Non-obstructive determinants of peak VO2 in hypertrophic cardiomyopathy: implications for therapy beyond gradient reduction

Background Exercise intolerance is a major determinant of quality of life in hypertrophic cardiomyopathy (HCM). Stress echocardiography is often used to detect latent left ventricular outflow tract (LVOT) obstruction, yet exercise capacity reflects integrated cardiovascular performance and may be limited by additional mechanisms. Purpose To evaluate determinants of exercise capacity, defined as peak oxygen uptake (pVO2), in HCM without significant obstruction at rest (LVOTO<50mmhg) using combined cardiopulmonary exercise testing and stress echocardiography (CPET–echo), focusing on chronotropic response and diastolic function in relation to beta-blocker therapy. Methods This multi-center retrospective study included 180 consecutive patients with HCM who underwent symptom-limited CPET-echo between April 2016 and September 2025. LVOT gradients were assessed at rest, during exercise, and during the recovery phase. Chronotropic response was assessed using heart rate reserve (HRR), defined as the proportion of the available heart rate increase achieved from rest to peak exercise. Diastolic function was assessed using echocardiographic indices of left ventricular filling pressure (septal E/e’), with a ratio ≥15 at rest or during stress testing classified as elevated filling pressures. Associations with pVO2 were assessed using multivariable linear regression and interaction testing for beta-blocker use. Results Chronotropic response, assessed across the full range of HRR, was independently associated with pVO2 (+0.06 mL/kg/min per 1% HRR increase, 95% CI 0.01–0.11; p = 0.016). Elevated filling pressures were common (68/169 [40.2%]) and negatively associated with pVO2 (−2.11 mL/kg/min, 95% CI −4.08 to −0.35; p = 0.021), consistent with limited diastolic reserve during exercise. Beta-blocker therapy was used in 98/180 (54.4%) of the cohort, and was associated with worsening chronotropic response (−9.03 HRR%, 95% CI −14.56 to −3.50; p = 0.002). No interaction was observed between beta-blocker use and filling pressure status (p for interaction = 0.227), suggesting that beta-blocker use was not associated with improvements in diastolic function. In a model with chronotropic response and filling pressure status, peak LVOT gradient was not an independent predictor of pVO2 (p = 0.406). However, peak LVOT gradient was associated with a lower proportion of patients with a pVO2 <80%. Conclusion In this CPET–echo cohort of HCM patients without significant obstruction at rest, exercise capacity was primarily related to chronotropic response and diastolic dysfunction. Beta-blocker use was associated with worsening chronotropic performance without evidence of benefit on diastolic function. In the era of myosin inhibitors that can effectively counteract obstructive LVOT gradients, it questions the central role of beta-blocker therapy given its potential adverse effects on chronotropic response without benefits on diastolic function.