Introduction: The Heterogeneity of Hypertrophic Cardiomyopathy
The clinical management of hypertrophic cardiomyopathy (HCM) has long been complicated by its phenotypic diversity. While characterized by unexplained left ventricular hypertrophy, the disease manifests in several distinct subtypes, including hypertrophic obstructive cardiomyopathy (HOCM), end-stage HCM (ES-HCM), and other variants such as nonobstructive, midventricular, or apical HCM. Among the various comorbidities associated with HCM, mitral regurgitation (MR) is one of the most prevalent and clinically challenging. Traditionally, MR in HCM was viewed primarily through the lens of systolic anterior motion (SAM) of the mitral valve in obstructive cases. However, the long-term prognostic implications of MR across the full spectrum of HCM subtypes have remained poorly understood. The REVEAL-HCM study provides critical clarity on this issue, suggesting that the clinical significance of MR is highly dependent on the underlying HCM subtype.
Study Highlight
The REVEAL-HCM study offers several key takeaways for the clinical community:
Subtype-Specific Risk
Moderate or greater MR is a significant independent predictor of all-cause death or heart failure hospitalization in nonobstructive, midventricular, and apical HCM subtypes, but not in HOCM or ES-HCM.
Temporal Dynamics
MR severity tends to improve over time in HOCM patients, likely due to therapeutic interventions or hemodynamic shifts, whereas it often worsens in other HCM subtypes.
Management Shift
The findings underscore the need for a subtype-specific approach to MR management in HCM patients, moving away from a one-size-fits-all prognostic assessment.
Study Design and Methodology
The REVEAL-HCM investigators conducted a retrospective study utilizing data from a Japanese multicenter registry. The study included a robust cohort of 3,602 patients, categorized into three primary groups:
HOCM (n=837)
Patients exhibiting left ventricular outflow tract (LVOT) obstruction.
ES-HCM (n=275)
Patients with systolic dysfunction or significant ventricular remodeling characteristic of the end-stage phase.
Other HCM (n=2,490)
A composite group including nonobstructive, midventricular obstruction, and apical HCM.The researchers compared patients based on MR severity, defining significant MR as moderate or greater versus mild or less. The primary endpoint was a composite of all-cause mortality and heart failure hospitalization. The median follow-up period was 5.3 years, providing sufficient longitudinal data to assess both hard outcomes and the temporal progression of MR.
Prevalence and Baseline Characteristics
The prevalence of moderate or greater MR varied significantly across the subtypes. In the HOCM group, 36.3% of patients had significant MR, the highest among all groups. This is consistent with the known mechanism of SAM-mediated MR in obstructive disease. In the ES-HCM group, the prevalence was 21.5%, often reflecting ventricular dilation and chordal tension. Interestingly, the “Other HCM” group had the lowest prevalence at 8.5%. Despite this lower prevalence, the prognostic impact within this specific group proved to be the most significant.
Key Findings: The Prognostic Paradox
The most striking result of the REVEAL-HCM study is the divergence in outcomes between the subtypes.
HOCM and ES-HCM: A Non-Significant Association
In patients with HOCM, the 5-year cumulative incidence of the primary endpoint was 14.6% for those with moderate+ MR compared to 12.4% for those with mild MR or less (P=0.35). Similarly, in ES-HCM, the rates were 60.7% versus 54.7% (P=0.84). After adjusting for clinical covariates, no significant association was found (HOCM: HR 1.13; ES-HCM: HR 0.84). These results suggest that in obstructive and end-stage disease, the presence of MR may be a marker of the underlying disease state rather than an independent driver of mortality or heart failure beyond the existing risks of obstruction or systolic failure.
Other HCM: A Major Risk Factor
In contrast, for patients with nonobstructive, apical, or midventricular HCM, moderate or greater MR was associated with a vastly higher 5-year incidence of death or heart failure hospitalization (34.2% versus 13.9%, P<0.001). This remained significant after multivariate adjustment (HR 1.45, 95% CI 1.09-1.91). This suggests that in these subtypes, MR acts as a potent independent prognostic indicator.
Longitudinal Progression of MR Severity
The study also tracked how MR severity changed over the follow-up period, revealing distinct trajectories:
HOCM
MR severity generally improved. This improvement may be attributed to successful septal reduction therapies (surgical myectomy or alcohol septal ablation) or medical management that reduces the pressure gradient and SAM.
ES-HCM
MR severity remained relatively stable, likely because the structural changes in end-stage disease are often irreversible.
Other HCM
MR severity tended to worsen over time. This progression in nonobstructive and apical subtypes may reflect a different underlying pathophysiology, such as progressive atrial enlargement or primary mitral valve degeneration that is not adequately addressed by current HCM-specific therapies.
Expert Commentary and Clinical Implications
The REVEAL-HCM study challenges the current paradigm of MR management in HCM. For years, clinicians have focused heavily on MR in the context of HOCM, where it is often considered a secondary phenomenon to obstruction. These data support that view, showing that MR in HOCM does not necessarily portend a worse outcome once the obstruction is accounted for or managed.However, the high hazard ratio for MR in the “Other HCM” group—which includes nonobstructive and apical forms—is a wake-up call. In these patients, MR is not merely a bystander; it is a critical predictor of heart failure. This may be because MR in nonobstructive HCM often stems from primary valvular abnormalities or significant left atrial remodeling, both of which contribute to pulmonary hypertension and heart failure symptoms.Clinical practice should adapt by implementing more rigorous monitoring of mitral valve function in nonobstructive HCM patients. If moderate MR is detected in these patients, it should be viewed as a high-risk marker, necessitating more aggressive heart failure prevention strategies and potentially earlier consideration of mitral valve intervention, even in the absence of LVOT obstruction.
Study Limitations
While the REVEAL-HCM study is large and multicenter, it is retrospective in nature. The criteria for MR grading, while standardized, may vary across institutions. Additionally, the study does not detail the specific types of interventions (e.g., specific medications or surgical techniques) performed during the follow-up period, which could influence the progression or regression of MR.
Conclusion
The REVEAL-HCM study provides a nuanced understanding of mitral regurgitation in hypertrophic cardiomyopathy. By demonstrating that MR carries significant prognostic weight in nonobstructive and apical subtypes—but not in HOCM or ES-HCM—the study advocates for a more tailored, subtype-specific approach to patient risk stratification. Clinicians should remain vigilant regarding MR progression in nonobstructive HCM, as it represents a significant and potentially modifiable risk factor for adverse outcomes.
References
1. Obayashi Y, Kato T, Shiomi H, et al. Prognostic Implications of Mitral Regurgitation Across Hypertrophic Cardiomyopathy Subtypes: A Report From REVEAL-HCM Study. Circulation: Heart Failure. 2026;19(3):e013977. PMID: 41636023.
2. Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy. Circulation. 2020;142(25):e558-e631.
3. Maron MS, Olivotto I, Zenavio C, et al. Hypertrophic cardiomyopathy is a contemporary treatable disease: characteristics and outcomes in a large multicenter cohort. J Am Coll Cardiol. 2012;60(11):981-989.