Highlights
- Bisoprolol significantly reduced peak oxygen consumption (pVO2) compared to both placebo and verapamil in patients with nonobstructive hypertrophic cardiomyopathy (HCM).
- Verapamil treatment resulted in improved global longitudinal strain (GLS) and a significant reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels.
- Contrary to traditional practice, bisoprolol was associated with a decrease in health-related quality of life scores and an increase in left atrial volume index (LAVI).
- These findings challenge the routine use of beta-blockers as first-line therapy for the nonobstructive phenotype of HCM, suggesting a more favorable physiologic profile for calcium-channel blockers.
Background
Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, characterized by unexplained left ventricular hypertrophy. While obstructive HCM (oHCM) is managed by reducing the left ventricular outflow tract (LVOT) gradient, approximately one-third of patients present with the nonobstructive phenotype (nHCM). In nHCM, the primary drivers of morbidity are diastolic dysfunction, impaired microvascular perfusion, and chronotropic incompetence, leading to symptoms of exertional dyspnea and reduced exercise tolerance.
For decades, beta-blockers and non-dihydropyridine calcium-channel blockers (CCBs) have been the cornerstone of symptomatic management for all HCM patients. However, this practice has largely been extrapolated from oHCM data, where these agents effectively reduce gradients. In nHCM, the evidence base is remarkably thin. There is a critical unmet need to determine whether the negative inotropic and chronotropic effects of these drugs are beneficial or potentially detrimental when no LVOT obstruction is present to counteract.
Key Content
The Triple-Crossover Trial Design
The study by Bjerregaard et al., published in the Journal of the American College of Cardiology (2026), utilized a rigorous randomized, double-blind, placebo-controlled triple-crossover design. This methodology allowed each of the 32 participants to serve as their own control, minimizing the impact of the high inter-individual variability seen in HCM. Patients had to demonstrate markers of disease severity, such as NYHA class ≥II, elevated NT-proBNP, or nonsustained ventricular tachycardia. The treatment arms included target doses of bisoprolol (7.5 mg), verapamil (360 mg), and a matching placebo, with each period lasting at least two weeks at steady-state dosing.
Exercise Capacity and Hemodynamics
The primary outcome was peak oxygen consumption (pVO2), a robust marker of functional capacity and prognosis in heart failure. The results revealed a distinct divergence between the two drug classes:
- Bisoprolol: Reduced pVO2 by 2.5 mL/kg/min compared to placebo (P = 0.002). This represents a clinically significant reduction in aerobic capacity.
- Verapamil: Showed no significant difference in pVO2 compared to placebo (-0.7 mL/kg/min; P = 0.990), essentially preserving exercise capacity.
When comparing the two active treatments, bisoprolol led to a lower pVO2 than verapamil (adjusted mean difference -1.8 mL/kg/min; P = 0.013). While both drugs reduced peak heart rate, the reduction was significantly more pronounced with bisoprolol (-37 beats/min) than with verapamil (-17 beats/min). Interestingly, oxygen consumption at the anaerobic threshold remained unchanged across all groups, suggesting that the primary limitation imposed by bisoprolol occurs at peak exertional levels, likely due to excessive chronotropic restriction.
Biomarkers and Structural Remodeling
The secondary endpoints provided deeper mechanistic insights into how these agents affect the nHCM heart:
- NT-proBNP: Bisoprolol increased NT-proBNP levels by 165 ng/L, whereas verapamil reduced them by 177 ng/L. NT-proBNP is a surrogate for wall stress and filling pressures, suggesting that verapamil may alleviate ventricular wall tension while bisoprolol might inadvertently increase it in the nonobstructive setting.
- Left Atrial Volume Index (LAVI): Bisoprolol treatment was associated with a significant increase in LAVI (+13.0 mL/m²), a marker of chronic diastolic pressure elevation. Verapamil did not significantly alter LAVI.
- Myocardial Function: Verapamil improved Global Longitudinal Strain (GLS) by -1.1% (P = 0.001), indicating an enhancement in systolic deformation. Bisoprolol had no such effect.
Patient-Reported Outcomes
The Kansas City Cardiomyopathy Questionnaire (KCCQ-OSS) was used to assess symptoms and quality of life. Bisoprolol treatment resulted in a 6.6-point reduction in the KCCQ-OSS compared to placebo (P = 0.001), falling below the threshold for a clinically meaningful worsening of symptoms. In contrast, verapamil did not significantly affect the KCCQ score.
Expert Commentary
This trial provides a crucial physiological “reality check” for the management of nonobstructive HCM. The conventional wisdom—that slowing the heart rate always improves diastolic filling—appears to be flawed in the context of nHCM.
Mechanistic Divergence: The detrimental effect of bisoprolol on pVO2 and KCCQ scores likely stems from a combination of severe chronotropic incompetence and an increase in filling pressures. In nHCM, where the stroke volume is often fixed or limited by a small ventricular cavity, the ability to increase heart rate is the primary mechanism for increasing cardiac output during exercise. By aggressively blunting this response, bisoprolol may precipitate a “low-output” state during exertion. Furthermore, the increase in NT-proBNP and LAVI suggests that the negative inotropic effect of beta-blockers might worsen the underlying restrictive physiology.
Verapamil as a Preferred Agent: Verapamil emerged as a more physiologically neutral, or even slightly beneficial, agent. Its ability to improve GLS and reduce NT-proBNP, without compromising pVO2, suggests it may improve myocardial relaxation or microvascular flow without the excessive chronotropic “ceiling” seen with bisoprolol. This aligns with older, smaller studies suggesting that CCBs improve the diastolic filling period in HCM.
Clinical Applicability: These findings suggest that for symptomatic patients with nHCM, verapamil should perhaps be favored over beta-blockers if the goal is to maintain or improve exercise capacity. However, clinicians must still consider individual patient factors, such as the presence of atrial fibrillation (where heart rate control is vital) or concomitant coronary artery disease.
Conclusion
The Bjerregaard et al. triple-crossover trial represents a landmark contribution to the evidence-based management of nonobstructive HCM. It demonstrates that bisoprolol significantly impairs exercise capacity and increases markers of wall stress and left atrial size. Verapamil, conversely, maintains exercise capacity and improves myocardial strain and natriuretic peptide levels. These results argue against the reflexive use of beta-blockers in nHCM and highlight the need for phenotype-specific therapeutic strategies. Future research should focus on whether long-term verapamil therapy can prevent disease progression or improve hard clinical outcomes in this underserved patient population.
References
- Bjerregaard L, Dybro AM, Saaby L, et al. Beta-Blocker (Bisoprolol) vs Calcium-Channel Blocker (Verapamil) in Nonobstructive Hypertrophic Cardiomyopathy: A Randomized Triple-Crossover Physiologic Trial. J Am Coll Cardiol. 2026;87(8):1063-1083. PMID: 41778690.
- Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2020;76(25):e159-e240. PMID: 33223352.
- Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. 2014;35(39):2733-2779. PMID: 25173338.
