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Laminopathies: natural history and risk prediction of heart failure
Philippe Charron1,2,3, Julie Proukhnitzky1,2,3, Rabah Ben Yaou4,5
1Sorbonne University, APHP, Department of Genetics, Centre de Référence des Maladies Cardiaques Héréditaires ou rares, INSERM UMRS 1166, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, 47 bvd de l'Hôpital, Paris 75013, France.
Insights
A new prediction model identifies severe heart failure (HF) events in patients with LMNA gene variants. This tool aids in early detection and management of HF-major adverse cardiac events (HF-MACE) in individuals with laminopathies.
Area of Science:
- Cardiology
- Genetics
- Predictive Modeling
Background:
- Patients with LMNA gene variants face high risks of dilated cardiomyopathy and heart failure (HF).
- No existing prediction models specifically address severe HF events in adult-onset laminopathies.
Purpose of the Study:
- To determine the incidence of severe HF events in adult laminopathy patients.
- To develop and validate a prediction model for HF-major adverse cardiac events (HF-MACE).
Main Methods:
- Utilized data from the French LMNA nationwide registry (470 patients) and an international validation cohort (245 patients).
- Assessed baseline characteristics and calculated cumulative incidence of HF-MACE (HF hospitalization, death, mechanical support, or transplantation).
- Employed a Fine-Gray competing risk model to identify predictors, excluding patients with baseline left ventricular ejection fraction (LVEF) <30%.
Main Results:
- Identified four independent predictors of HF-MACE: male sex, LVEF <50%, missense variants in head/rod domains, and complete left bundle branch block.
- The model achieved a C-index of 0.750 in the derivation cohort and 0.758 in the validation cohort.
- The 5-year cumulative incidence of HF-MACE varied significantly based on the number of risk factors (0, 1, or ≥2).
Conclusions:
- Developed the first prediction model for severe HF events in adult laminopathies.
- This model can aid in early identification and optimized preventive strategies for at-risk patients.
Background And Aims:
Patients with LMNA gene variants are at high risk for dilated cardiomyopathy and heart failure (HF), but no prediction model for severe HF events exists. This study aimed to describe the incidence of severe HF events and develop a prediction model in a large cohort of patients with adult-onset laminopathies.
Methods:
From a population of 660 patients enrolled in the French LMNA nationwide registry, 470 adults were included in the derivation cohort. An independent international validation cohort included 245 additional patients. Baseline characteristics at genetic testing were assessed and the cumulative incidence of the primary endpoint HF-major adverse cardiac events (HF-MACE) was calculated, defined as HF hospitalization, HF-related death, mechanical circulatory support, or heart transplantation. Predictors of HF-MACE were studied after excluding patients with left ventricular ejection fraction (LVEF) <30% at baseline using a Fine-Gray competing risk model, adjusted hazard ratio (aHR) with 95% confidence interval (CI), and Harrell's concordance (C-) index. A secondary composite endpoint, without hospitalization, was also studied.
Results:
Among 470 patients of the derivation cohort, HF-MACE occurred in 65 over a median follow-up of 7.1 years (interquartile range: 3.4-12.1). Four independent predictors of HF-MACE were identified: male sex (aHR 1.86; 95% CI 1.060-3.290), LVEF <50% (aHR 2.18; 95% CI 1.080-4.400), missense variants in head and rod domains (aHR 2.91; 95% CI 1.110-7.630), and complete left bundle branch block (aHR 2.99; 95% CI 1.400-6.400). The C-index of the model was 0.750 (95% CI 0.720-0.780) in the derivation cohort and 0.758 (95% CI 0.720-0.800) in the validation cohort. The 5-year cumulative incidence of HF-MACE was 1.5% (95% CI 0.6-3.6), 5.0% (95% CI 1.8-8.2), and 22.0% (95% CI 15.6-28.4) among patients with 0, 1, and ≥2 risk factors, respectively. In patients with LVEF <30% at baseline, the 1-year incidence of HF-MACE was 50%, and those patients were excluded from the risk score.
Conclusions:
The first prediction model for severe HF events in adult laminopathies was developed, which may facilitate early and optimal preventive management.
Clinical Trial Registration:
URL: https://www.clinicaltrials.gov Unique identifier: NCT03058185.
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