Echocardiographic Remodeling and Atrial Dynamics with Mavacamten in Nonobstructive Hypertrophic Cardiomyopathy: Insights from the ODYSSEY-HCM Trial

Highlights

• Mavacamten, a first-in-class cardiac myosin inhibitor, demonstrated significant structural and functional improvements in patients with symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM).
• The treatment resulted in a placebo-corrected reduction in maximal left ventricular (LV) wall thickness (-2.1 mm) and LV mass index (-3.8 g/m²), indicating favorable cardiac remodeling.
• Markers of diastolic function (E/e’ ratio) and left atrial (LA) mechanics (strain and volume) improved significantly, suggesting reduced intracardiac filling pressures.
• While systolic function generally remained preserved in responders, 21.5% of the mavacamten group experienced an LVEF drop below 50%, highlighting the need for vigilant echocardiographic monitoring.

Background

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease, characterized by unexplained left ventricular hypertrophy (LVH), myocardial disarray, and fibrosis. While much of the recent therapeutic focus has been on the obstructive phenotype (oHCM), where mavacamten is already FDA-approved, the nonobstructive phenotype (nHCM) represents approximately one-third of the HCM population and remains a significant therapeutic challenge. Patients with nHCM suffer from debilitating symptoms of dyspnea, exercise intolerance, and chest pain, primarily driven by severe diastolic dysfunction and increased filling pressures rather than outflow tract obstruction.

Symptomatic nHCM has historically lacked evidence-based, disease-specific therapies. Conventional treatments like beta-blockers or calcium channel blockers focus on symptom management through heart rate control but do not address the underlying pathophysiology of sarcomeric hypercontractility. The ODYSSEY-HCM trial (NCT05582395) was designed as the largest phase 3 study to evaluate mavacamten in this specific population. Although the primary functional endpoints (pVO2 and KCCQ scores) did not reach statistical significance in the main trial, this exploratory echocardiographic analysis provides critical insights into the drug’s biological impact on cardiac structure and hemodynamics.

Key Content

Study Population and Methodological Approach

The ODYSSEY-HCM trial randomized 580 symptomatic nHCM patients (mean age 56 years) to receive either mavacamten or placebo for 48 weeks. Mavacamten was initiated at 5 mg/day and titrated (1–15 mg) based on site-read left ventricular ejection fraction (LVEF). Comprehensive echocardiographic assessments were performed at core labs, focusing on three domains: LV geometry, diastolic performance, and left atrial (LA) function. At baseline, the cohort exhibited significant hypertrophy (max wall thickness 20.8 mm) and impaired global longitudinal strain (GLS -13.2%), typical of advanced nHCM.

Regression of Left Ventricular Hypertrophy

One of the most striking findings of the 48-week analysis was the significant reduction in myocardial mass and thickness. The placebo-corrected treatment difference showed a reduction of -2.1 mm in maximal LV wall thickness and -3.8 g/m² in LV mass index. In the context of a genetic cardiomyopathy, where hypertrophy is traditionally considered progressive or static, these findings suggest that inhibiting the excess actin-myosin cross-bridging can lead to actual anatomical regression of the hypertrophic phenotype. This aligns with the “unloading” hypothesis seen in prior oHCM trials (EXPLORER-HCM), but confirms that the effect is independent of the presence of a gradient.

Enhancement of Diastolic and Atrial Function

In nHCM, the primary driver of heart failure symptoms is the inability of the ventricle to relax and fill at low pressures. The ODYSSEY-HCM data showed a significant placebo-corrected improvement in the average E/e’ ratio (-1.3), a surrogate for LV filling pressure. Furthermore, LA function, which acts as a barometer for chronic LV diastolic stress, showed marked improvements:

• LA Strain: Significant increases in both contractile and conduit strain were observed.
• LA Volume: In patients without atrial fibrillation, the LA volume index decreased by 2.6 mL/m², indicating a reduction in the chronic hemodynamic load on the atrium.

These changes suggest that mavacamten improves myocardial compliance, allowing for better reservoir and conduit function of the left atrium.

Systolic Function and Safety Signals

The mechanism of mavacamten—reducing the number of active myosin-actin cross-bridges—inherently carries a risk of reducing systolic force. The trial observed a mean LVEF reduction of 5.3% in the mavacamten arm. Crucially, 21.5% (62 patients) in the treatment arm experienced a drop in LVEF to <50%, compared to only 1.7% in the placebo arm.

However, the analysis provides two important caveats:
1. Reversibility: All instances of LVEF reduction recovered following drug interruption, consistent with the reversible nature of cardiac myosin inhibition.
2. True Contractility: In patients who maintained an LVEF ≥50%, there was actually an improvement in LV-global longitudinal strain (GLS) by -0.4%. This suggests that for many patients, the drug optimizes the efficiency of contraction rather than merely depressing it.

Expert Commentary

The exploratory results of ODYSSEY-HCM present a complex clinical picture. On one hand, the echocardiographic data are objectively positive: mavacamten clearly achieves “reverse remodeling” of the ventricle and improves atrial dynamics. On the other hand, the failure of the primary functional endpoints (pVO2) in the main trial suggests a dissociation between anatomical improvement and short-term functional gain in nHCM.

From a mechanistic perspective, nHCM might represent a more advanced stage of myocardial fibrosis compared to oHCM, where mechanical relief of a gradient provides immediate symptomatic benefit. In nHCM, the regression of hypertrophy and improvement in filling pressures may require a longer duration than 48 weeks to translate into measurable improvements in aerobic capacity.

Furthermore, the 21.5% incidence of LVEF <50% is substantially higher than the ~5% seen in oHCM trials. This suggests that the "therapeutic window" in nHCM may be narrower. Clinicians must weigh the benefit of structural remodeling against the risk of transient systolic dysfunction. The current findings reinforce the necessity of strict REMS (Risk Evaluation and Mitigation Strategy) protocols should this class of drug eventually be indicated for nHCM.

Conclusion

In summary, the ODYSSEY-HCM echocardiographic substudy demonstrates that mavacamten is a potent modulator of cardiac structure and function in nHCM. It successfully reduces LV mass, thins the ventricular walls, and eases the burden on the left atrium. While these physiological changes did not immediately translate to improved functional capacity in the primary trial, they represent a significant step forward in our ability to modify the biology of nonobstructive HCM. Future research should focus on identifying which nHCM subgroups (e.g., those with earlier-stage disease or specific genetic markers) are most likely to translate these structural improvements into functional and symptomatic relief.

References

• Desai MY, et al. Echocardiographic Changes With Mavacamten in Nonobstructive Hypertrophic Cardiomyopathy: Exploratory Insights From the ODYSSEY-HCM Trial. J Am Coll Cardiol. 2025;86(24):2434-2449. PMID: 40864019.
• Olivotto I, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396(10253):759-769. PMID: 32871100.
• Ho CY, et al. Genotype and Outcomes in Hypertrophic Cardiomyopathy: The Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation. 2018;138(14):1387-1398. PMID: 29752318.