Laminopathies: Natural History and Risk Prediction of Heart Failure

Highlights

• LMNA gene mutations cause a unique dilated cardiomyopathy phenotype characterized by early onset conduction abnormalities, arrhythmias, and high risk of heart failure (HF).
• The first robust, externally validated risk prediction model for severe HF events in adult laminopathy patients incorporates clinical and genetic markers including sex, LVEF, variant location, and conduction defects.
• Cardiovascular magnetic resonance imaging (CMR) phenotyping reveals distinct subclinical myocardial abnormalities, with fibrosis and strain metrics predicting adverse events.
• Despite advances in clinical management, LMNA-related DCM continues to present significant morbidity and mortality, underscoring the need for early identification and tailored preventive strategies.

Background

Laminopathies are a spectrum of genetic disorders caused by mutations in the LMNA gene encoding nuclear envelope proteins lamin A and C. Among the most clinically impactful presentations is LMNA-related dilated cardiomyopathy (DCM), characterized by high penetrance, frequent conduction system disease, malignant arrhythmias, and a progressive risk of severe HF outcomes including hospitalization, mechanical support, transplantation, and death. The disease burden is notable due to young age of onset, rapid progression in certain phenotypes, and limited disease-modifying therapies. Prior to recent efforts, no validated risk stratification scheme existed to predict severe HF events in these patients. Understanding the natural history and identifying predictors of clinical deterioration are crucial to optimize surveillance, timing of advanced therapies, and improve patient outcomes.

Key Content

Natural History and Phenotypic Characterization

Earlier studies, including a comprehensive Norwegian cohort analysis (Nikolova et al., Eur Heart J 2018), document that LMNA mutations account for approximately 6% of familial DCM cases. Cardiac penetrance is high, even among asymptomatic carriers, with annual incidence of new cardiac manifestations around 9%. Clinical features include atrioventricular (AV) conduction block, atrial fibrillation/flutter, ventricular tachyarrhythmias, and reduced left ventricular ejection fraction (LVEF). Nearly 20% of patients require heart transplantation over median 7-8 years follow-up, highlighting disease severity.

The phase 3 REALM-DCM trial (Pasquier et al., ESC Heart Fail 2024) further delineated the phenotype and natural progression, demonstrating significant morbidity including frequent ventricular arrhythmias (25%) and heart failure hospitalizations or worsening (13%). Baseline HF status assessed by NYHA class correlated with functional capacity, biomarker levels (NT-proBNP), and echocardiographic parameters. Notably, variability in clinical course underscores importance of individualized risk assessment.

Imaging and Biomarkers: Insights from Cardiovascular Magnetic Resonance (CMR)

A multicenter study (Low et al., JACC Cardiovasc Imaging 2025) provided detailed CMR phenotyping in LMNA mutation carriers, stratified by preserved or reduced LVEF. Findings included increased myocardial T2 relaxation times and extracellular volume fraction (ECV), suggestive of inflammation and diffuse fibrosis, even in patients with preserved systolic function. Elevated serum troponin and C-reactive protein further supported ongoing myocardial injury and inflammation.

Importantly, focal fibrosis detected by late gadolinium enhancement (LGE) and impaired myocardial strain identified by Procrustes shape analysis independently predicted major adverse cardiovascular events (MACE), including heart failure, ventricular arrhythmias, and transplantation. These imaging biomarkers provide mechanistic insights into disease progression and have potential utility beyond conventional clinical markers.

Risk Prediction Model for Severe Heart Failure Events

The landmark 2026 European Heart Journal publication by Charron et al. reported the first validated risk prediction model for severe HF events in adult laminopathy patients, derived from the largest LMNA registry cohort to date (French LMNA registry, n=470) and externally validated in an international cohort (n=245).

