Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

Abstract

Lamin A/C gene mutations can be associated with cardiac diseases, usually referred to as ‘cardiolaminopathies’ characterized by arrhythmic disorders and/or left ventricular or biventricular dysfunction up to an overt picture of heart failure. The phenotypic cardiac manifestations of laminopathies are frequently mixed in complex clinical patterns and specifically may include bradyarrhythmias (sinus node disease or atrioventricular blocks), atrial arrhythmias (atrial fibrillation, atrial flutter, atrial standstill), ventricular tachyarrhythmias and heart failure of variable degrees of severity. Family history, physical examination, laboratory findings (specifically serum creatine phosphokinase values) and ECG findings are often important ‘red flags’ in diagnosing a ‘cardiolaminopathy’. Sudden arrhythmic death, thromboembolic events or stroke and severe heart failure requiring heart transplantation are the most dramatic complications of the evolution of cardiolaminopathies and appropriate risk stratification is clinically needed combined with clinical follow-up. Treatment with cardiac electrical implantable devices is indicated in case of bradyarrhythmias (implant of a device with pacemaker functions), risk of life-threatening ventricular tachyarrhythmias (implant of an ICD) or in case of heart failure with wide QRS interval (implant of a device for cardiac resynchronization). New technologies introduced in the last 5 years can help physicians to reduce device-related complications, thanks to the extension of device longevity and availability of leadless pacemakers or defibrillators, to be implanted in appropriately selected patients. An improved knowledge of the complex pathophysiological pathways involved in cardiolaminopathies and in the determinants of their progression to more severe forms will help to improve clinical management and to better target pharmacological and non-pharmacological treatments.

The Cutting Edge: The Role of mTOR Signaling in Laminopathies

“…Most laminopathies are rare to very rare diseases and feature an autosomal dominant inheritance, although recessive inheritance can also occur, as in mandibuloacral dysplasia (MADA), Charcot–Marie tooth neuropathy (CMT2B1), and restrictive dermopathy (RD). Muscular laminopathies include muscular dystrophies characterized by joint contractures, muscle weakness and wasting, and cardiomyopathy— LMNA -linked congenital muscular dystrophy (L-CMD) and isolated cardiomyopathies with conduction defects [ 30 , 35 ]. Among muscular dystrophies, EDMD1 is linked to emerin mutations ( EMD gene), EDMD2 and limb -girdle muscular dystrophy type 1B are caused by dominant lamin A/C mutations ( LMNA gene), other forms of EDMD are caused by nesprin ( SYNE1 and SYNE2 genes), FHL1, SUN1, or SUN2 mutations ( Table 1 ) [ 1 , 30 ].…”

Ankrd2 in Mechanotransduction and Oxidative Stress Response in Skeletal Muscle: New Cues for the Pathogenesis of Muscular Laminopathies

“…Mutations in LMNA gene cause a variety of muscular diseases including EDMD, limb-girdle muscular dystrophy 1B (LGMD1B), dilated cardiomyopathy with conduction defects (DCM1A), and LMNA -related congenital muscular dystrophy (L-CMD) [60, 81, 82]. Moreover, muscle functionality may be impaired in cases of progeroid laminopathies or lipodystrophies [59, 83].…”

“…The L-CMD onset is at birth, whereas EDMD2 and EDMD3 (respectively, with dominant and recessive inheritance) have an onset in childhood or young adulthood, as most cases of LGMD1B. DCM1A, which is usually diagnosed in the second decade, is often associated with conduction disorders and cardiac arrhythmias with life-threatening outcome requiring defibrillator implantation and, in severe cases, heart transplantation [81]. Extracardiac features including skeletal muscle weakness and contractures may occur later in DCM1A, causing a phenotype overlapping with EDMD2 [84].…”

Pulmonary vein isolation treats symptomatic AF in a patient with Lamin A/C mutation: case report and review of the literature

“…Patients with laminopathies often present with a phenotype of dilated cardiomyopathy [2] and as in most other cardiomyopathyies the incidence of atrial fibrillation (AF) is increased in this patient collective [3]. Little is known so far about the effect of pulmonary vein isolation (PVI) and its outcomes as a symptomatic treatment for atrial fibrillation (AF) in this patient cohort with LMNA mutations at an early stage of atrial remodeling [4].…”