PO-04-143 CARDIOVASCULAR OUTCOMES IN LMNA-MEDIATED CARDIAC LAMINOPATHY: THE MAYO CLINIC EXPERIENCE

Abstract

Pathogenic loss-of-function variants in LMNA-encoding lamin A/C cause a range of phenotypes, including lipodystrophy, premature aging, muscular dystrophy, and cardiomyopathy. LMNA-mediated cardiac laminopathy is viewed as a particularly malignant form of arrhythmogenic dilated cardiomyopathy (DCM). However, a paucity of data exists comparing the cardiovascular outcomes in cardiac laminopathy to other DCM genotypes. Therefore, we sought to ascertain whether the prevalence of advanced heart failure (AHF), ventricular arrhythmia (VA), and stroke events differ between patients with either LMNA-mediated DCM or TTN-mediated DCM who were evaluated in a single tertiary medical center. All patients with either a pathogenic (P) or likely pathogenic (LP) variant in either LMNA or TTN in the Mayo Clinic Genetic ACM Registry (n=389) were included. A VA event was defined as sudden cardiac death (SCD), sudden cardiac arrest (SCA), sustained VA, or an appropriate ICD shock while an AHF event was defined as ventricular assist device implantation or heart transplantation. Overall, 88 patients with a P/LP variant in LMNA (61% female) and 72 patients with a P/LP variant in TTN (42% female) were identified. LMNA-positive patients were more likely to have a family history of SCA/SCD (56% vs 35%; p=0.008) and more likely to receive an ICD (60% versus 33%; p=0.001). Interestingly, the prevalence of atrial fibrillation (51% vs. 40%; p=0.2), stroke (8% vs. 8%; p=0.9), and AHF events (12% vs 8%; p=0.4) was similar between LMNA- and TTN-positive patients. However, LMNA-positive patients trended towards more VA events (32% vs 20%; p=0.08). Independent of sex, time-to-event analysis showed LMNA patients had an earlier time (p=0.0009) to a composite endpoint (AHF event or VA event) and remained significant when separating the endpoints: AHF event (p=0.008) and VA event (p=0.0009). LMNA-mediated cardiac laminopathy is a highly arrhythmogenic form of DCM with nearly one-third experiencing a SCA and/or appropriate ICD therapy and half with a history of atrial fibrillation. Although the overall rate of ventricular arrhythmic and AHF events was similar between LMNA and TTN P/LP variant-positive patients, cardiac laminopathy results in earlier end stage heart failure and potentially lethal ventricular arrhythmias.