Background: Myosin inhibitor therapy, has emerged as a new treatment option for hypertrophic obstructive cardiomyopathy (HoCM), directly targeting the underlying hypercontractility by reducing excessive actin-myosin cross-bridge formation. β-blockers) remain the standard first-line treatment, yet they are frequently associated with chronotropic incompetence and reduced exercise capacity, in patients with heart failure with preserved ejection fraction. The aim of this study is to investigate whether withdrawal of β-blockers improves symptoms and exercise capacity in HoCM patients on combined β-blocker and mavacamten therapy with persistent symptoms and chronotropic limitation.
Methods: In this ongoing single-arm, prospective study, we enroll adult patients with HoCM who are treated with a combination of a β-blocker and mavacamten, have a peak LVOT gradient <30 mmHg and chronotropic incompetence (defined as a chronotropic index [the ratio of achieved to predicted heart-rate reserve during cardiopulmonary exercise testing] below 0.62). After baseline assessment, β-blockers are tapered over the period of one week and a 4-week follow-up, consisting of transthoracic echocardiography, cardiopulmonary exercise testing and measurement of biomarkers is conducted. Functional capacity is evaluated using the NYHA classification. Data are presented as median and interquartile range (IQR) non-parametric Wilcoxon signed-rank test was used for group comparison.
Results: A total of 11 patients (median age 52 years [44-65], 100% male) were enrolled so far, of whom 8 completed the 4-week follow-up. Three participants restarted β-blocker therapy prematurely, either on their own initiative or in consultation with their general practitioner, because of dizziness, rebound tachycardia, or worsening dyspnea. Among the 8 patients who completed follow-up, at baseline the majority (87.5%) was in NYHA class II, and the median LVOT peak gradient was 14 mmHg (9.5-20.8) at baseline. Four weeks after β-blocker withdrawal, heart rate at rest increased from 72 (64-75) to 86 beats/min (76-99; p = 0.008). The chronotropic index increased significantly from 0.44 (0.38-0.51) to 0.70 (0.63-0.81; p = 0.008), corresponding to a median improvement of 0.26. The proportion of patients with persistent chronotropic incompetence decreased from 100% to 25%. Median peak VO₂ rose from 18.8 (17.3-20.7) to 21.8 mL/kg/min (19.3-24.1; p = 0.055), indicating a strong trend toward improved exercise capacity. Resting and provoked LVOT gradients remained unchanged (rest 7.0 [5.8-11.5] vs 9.0 [5.0-10.3] mmHg, p = 0.61; peak 14.0 [9.5-20.8] vs 14.0 [10.0-16.8] mmHg, p = 0.95). NYHA class improved in 2 patients, worsened in 1, and was unchanged in 5 (p = 0.56). PetCO₂ and NT-proBNP did not change significantly.
Conclusions: In patients with HoCM and chronotropic incompetence treated with mavacamten, withdrawal of β-blocker therapy was feasible and associated with a significant improvement in chronotropic competence and a trend toward higher exercise capacity, without an increase in LVOT gradients. However, some patients required reinitiation of β-blocker therapy due to worsening symptoms. These preliminary findings suggest that mavacamten monotherapy may be a viable strategy in selected patients, warranting confirmation in larger, controlled studies.
