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Gender-specific differences in major cardiac events and mortality in lamin A/C mutation carriers
Ingrid A W van Rijsingen1, Eline A Nannenberg, Eloisa Arbustini
1Department of Cardiology (Heart Failure Research Center), Academic Medical Center, Amsterdam, The Netherlands.
Insights
Mutations in the lamin A/C gene (LMNA) significantly increase cardiac disease risk and mortality. Male carriers face a worse prognosis due to higher rates of malignant arrhythmias and heart failure.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Diseases
Background:
- Mutations in the lamin A/C gene (LMNA) are a frequent cause of dilated cardiomyopathy.
- LMNA mutations are linked to increased risks of arrhythmias, sudden cardiac death, and heart failure.
- Limited data exist on how age and gender influence cardiac disease penetrance and mortality in LMNA mutation carriers.
Purpose of the Study:
- To investigate the impact of age and gender on cardiac disease penetrance and major cardiac events in LMNA mutation carriers.
- To determine the all-cause mortality in LMNA mutation carriers.
- To identify gender-specific differences in cardiac involvement and prognosis.
Main Methods:
- A multicentre cohort study of 269 LMNA mutation carriers.
- Evaluation of gender-specific penetrance of cardiac involvement and major cardiac events.
- Assessment of all-cause mortality using standardized mortality ratios (SMR) and hazard ratios (HR).
Main Results:
- Cardiac disease penetrance was age-dependent, nearing complete by age 70.
- Men showed a higher prevalence of reduced left ventricular ejection fraction (LVEF ≤45%).
- Malignant ventricular arrhythmias and end-stage heart failure were significantly more common in men.
- All-cause mortality was substantially increased in mutation carriers (SMR 4.0).
- Mortality risk was higher in men compared to women (HR 2.2).
Conclusions:
- LMNA mutation carriers exhibit high cardiac disease penetrance and mortality.
- Male carriers have a poorer prognosis, characterized by increased malignant ventricular arrhythmias and end-stage heart failure.
- Age and gender are critical factors influencing the clinical manifestation and outcomes of LMNA-related cardiomyopathy.
Aims:
Mutations in the lamin A/C gene (LMNA) cause a variety of clinical phenotypes, including dilated cardiomyopathy. LMNA is one of the most prevalent mutated genes in dilated cardiomyopathy, and is associated with a high risk of arrhythmias, sudden cardiac death, and heart failure. There are few data on the impact of age and gender on cardiac disease penetrance and mortality.
Methods And Results:
In a multicentre cohort of 269 LMNA mutation carriers, we evaluated gender-specific penetrance of cardiac involvement and major cardiac events. All-cause mortality of mutation carriers [standardized mortality ratio (SMR)] was determined. Cardiac disease penetrance was age dependent and almost complete at the age of 70 years. The presence of an LVEF ≤45% was significantly higher in men (P < 0.001). However, there was no difference between genders in the prevalence of atrioventricular block, atrial tachyarrhythmias, and non-sustained ventricular tachycardia. Malignant ventricular arrhythmias (26% vs. 8%) and end-stage heart failure (28% vs. 14%) were more common in men than in women (P < 0.001 and P = 0.006, respectively). All-cause mortality of mutation carriers was significantly increased [SMR 4.0, 95% confidence interval (CI) 2.8-5.2] between the ages of 15 and 75 years. Mortality in men was higher than in women (hazard ratio 2.2, 95% CI 1.2-4.3).
Conclusions:
This large cohort of LMNA mutation carriers demonstrates a high cardiac disease penetrance and a high mortality in mutation carriers. Male mutation carriers have a worse prognosis due to a higher prevalence of malignant ventricular arrhythmias and end-stage heart failure.
