Updated clinical overview on cardiac laminopathies: an electrical and mechanical disease

Abstract

Cardiac laminopathies, associated with mutations in the LMNA gene, encompass a wide spectrum of clinical manifestations, involving electrical and mechanical alterations of cardiomyocytes. Thus, dilated cardiomyopathy, bradyarrhythmias and atrial or ventricular tachyarrhythmias may occur in a number of combined phenotypes. Nowadays, some attempt has been made to identify clinical predictors for the most life-threatening complications of LMNA-associated heart disease, i.e. sudden cardiac death and end-stage heart failure. The goal of this manuscript is to combine the most recent evidences in an updated review to show the state-of-the-art of such a complex disease group. This is supposed to be the starting point to collect more data and design new ad hoc studies to identify clinically useful predictors to stratify risk in mutation carriers, including probands and their asymptomatic relatives.

Keywords: LMNA; arrhythmias; cardiomyopathy; genetics; heart failure; lamin; sudden cardiac death.

Figure 1.

Pathophysiological overview of human laminopathies. The figure shows the complexity of pathophysiological mechanisms that, from mutations in the LMNA gene, finally lead to a broad spectrum of possible clinical phenotypes, including but not limited to heart disease. In particular, genotype-to-phenotype transition is divided into three levels represented by concentric lines: the internal one (molecular level) represents molecular pathways more commonly involved in LMNA gene mutations; the intermediate one (cellular level) summarizes the subsequent alterations of cell functions; the external one (phenotypic level) shows the main clinical syndromes associated to LMNA gene mutations, with a wide spectrum of possible overlapping phenotypes.

Figure 2.

Mechanical and electrical disease management in cardiac laminopathies. The figure shows the best clinical management for patients presenting with mechanical (green panel, on the left) or electrical disease (blue panel, on the right), according to the main studies published so far. Abbreviations: AF/Flu = atrial fibrillation/flutter; AVB = atrioventricular block; BB = betablockers; CCB = calcium-channel blockers; CRT = cardiac resynchronization therapy with (CRT-D) or without (CRT-P) defibrillator function; DCM = dilated cardiomyopathy; HF = heart failure; HTx = heart transplantation; ICD = implantable cardioverter defibrillator; LBBB = left bundle branch block; LV = left ventricle; LVEF = left ventricular ejection fraction; NMM = non-missense mutation; NSVT = non-sustained ventricular tachycardia; OAC = oral anticoagulants; OMT = optimal medical therapy; PM = pacemaker; RyC/RaC = rhythm/rate control; SSS = sick sinus syndrome; VT/VF = ventricular tachycardia/fibrillation.