Author + information
- Jeffrey B. Geske, MD,
- Thomas G. Allison, PhD and
- Bernard J. Gersh, MB, ChB, DPhil∗ ()
- ↵∗Reprint requests and correspondence:
Dr. Bernard J. Gersh, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Gonda 05, 200 First Street Southwest, Rochester, Minnesota 55905.
- cardiopulmonary stress testing
- hypertrophic cardiomyopathy
- impedance cardiography
- stress echocardiography
In this issue of JACC: Heart Failure, Finocchiaro et al. (1) present a single-center analysis of 156 patients with hypertrophic cardiomyopathy (HCM) who underwent noninvasive hemodynamic assessment inclusive of rest and stress transthoracic echocardiography as well as cardiopulmonary exercise testing (CPET) with impedance cardiography. The authors correlate functional assessment (exercise capacity, maximal oxygen consumption [Vo2], and ventilatory efficiency [VE/Vco2 slope]) with demographic, echocardiographic, and impedance variables. Furthermore, they assess the impact of measured variables on a short-term (mean 27 months) combined outcome of death, transplant, and need for septal reduction therapy (SRT). The authors conclude that peak cardiac index is the primary driver of exercise capacity and that peak Vo2, VE/Vco2 slope, and left atrial volume index are adverse predictors of the specified outcome.
HCM is a phenotypically diverse condition, both anatomically and with regard to symptom presentation. Although inheritance is autosomal dominant, variable expression can result in varying degrees of hypertrophy, differing septal geometry, and predisposition to dynamic left ventricular outflow tract obstruction, even amongst first-degree relatives. While the degree of hypertrophy generally portends an adverse clinical course (with massive hypertrophy a predictor of sudden cardiac death), there is substantial variability in the clinical presentations of the disease. Physicians who frequently care for patients with HCM are not infrequently met with the paradox of an asymptomatic patient with dynamic obstruction and robust hypertrophy or a highly symptomatic patient with minimal hypertrophy. Thus, the question arises: What mechanisms determine functional limitation within HCM?
An empiric approach might lead one to assume that degree of hypertrophy would be the primary determinant of cardiopulmonary limitation given its central role in pathogenesis and diagnosis. However, investigations have failed to demonstrate such a link (2,3). Therefore, in approaching this question, we must recognize that there are critical differences between subsets of patients with HCM. Patients with obstructive physiology have a different mechanism of symptom limitation than those without. In obstructive HCM the main determinants of exercise limitation are systolic, whereas diastolic function is the more critical contributor to decrease in exercise performance in nonobstructive patients (4). In HCM, exercise limitations in systolic function (or more specifically cardiac index) are driven by stroke volume index as opposed to heart rate augmentation (5). Assessment of diastolic correlates of exercise limitation has yielded varied results, with some investigations noting correlations of cardiopulmonary parameters with mitral inflow and tissue annular assessments (2) and others failing to do so (6). This may in part stem from current limitations of noninvasive assessment of filling pressures, as we have previously demonstrated (7,8).
In the present investigation, the authors assess a referral population of HCM patients. 86% of patients at initial presentation did not demonstrate New York Heart Association (NYHA) functional class III symptoms, nearly one-half of patients (47%) were not on beta-blockade at evaluation and only 39% of patients demonstrating a peak Vo2 <80% predicted. The presence of resting obstruction (27%) and provocable obstruction (35%) are similar to our HCM clinic population. Interestingly, a relatively high proportion demonstrated left ventricular systolic dysfunction (8%) and reverse curve septal morphology (53%).
The authors utilized noninvasive cardiac impedance monitoring with CPET for determination of peak cardiac index. This technique involves placement of 2 skin electrodes on the neck, allowing measurement of an impedance signal, which can be translated into thoracic flow (and thus stroke volume). While validated in a general heart failure cohort (9), this is the first application of this diagnostic tool to HCM. The finding that cardiac index (and stroke volume index) is a key determinant of peak Vo2 is once again demonstrated, though the relationship is not straightforward, as cardiac index was significant in the model to predict peak Vo2 only if heart rate was eliminated. This reminds us that cardiac output is equal to the product of stroke volume and heart rate, and that one of these parameters may compensate—or fail to compensate—for an impairment in the other. The authors provide multivariate modeling both inclusive of impedance data and without, which is helpful to see the effect of dynamic systolic changes on determinants of cardiopulmonary parameters, however, provoked left ventricular outflow tract gradient is not considered in these models. The fact that left ventricular systolic, left ventricular diastolic, and right ventricular measures all factor into determination of peak Vo2 underscores the complex interplay of hemodynamic components resulting in functional status. It is likely that reductions in stroke volume, diastolic dysfunction, microcirculatory dysfunction, dynamic left ventricular outflow tract obstruction, and secondary mitral regurgitation all contribute in varying degrees to exercise intolerance.
In consideration of outcome, the authors solely present a combined endpoint of death, transplant, and need for SRT. Interpretation of this data is challenging. The decision to pursue SRT is based on persistent symptoms despite use of optimal medical therapy (10). Despite the limitations of NYHA functional classification, the fact remains that Table 1 in the article by Finocchiaro et al. (1) would suggest a patient population with substantial room for medication optimization. A total of 67% of patients who met the combined outcome were not NYHA functional class III or greater at initial presentation. The decision to pursue SRT was not blinded to CPET results, nor was there adjudication as to whether or not to pursue SRT. It would be interesting to determine how frequently the CPET was repeated with a significant decrease in peak Vo2 used as one of the reasons for moving to SRT. Unlike death or cardiac transplantation, SRT only represents a “hard” adverse outcome if optimal medical therapy has truly failed. Data on need for medication optimization is not presented. Furthermore, need for SRT does not carry the same prognostic value as death or transplantation and thus a combined endpoint is difficult to interpret. With these numerous caveats aside, the authors note reduced indices of cardiopulmonary health as adverse prognostic indicators, which we suspect is correct.
Have we unscrambled the Rubik’s cube that is translation of individual hemodynamic contributors to functional capacity? While the present study provides further insight and addition of impedance monitoring to the noninvasive toolkit has the potential to shape future investigations, much remains to explore. The authors did not consider the issue of adiposity and deconditioning on functional status as determined by peak Vo2; are we missing a key contributor? What influences the symptom threshold in such a dynamic system? Are there alternate noninvasive measures of diastolic function in HCM that we should consider? Can we utilize impedance measures in combination with CPET to help further titrate medical therapies? How do the studied variables affect hard outcomes in the longer term? As with many studies, the results herein generate even more questions. The search for a better understanding of the mechanisms of this fascinating disease promises to be of continued interest.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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