BACKGROUND Randomized evidence supporting treatment with beta-blockers and calcium antagonists in nonobstructive hypertrophic cardiomyopathy (HCM) is absent.
OBJECTIVES The authors sought to analyze the effect of bisoprolol and verapamil treatment in nonobstructive HCM in a randomized, double-blinded, placebo-controlled triple-crossover trial.
METHODS Nonobstructive HCM patients with $1 marker of disease severity (NYHA functional class $II, N-terminal pro– B-type natriuretic peptide [NT-proBNP] >300 ng/L, or documented nonsustained ventricular tachycardia) were included. Each patient underwent 3 treatment periods with target doses of 7.5 mg bisoprolol, 360 mg verapamil, and placebo. Outcomes were evaluated after 2 weeks on steady-state treatment. The primary outcome was peak oxygen consumption (pVO 2 ). In addition, exercise response, symptom, biomarker, structural, and myocardial changes were evaluated.
RESULTS Thirty-two patients (34% women) aged 54 ± 15 years were included. The pVO 2 was 25.7 ± 8.7 mL/kg/min with bisoprolol, 28.2 ± 8.6 mL/kg/min with verapamil and 28.7 ± 8.7 mL/kg/min with placebo. The adjusted mean difference in pVO 2 was 1.8 mL/kg/min (P = 0.013) bisoprolol vs verapamil, 2.5 mL/kg/min (P = 0.002) bisoprolol vs placebo and 0.7 mL/kg/min (P = 0.990) verapamil vs placebo. The peak heart rate was lower with bisoprolol ( 37 beats/min; P < 0.001) and with verapamil ( 17 beats/min; P < 0.001) compared with placebo. Neither bisoprolol nor verapamil changed the oxygen consumption at anaerobic threshold or the minute ventilation/CO 2 production slope. Global longitudinal strain was improved by verapamil ( 1.1%; P = 0.001) but unchanged by bisoprolol ( 0.6%; P = 0.263) compared with placebo. Compared with placebo, treatment with bisoprolol reduced Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS; 6.6 points; P = 0.001), increased NT-proBNP (+165 ng/L; P = 0.006), increased left atrial volume index (LAVI; +13.0 mL/m 2 ; P < 0.001), and increased tricuspid regurgitation (TR) pressure gradient (+4.3 mm Hg; P = 0.049). Treatment with verapamil did not change KCCQ-OSS ( 2.3 points; P = 0.668), LAVI (+5.2 mL/m 2 ; P = 0.194), or TR pressure gradients (+1.1 mm Hg; P = 1.000), but reduced NT-proBNP ( 177 ng/L; P < 0.001) compared with placebo. NYHA functional classification was unchanged by treatments.
CONCLUSIONS In nonobstructive HCM, treatment with bisoprolol reduced pVO 2 , whereas it was unchanged with verapamil. There were a number of significant differences in exercise response, structural changes, myocardial function, symptoms, and biomarkers. This study provides new insights into the mechanisms of these drugs that might be taken into consideration in management of nonobstructive HCM. (JACC. 2026;87:1063–1083) © 2026 by the American College of Cardiology Foundation.
Editors
Editor-in-Chief
Harlan M. Krumholz, MD, SM, FACC
CME Editor
Ragavendra R. Baliga, MD
Author
Louise Bjerregaard, MD, PhD
Important Dates
Date of Release: March 3, 2026
Term of Approval/Date of CME/MOC Expiration: March 2, 2027