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

https://doi.org/10.1016/j.jacc.2016.08.058Get rights and content
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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.

Key Words

atrial fibrillation
cardiomyopathy
complete atrioventricular block
genetics
heart failure
ventricular tachycardia

Abbreviations and Acronyms

AA
atrial arrhythmia
AF
atrial fibrillation
AVB
atrioventricular block
CRT
cardiac resynchronization therapy
ICD
implantable cardioverter-defibrillator
LMNA
gene-encoding lamin A/C
LVD
left ventricular systolic dysfunction
VA
ventricular arrhythmia
VF
ventricular fibrillation
VT
ventricular tachycardia

Cited by (0)

Dr. Kumar is a recipient of the Neil Hamilton Fairley Overseas Research scholarship co-funded by the National Health and Medical Research Council and the National Heart Foundation of Australia; and the Bushell Travelling Fellowship funded by the Royal Australasian College of Physicians. Dr. Lakdawala has received support from the O’Hare Family Foundation directed toward research on cardiolaminopathy. Dr. Gandjbakhch has received consultant fees from Sorin, Medtronic, Boston Scientific, and Bayer. Dr. Stevenson has intellectual property and a patent for needle ablation consigned to Brigham and Women’s Hospital. Dr. Sacher has received speaker honoraria from St. Jude Medical. Dr. Tedrow is on the faculty of St. Jude Medical and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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