Unmasking mechanisms of symptomatic burden in hypertrophic cardiomyopathy using exercise CMR

Background Hypertrophic cardiomyopathy (HCM) is the most common monogenic cardiac disease. Following advances in sudden cardiac death prevention, reducing limiting symptoms has become a key therapeutic goal, as nearly half of patients experience functional impairment. Although left ventricular (LV) outflow tract (LVOT) obstruction is frequently a major contributor to symptoms, clinical presentation is often discordant with both the presence and the severity of obstruction. Purpose To determine whether exercise MRI identifies mechanisms associated with higher symptomatic burden in HCM. Methods Between 2023 and 2026, patients with obstructive or nonobstructive HCM from three academic centers were prospectively enrolled. Patients with more than moderate valvular disease, prior septal reduction therapy, or myosin inhibitor therapy were excluded. Symptom burden was assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ). Obstructive HCM was defined as LVOT gradient ≥30mmHg at rest or provocation. Exercise imaging was performed in a 3T MRI-Scanner using a supine bicycle ergometer with a symptom-adapted ramp protocol (Figure 1A). Biventricular volumes were quantified by real-time MRI. Resting function and exercise reserve were compared between patients with low (KCCQ ≥75) and moderate/high (KCCQ <75) symptom burden. Multivariable regression assessed associations between exercise parameters and KCCQ and a cubic spline was fitted for independent predictors. Results The final cohort included 72 patients (63±10 years; 42% female, 43% non-obstructive HCM). Mean KCCQ-OSS was 84; 20 patients (28%) had KCCQ<75. Patients with higher symptom burden were younger and more frequently had obstructive HCM, although magnitude of gradients, wall thickness, and biventricular function did not differ (Table 1). During exercise, patients with less symptoms burden had larger increases in stroke volume (SV) (18+/-11 vs 5+/-8) driven predominantly by a greater reduction in LV end-systolic volume (LVESV) (−11.7±8.2%), whereas more symptomatic patients had less stroke volume augmentation driven by a paradoxical increase in LVESV (+7.0±10.0%; p < 0.001), indicating impaired contractile reserve, blunted SV and LV ejection fraction augmentation. RV SV augmentation was preserved in less symptomatic patients (+22.7±16.0%) but reduced in symptomatic patients (+14.2±12.3%; p = 0.004), consistent with biventricular limitation. In multivariable analysis adjusting for age, sex, wall thickness, LVOT gradient, beta-blocker therapy, and heart rate increase, LVESV percentage change during exercise independently predicted worse KCCQ (β = −1.04 per 1% increase; p<0.001, Figure 1B). Conclusion Paradoxical LVESV augmentation during exercise, reflecting impaired systolic reserve, is strongly associated with symptomatic burden independent of obstruction or wall thickness, underscoring the role of dynamic contractile reserve in symptom generation.