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Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers
Saurabh Kumar1, Samuel H Baldinger2, Estelle Gandjbakhch3
1Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
Insights
Mutations in LMNA cause progressive heart disease, including arrhythmias and heart failure. Early genetic diagnosis and proactive management are crucial for preventing adverse events in affected individuals.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Mutations in the Lamin A/C gene (LMNA) are linked to various cardiac conditions, including cardiomyopathy, atrioventricular block (AVB), atrial arrhythmias (AAs), and ventricular arrhythmias (VAs).
- Limited natural history data exists for LMNA-associated cardiac outcomes, and the predictive value of the initial cardiac presentation is unclear.
Purpose of the Study:
- To characterize the long-term arrhythmic and nonarrhythmic outcomes in individuals with LMNA mutations.
- To evaluate whether the initial cardiac phenotype can predict future adverse events.
Main Methods:
- Retrospective analysis of 122 LMNA mutation carriers across 5 centers, with a median follow-up of 7 years.
- Assessment of the incidence of AVB, AAs, VAs, left ventricular dysfunction (LVD), and end-stage heart failure (HF).
- Identification of predictors for VAs and end-stage HF or death.
Main Results:
- Significant progression of cardiac manifestations observed, with increased prevalence of AVB (46% to 57%), AAs (39% to 63%), VAs (16% to 34%), and LVD (44% to 57%) over follow-up.
- 19% developed end-stage HF, and 13% died; LVD at presentation predicted these outcomes (p < 0.001).
- Male sex, non-missense mutations, and baseline LVD were associated with VA development.
Conclusions:
- LMNA-related heart disease exhibits significant phenotypic progression and a high rate of adverse cardiac events.
- The initial cardiac presentation does not reliably predict long-term outcomes.
- Genetic testing and vigilant follow-up are essential for timely intervention and management of LMNA-associated cardiovascular disease.
Background:
Mutations in LMNA are variably expressed and may cause cardiomyopathy, atrioventricular block (AVB), or atrial arrhythmias (AAs) and ventricular arrhythmias (VA). Detailed natural history studies of LMNA-associated arrhythmic and nonarrhythmic outcomes are limited, and the prognostic significance of the index cardiac phenotype remains uncertain.
Objectives:
This study sought to describe the arrhythmic and nonarrhythmic outcomes of LMNA mutation carriers and to assess the prognostic significance of the index cardiac phenotype.
Methods:
The incidence of AVB, AA, sustained VA, left ventricular systolic dysfunction (LVD) (= left ventricular ejection fraction ≤50%), and end-stage heart failure (HF) was retrospectively determined in 122 consecutive LMNA mutation carriers followed at 5 referral centers for a median of 7 years from first clinical contact. Predictors of VA and end-stage HF or death were determined.
Results:
The prevalence of clinical manifestations increased broadly from index evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to 34%; and LVD, 44% to 57%. Implantable cardioverter-defibrillators were placed in 59% of patients for new LVD or AVB. End-stage HF developed in 19% of patients, and 13% died. In patients without LVD at presentation, 24% developed new LVD, and 7% developed end-stage HF. Male sex (p = 0.01), nonmissense mutations (p = 0.03), and LVD at index evaluation (p = 0.004) were associated with development of VA, whereas LVD was associated with end-stage HF or death (p < 0.001). Mode of presentation (with isolated or combination of clinical features) did not predict sustained VA or end-stage HF or death.
Conclusions:
LMNA-related heart disease was associated with a high incidence of phenotypic progression and adverse arrhythmic and nonarrhythmic events over long-term follow-up. The index cardiac phenotype did not predict adverse events. Genetic diagnosis and subsequent follow-up, including anticipatory planning for therapies to prevent sudden death and manage HF, is warranted.
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