In patients with hypertrophic cardiomyopathy, metabolic stress testing has been shown to quantify disease limitations, to differentiate between hypertrophic cardiomyopathy and athletic hearts, and has shed light on the determinants of functional limitation. In this editorial, the authors contextualize the findings reported by Sorajja et al in this issue of The American Journal of Cardiology within the existing published research on the use of metabolic stress testing. Additionally, the authors address study findings that have implications on our understanding of the natural history of the disease. Finally, the authors emphasize the value of routine use of metabolic stress testing in the evaluation and management of hypertrophic cardiomyopathy.

Metabolic stress testing (CPX) combines maximal exercise testing with breath-by-breath measurement of oxygen uptake (V o ₂ ), carbon dioxide output, and ventilation. This approach allows quantification of exertional limitation and determination of the causes of that limitation, be they cardiac, respiratory, skeletal muscle, or a combination thereof. CPX has long been recognized as a critical tool in the prognostic assessment of patients with advanced heart failure and left ventricular systolic dysfunction. To date, in patients with hypertrophic cardiomyopathy (HC), CPX has been shown to effectively differentiate between HC and athletic hearts, to objectively quantify disease limitations, and has shed light on the determinants of functional limitation.

Sharma et al investigated the use of CPX in differentiating HC from athletic hearts. Eight athletic men with genetically proved HC (left ventricular wall thickness 13.8 mm) were compared to 8 elite athletes whose left ventricular wall thicknesses were deemed to be in the “gray zone” (mean 13.4 mm). A peak V o ₂ (pV o ₂ ) >50 ml/kg/min or >20% of the predicted peak fully discriminated between the 2 groups. In a second study, the same group evaluated 135 consecutive patients with HC using CPX to assess the determinants of functional limitation. Ninety-eight percent were limited to pV o ₂ <80% of predicted, with <1.5% outperforming their predicted pV o ₂ . In this cohort, New York Heart Association classes I, II, and III were correlated loosely with pV o ₂ , with average percentage predicted pV o ₂ of 70%, 56%, and 35%, respectively. Interestingly, the most important determinants of functional limitation on multivariate analysis were left ventricular outflow tract (LVOT) gradient, abnormal blood pressure response to exercise (mediated by abnormal peripheral vascular and splanchnic flow regulation), and chronotropic incompetence. Supporting the association of severe LVOT obstruction with reduced pV o ₂ , studies have consistently demonstrated improvement in pV o ₂ after septal modification therapy (transcatheter and surgical).

Although these data describe broad utility of CPX in the management of HC, the prognostic value of CPX in HC has not been directly explored until now. In this issue of The American Journal of Cardiology , Sorajja et al address this issue. Using retrospective data from a cohort of minimally symptomatic patients with varying degrees of obstruction, the investigators identify percentage pV o ₂ cutoffs that predict adverse clinical events (high risk: <60% predicted pV o ₂ ; moderate risk: 60% to 80% predicted pV o ₂ ; and low risk: >80% predicted pV o ₂ ). Those at highest risk had 4-year event-free survival of only 58.5%, whereas those in the low-risk group had event-free survival of 85.4%. The investigators suggest that patients in the high-risk group, those with pV o ₂ <60% predicted, may benefit from increased frequency of clinical follow-up.

Although these data are a compelling addition to the evidence for routine use of CPX in the assessment of patients with HC, they also raise important questions about the natural history of HC and the determinants of limitation in this disease. By study definitions, approximately 1 in 4 minimally symptomatic patients experienced significant adverse events during approximately 4 years of follow-up. This relatively high event rate cannot be readily explained by progression of hypertrophy, because in most patients with HC, the development of hypertrophy occurs during adolescence or early adulthood. Other than the occurrence of a natural inflection point in disease progression in late middle age, what factors might explain this finding?

Selection bias is known to play an important role in the perception of the natural history of HC, so it is worth asking whether adverse events in the present study reflect the fact that sicker patients are primarily referred for evaluation and CPX. Are Sorajja et al’s patients sicker than the usual HC patient? On the basis of other available data, this does not seem to be the case. Elliott et al compared the natural history of a cohort of >900 unselected patients with HC (obstructive and nonobstructive) at a single large HC center. The average percentage pV o ₂ attained was 71.5% in this cohort, compared to 75% in the present study. The mortality rate over nearly equivalent follow-up was 12% in Elliott et al’s cohort, compared to 10% in the present study. Interestingly, Elliott et al then compared the natural history of HC in studies published during the 1990s with those published >10 years previously. Survival appeared to improve over time, reflecting decreased referral bias and the implementation of routine use of implantable cardioverter-defibrillator therapy in those at highest risk.

The development of severe symptoms accounted for most events. This end point is subject to patient expectation and disease duration and is therefore difficult to interpret in relation to clinically important decompensation. In clinical practice, the difference between class II and class III symptoms can be slight, and interphysician assessment may not be reproducible. Additionally, there is inherently a good deal of wobbliness in the symptoms of patients with dynamic obstruction. Those with stable disease may experience occasional exacerbation on the basis of hydration status, episodic exertion (e.g., snow shoveling in the winter), and vasodilatory state (e.g., a few glasses of wine with a big dinner). In this setting, an isolated episode of class III or even class IV heart failure or angina does not represent important disease progression or morbidity. Although not feasible, exercise V o ₂ data in patients during symptomatic events would shed important light on these issues.

What of the determinants of adverse events? Using multivariate analysis, the investigators demonstrate that both LVOT gradient and pV o ₂ independently predict events. This is consistent with previous data indicating that LVOT gradient is neither the sole nor in many cases the most important determinant of exertional limitation. Although the investigators chose to include only those patients with HC with obstruction, these data strongly suggest that obstruction is not the primary driver of adverse events in an important proportion of patients with obstructive HC. Indeed, our expectation would be that examination of patients with nonobstructive HC would yield similar results.

Publication of this study comes at an important time. Updated guidelines on the care of HC have been released just recently by the American College of Cardiology and the American Heart Association. In these guidelines, the authors write that “the role of CPX (i.e., determination of maximum oxygen consumption) in the routine evaluation of patients with [hypertrophic cardiomyopathy] remains to be decided, particularly with regard to clinical outcome.” Even before the release of this study, our view has been that CPX provides important, clinically relevant data in the assessment and management of patients with HC. This study solidifies the role for routine use of CPX in the evaluation and management of HC.