Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers

• Published in: Journal of the American College of Cardiology Vol. 68; no. 21; pp. 2299 - 2307
• Main Authors: Kumar, Saurabh, BSc(Med)/MBBS, PhD, Baldinger, Samuel H., MD, Gandjbakhch, Estelle, MD, PhD, Maury, Philippe, MD, Sellal, Jean-Marc, MD, Androulakis, Alexander F.A., MD, Waintraub, Xavier, MD, Charron, Philippe, PhD, Rollin, Anne, MD, Richard, Pascale, PhD, Stevenson, William G., MD, Macintyre, Ciorsti J., MD, Ho, Carolyn Y., MD, Thompson, Tina, RN, Vohra, Jitendra K., MD, Kalman, Jonathan M., MBBS, PhD, Zeppenfeld, Katja, MD, Sacher, Frederic, MD, Tedrow, Usha B., MD, MSc, Lakdawala, Neal K., MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29-11-2016; Elsevier Limited
• Subjects: Adolescent; Adult; Aged; Arrhythmias, Cardiac - epidemiology; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - physiopathology; atrial fibrillation; Cardiac arrhythmia; Cardiology; Cardiomyopathy; Cardiovascular; complete atrioventricular block; Deoxyribonucleic acid; DNA; Female; Follow-Up Studies; France - epidemiology; genetics; Genotype & phenotype; Heart failure; Humans; Incidence; Internal Medicine; Kinases; Lamin Type A - genetics; Lamin Type A - metabolism; Male; Middle Aged; Mortality; Muscular dystrophy; Mutation; Netherlands - epidemiology; Prevalence; Prognosis; Retrospective Studies; Survival Rate - trends; Time Factors; Variables; Ventricular Function, Left - physiology; ventricular tachycardia; Victoria - epidemiology; Young Adult; AA; ventricular arrhythmia; heart failure; ventricular fibrillation; gene-encoding lamin A/C; CRT; AF; cardiac resynchronization therapy; ICD; VA; AVB; VF; atrial fibrillation; genetics; atrial arrhythmia; ventricular tachycardia; atrioventricular block; LMNA; left ventricular systolic dysfunction; LVD; cardiomyopathy; complete atrioventricular block; implantable cardioverter-defibrillator; VT
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2016.08.058

Abstract 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.