Myosin Inhibition in Hypertrophic Cardiomyopathy: A Nuanced Approach
Hypertrophic cardiomyopathy (HCM) is a condition characterized by thickening of the heart muscle. Although significant advances have been made in treating obstructive HCM (oHCM), managing non-obstructive HCM (nHCM) remains a challenge. Recent research, particularly the ODYSSEY-HCM trial, has illuminated a complex picture: biologic improvements can occur without corresponding clinical benefits, highlighting the need for a more nuanced understanding of the disease and its treatment.
Understanding the Landscape of HCM
Traditionally, HCM treatment for symptomatic patients has focused on beta-blockers or non-dihydropyridine calcium channel blockers [1]. However, the remarkable efficacy of cardiac myosin inhibitors in oHCM prompted investigation into their potential role in nHCM. The initial MAVERICK-HCM study showed promising biomarker changes with mavacamten, suggesting potential benefits in nHCM [1].
The ODYSSEY-HCM Trial: Biologic Improvement, Clinical Neutrality
The ODYSSEY-HCM trial, the first phase 3 study evaluating mavacamten in nHCM, involved 580 adults with symptomatic nHCM. Participants had to meet rigorous criteria, including NYHA class II or III symptoms, preserved left ventricular ejection fraction (≥60%), and a left ventricular outflow tract (LVOT) gradient <30 mm Hg at rest and <50 mm Hg with provocation [3]. While mavacamten led to significant reductions in NT-proBNP (58%) and high-sensitivity cardiac troponin I (51%) levels, these biologic improvements did not translate into statistically significant gains in peak oxygen consumption (VO2) or Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) [3], [4].
Why the Disconnect?
Several factors likely explain the discrepancy between biologic response and clinical outcomes. Symptoms in nHCM are multifactorial, stemming from diastolic dysfunction, impaired LV reserve, microvascular ischemia, and other factors. Reducing myosin-actin cross-bridge cycling may not fully address these complex issues. Many patients in the ODYSSEY-HCM trial had long-standing disease with fixed structural remodeling and comorbidities, potentially limiting the impact of reverse remodeling within the study timeframe [3].
Safety Considerations
A notable safety concern in the ODYSSEY-HCM trial was a decline in left ventricular ejection fraction (LVEF) to <50% in 21.5% of patients receiving mavacamten, compared to 1.7% in the placebo group. This necessitated dose interruptions, potentially hindering sustained sarcomere modulation [3], [4].
Aficamten and Ongoing Research
Other myosin inhibitors, such as aficamten, have shown more promising results in oHCM. The REDWOOD-HCM trial demonstrated improvements in NYHA class, NT-proBNP levels, and KCCQ-CSS with aficamten [3]. This has led to the ACACIA-HCM trial, currently evaluating aficamten in symptomatic nHCM [3].
Key Differences Between oHCM and nHCM
It’s crucial to recognize that nHCM is not simply oHCM without a gradient. The symptom drivers and therapeutic responsiveness differ significantly. Myosin inhibitors have consistently demonstrated robust clinical benefits in oHCM, reducing LVOT gradients and improving exercise capacity, whereas their impact in nHCM appears more limited [3].
| Domain | nHCM (Mavacamten/Aficamten) | oHCM (Mavacamten/Aficamten) |
|---|---|---|
| Peak VO2 | +0.47 vs. +0.05 mL/kg/min | +1.4 (mava); +1.8 (afic) |
| KCCQ-CSS | +13 vs. +10 | +11 ± 15 (afic); +12-14 |
| NYHA improvement of at least one class | 55% (afic) | 65% (mava); 63% (VALOR-HCM) |
| NT-proBNP level | -58% (mava) | Improved |
| hs-cTnI level | -51% (mava) | Improved |
| Structural metrics | ↓ WT, ↓ LAVi, ↓ E/e′ | ↓ LVOT gradient |
| LVOT gradient | NA | -36/-47 mm Hg (mava); -55 mm Hg (afic) |
| Need for SRT | NA | 18% vs. 77% (VALOR-HCM) |
| LVEF <50% | 21.5% (mava) vs. 1.7% | Lower incidence |
Current Recommendations
Currently, myosin inhibitors should not be used to treat symptomatic nHCM outside of clinical trials. Guideline-directed management remains focused on beta-blockers and non-dihydropyridine calcium channel blockers, along with management of atrial fibrillation, comorbidities, and cautious diuretic use [3].
The ODYSSEY-HCM results underscore the need for further research into nHCM, including better phenotyping, earlier intervention, longer-duration trials, and combination therapies targeting multiple aspects of the disease.
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