Using competing risk Fine-Gray modeling and thorough exclusion of patients with severe baseline LV dysfunction (LVEF <30%), four independent predictors of HF-major adverse cardiac events (HF-MACE) were identified:

• Male sex (adjusted hazard ratio [aHR] 1.86)
• LVEF less than 50% at baseline (aHR 2.18)
• Missense variants located in the head and rod domains of lamin A/C (aHR 2.91)
• Presence of complete left bundle branch block (LBBB) on electrocardiogram (aHR 2.99)

The model demonstrated good discrimination with Harrell’s concordance indices of approximately 0.75 in both derivation and validation cohorts. Five-year HF-MACE cumulative incidence stratified by risk factor count showed marked escalation: 1.5% with zero, 5% with one, and 22% with two or more risk factors. Patients with very low baseline LVEF (<30%) exhibited extremely high risk (50% HF-MACE at 1 year) and were excluded from risk scoring, underscoring the model’s focus on earlier disease stages.

Treatment Perspectives and Prognostic Implications

Despite limited disease-modifying therapies, recent clinical trial attempts such as the REALM-DCM trial (phase 3) concluded without significant therapeutic benefits. Nonetheless, these studies reinforced the grim prognosis and clinical heterogeneity of LMNA-related DCM.

Lonafarnib treatment in Hutchinson-Gilford Progeria Syndrome (a laminopathy syndrome with LMNA mutations) was associated with improved survival, indicating potential therapeutic avenues targeting lamin A/C pathways, relevant albeit in a different clinical context (Gordon et al., JAMA 2018).

The delineation of risk profiles facilitates focused monitoring, timely referral for advanced HF therapies (e.g., mechanical circulatory support, transplantation), and guides personalized counseling. Emerging imaging biomarkers may complement genetic and clinical risk factors to refine prognostication.

Expert Commentary

The elucidation of risk factors for severe HF in laminopathies represents a critical advance, filling a major gap in managing this high-risk population. The integration of genetic variant localization alongside clinical parameters underscores the biological complexity of LMNA pathogenicity. The role of conduction abnormalities such as complete LBBB as a marker of electrical and mechanical dyssynchrony contributing to HF progression is mechanistically plausible.

The CMR phenotyping studies provide valuable subclinical disease insights, suggesting that fibrosis and myocardial inflammation precede overt functional decline, presenting an opportunity for earlier intervention. However, the translation of these imaging biomarkers into clinical decision tools awaits validation in larger cohorts with standardized protocols.

Current guidelines advise rigorous surveillance of LMNA carriers with electrophysiologic evaluation and imaging. The new risk model enables stratification that may guide intensity of follow-up and preemptive therapies.

Limitations include the exclusion of patients with very advanced systolic dysfunction in the risk model derivation, reflecting challenges in late-stage prediction. Also, therapeutic interventions were heterogeneous, and the impact of contemporary HF therapies specifically in LMNA cardiomyopathy remains incompletely defined.

Conclusion

Laminopathies due to LMNA mutations manifest a distinctive, often aggressive cardiomyopathy phenotype with a high risk of severe heart failure and arrhythmias. Recent large-scale registry data and imaging studies have enriched understanding of disease progression and prognostic markers.

The pioneering risk prediction model incorporating sex, LVEF, genetic variant location, and conduction disturbance offers clinicians a practical tool for early risk stratification and management optimization. Future research should focus on integrating advanced imaging biomarkers and evaluating targeted therapeutics to modify disease trajectory.

Clinicians managing LMNA mutation carriers should emphasize early diagnosis, systematic monitoring, and personalized intervention informed by prognostic models to mitigate the substantial morbidity and mortality associated with these complex genetic cardiomyopathies.

References

• Charron P et al. Laminopathies: natural history and risk prediction of heart failure. Eur Heart J. 2026 Jun 23;47(24):3135-3148. PMID: 41790128.
• Low RN et al. The Cardiovascular Magnetic Resonance Phenotype of Lamin Heart Disease. JACC Cardiovasc Imaging. 2025 Jun;18(6):644-660. PMID: 40372342.
• Pasquier M et al. Characterization and natural history of patients with LMNA-related dilated cardiomyopathy in the phase 3 REALM-DCM trial. ESC Heart Fail. 2024 Dec;11(6):4201-4208. PMID: 39145700.
• Nikolova T et al. Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation. Eur Heart J. 2018 Mar 7;39(10):853-860. PMID: 29095976.
• Gordon LB et al. Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome. JAMA. 2018 Apr 24;319(16):1687-1695. PMID: 29710166.