional capacity and outcome. The study by Desai et al. (9) reminds us of the value of going back to the basics in the risk stratification of patients with HCM.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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