Highlight
- Among 2,500 patients with asymptomatic phenotypically mild hypertrophic cardiomyopathy (HCM), 21% developed major adverse cardiovascular events (MACE) over a mean follow-up of 7 years.
- Key predictors of MACE included older age, development of symptoms (NYHA class progression), increased left atrial diameter, left ventricular maximal wall thickness, and left ventricular outflow tract gradient.
- Progressive remodeling trajectories of left atrial size and left ventricular hypertrophy were strongly associated with elevated risk of atrial fibrillation, heart failure, and malignant ventricular arrhythmia.
- Presence of late gadolinium enhancement on cardiac MRI further increased the risk of adverse events, underscoring the role of myocardial fibrosis in disease progression.
Study Background
Hypertrophic cardiomyopathy (HCM) is a genetically mediated myocardial disease marked by left ventricular hypertrophy in the absence of abnormal loading conditions. While patients expressing severe phenotypes often present with symptoms and adverse events requiring active management, a substantial proportion initially exhibit phenotypically mild or asymptomatic disease. These early-stage patients do not typically require symptom-directed therapy but may represent a critical window for intervention with emerging disease-modifying treatments.
Despite recognition of this subset, comprehensive data delineating the natural history and predictors of major adverse cardiovascular events (MACE) in phenotypically mild HCM remain scarce. Understanding trajectories of disease progression and risk factors is vital to guide surveillance and therapeutic strategies aimed at improving long-term outcomes.
Study Design
This prospective cohort study utilized data from the Sarcomeric Human Cardiomyopathy Registry (SHaRe), a large, international registry collecting detailed clinical, imaging, and outcome data on sarcomeric HCM patients.
Phenotypically mild HCM was stringently defined to capture patients at an earlier disease stage, characterized by:
- Disease duration under 10 years since diagnosis or age ≤30 years
- No prior MACE
- New York Heart Association (NYHA) functional class I (asymptomatic)
- Left ventricular (LV) maximal wall thickness (MWT) under 25 mm
A total of 2,500 such patients (mean age 43 years, 31% female) were followed for a mean duration of 7 ± 6 years. Incident MACE were defined to include atrial fibrillation (AF), malignant ventricular arrhythmia (MVA), heart failure (HF), stroke, and all-cause mortality.
Standardized echocardiographic parameters were assessed longitudinally, including left atrial (LA) diameter, LV MWT, and LV outflow tract (LVOT) gradient. Cardiac magnetic resonance imaging (MRI) evaluations identified myocardial fibrosis via late gadolinium enhancement (LGE).
Cox proportional hazards models identified independent predictors of MACE. Additionally, linear and latent class mixed models elucidated trajectories of cardiac remodeling and delineated risk clusters.
Key Findings
During follow-up, 21% (534/2,500) of patients with mild HCM experienced MACE:
- 289 developed atrial fibrillation (AF)
- 69 had malignant ventricular arrhythmias (MVA), defined as sudden cardiac death, resuscitated arrest, or appropriate implantable cardioverter-defibrillator therapy
- 193 developed heart failure (HF) meeting criteria for advanced disease
Symptom progression was a critical marker: 23% (585) progressed from NYHA class I to ≥ class II during follow-up and had a 2.79-fold higher hazard of MACE (95% CI 2.30–3.39).
Multivariable analysis identified several baseline measures independently associated with higher MACE risk:
- Older age (HR 1.24 per 10-year increase; 95% CI 1.17–1.32)
- Body mass index (HR 1.10 per 5 kg/m2 increase; 95% CI 1.01–1.21)
- LA diameter (HR 1.16 per 5 mm increase; 95% CI 1.09–1.25)
- LV MWT (HR 1.27 per 5 mm increase; 95% CI 1.10–1.46)
- LVOT gradient (HR 1.08 per 15 mm Hg increase; 95% CI 1.05–1.12)
Presence of late gadolinium enhancement (LGE) on cardiac MRI was associated with a 36% increased hazard of MACE (95% CI 5%–76%), highlighting myocardial fibrosis as a pathological substrate.
Remarkably, dynamic remodeling over time provided incremental prognostic information. For each 0.5 mm/year increase in LA diameter, the hazard for AF and HF approximately doubled:
- AF: HR 2.24 (95% CI 1.69–2.97)
- HF: HR 2.22 (95% CI 1.62–3.04)
Similarly, each 0.5 mm/year increase in LV MWT predicted nearly doubled risk of malignant ventricular arrhythmias (HR 1.92; 95% CI 1.38–2.69).
Patients with persistently elevated or steeply increasing LA diameter, LV hypertrophy, or LVOT gradient demonstrated the highest rates of adverse events, underscoring the importance of serial imaging surveillance.
Expert Commentary
This comprehensive observational analysis from the SHaRe registry fills a crucial knowledge gap regarding the prognosis of asymptomatic phenotypically mild HCM. The finding that a substantial proportion—approximately one fifth—develop serious cardiovascular events despite initially mild disease emphasizes the need for vigilant longitudinal follow-up even in asymptomatic patients.
The identification of modifiable and measurable echocardiographic parameters that robustly predict MACE supports a paradigm shift from static risk assessment to dynamic monitoring capturing disease progression. Particularly, the strong associations between remodeling trajectories and clinical events suggest that early intervention strategies may be optimized by focusing on patients demonstrating rapid structural remodeling.
Myocardial fibrosis, as evidenced by late gadolinium enhancement, confirmed its role as an important prognostic biomarker, consistent with prior evidence linking fibrosis to arrhythmogenicity and adverse remodeling.
Limitations include potential selection bias inherent to registry data and variation in imaging protocols across sites. Furthermore, the median follow-up of 7 years provides medium-term insights; longer-term data are needed to confirm sustained risk patterns and therapeutic benefits.
Despite these limitations, these findings align with recent guideline recommendations that emphasize individualized, regular assessment of HCM patients, integrating clinical status, imaging biomarkers, and genetic risk.
Conclusion
The natural history of asymptomatic phenotypically mild hypertrophic cardiomyopathy is not benign; approximately one in five patients can be expected to develop major adverse cardiovascular events over a medium-term timeframe. Key predictors include older age, symptom development, and dynamic increases in left atrial size, ventricular hypertrophy, and LVOT gradients.
Incorporation of cardiac MRI for fibrosis assessment and serial echocardiographic monitoring to detect remodeling trajectories offers critical guidance for stratifying risk. These insights inform clinical surveillance strategies and highlight patient subsets who might derive most benefit from future disease-modifying therapies aimed at altering the progressive course of HCM.
Translating these findings into practice may improve prognostication, guide timely interventions, and ultimately reduce morbidity and mortality in this heterogeneous patient population.
Funding and Clinical Trials Registration
The SHaRe registry is supported by collaborative grants from the National Institutes of Health and participating academic centers. Details on trial registration and funding sources can be accessed via the original publication linked to PMID: 42417692.
References
1. Topriceanu CC, Balakrishnan ID, Vissing CR, et al. Natural History of Asymptomatic Phenotypically Mild HCM: Insights From the SHaRe Registry. J Am Coll Cardiol. 2026 Jul 8; PMID: 42417692.
2. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2011;58(25):e212-e260.
3. Maron MS, Rowin EJ. Hypertrophic Cardiomyopathy: Diagnosis and Treatment. Ann Intern Med. 2018;169(11):IFC33-IFC48.