Integrating Cardiopulmonary Exercise Testing and Stress Echocardiography to Predict Clinical Outcomes in Hypertrophic Cardiomyopathy

<b>Background:</b> Hypertrophic cardiomyopathy (HCM) is a heterogeneous myocardial disease in which conventional prognostic models, primarily focused on sudden cardiac death, often fail to identify patients at risk of clinically relevant events such as heart failure progression or rehospitalization. Cardiopulmonary exercise testing (CPET) quantifies functional capacity, while stress echocardiography (SE) provides mechanistic insights into exercise-induced hemodynamic changes. Their combined application (CPET-SE) may enhance risk stratification in patients with HCM. <b>Methods:</b> In this retrospective study, 388 patients with obstructive and non-obstructive HCM (mean age 48 ± 15 years, 63.1% male) underwent baseline CPET-SE between 2010 and 2022 and were followed for a median of 7.4 years [IQR 4.3-10.2]. Echocardiographic parameters were assessed at rest and peak exercise, and CPET indices included peak oxygen consumption (pVO₂), ventilatory efficiency, and anaerobic threshold. The primary outcome was a composite of heart failure hospitalization or progression to end-stage HCM. <b>Results:</b> Over a median follow-up of 7.4 years, 63 patients (16.2%) experienced an event of the primary outcome. Patients who developed a primary outcome had greater left atrial diameter (45.0 vs. 41.0 mm, <i>p</i> < 0.001) and indexed volume at rest (36.4 vs. 29.0 mL/m², <i>p</i> < 0.001), with further dilation during stress (<i>p</i> = 0.046); increased LV wall thickness (<i>p</i> = 0.001); higher average E/e' at rest and during stress (<i>p</i> ≤ 0.004); and higher pulmonary artery systolic pressure at rest (<i>p</i> = 0.027) and during stress (<i>p</i> = 0.044). CPET findings included lower pVO₂ (16.0 vs. 19.5 mL/kg/min, <i>p</i> = 0.001), reduced % predicted pVO₂ (<i>p</i> = 0.006), earlier anaerobic threshold (<i>p</i> = 0.032), impaired ventilatory efficiency (<i>p</i> = 0.048), and chronotropic incompetence (<i>p</i> < 0.001) in patients who experienced a primary outcome. Multivariable analysis identified dyslipidemia (OR 2.58), higher E/e' (OR 1.06), and lower pVO₂ (OR 0.92) as independently associated with the primary outcome. <b>Conclusions:</b> CPET-SE provided a comprehensive evaluation of patients with HCM, associating aerobic capacity to its hemodynamic determinants. Reduced pVO₂ showed the strongest association with adverse outcomes, while exercise-induced diastolic dysfunction and elevated pulmonary pressures identified a high-risk phenotype. Incorporating CPET-SE into longitudinal management of patients with HCM may enable earlier detection of physiological decompensation and guide personalized therapeutic strategies.