Lamin Variants Sample Clauses

Lamin Variants. Lamin A/C gene (LMNA) encodes structural nuclear envelope proteins, with pathogenic mutations leading to metabolic disorders, and skeletal as well as cardiac myopathies (65). Variants in LMNA account for approximately 4-6% of DCM, occurring in isolation or association with varying degrees of muscular dystrophy (151). Unlike TTN, LMNA mutations can be highly penetrant with an increased risk of rapidly advancing conduction disease and malignant arrhythmias in association with an earlier-onset DCM and a very high risk of sudden cardiac death (3,65,151). The new entity of ‘hypokinetic non-dilated’ DCM as described by the ESC is specific to LMNA mutations and describes an overt phase of systolic dysfunction not associated with dilated ventricular ▇▇▇▇▇▇▇▇ (6). Certain risk factors have been elucidated for predicting the malignant arrhythmia component which commonly precedes the onset of ventricular dysfunction and is generally considered clinically as part of the risk stratification (152). In a European multicentre study of 269 patients with LMNA mutation carrier status, after a median follow-up of 3 ½ years, the presence of NSVT, LVEF <45% at baseline, male sex and non-missense mutations arose as independent risk factors for malignant ventricular arrhythmias, with the cumulative risk increasing with each additional risk factor (152). It is not entirely clear if all LMNA carriers are at similar risk of arrhythmic death and given that data already indicates the majority of deaths may be unrelated to heart failure and occur in those without manifest cardiac abnormalities, better risk stratification tools are needed to individualise the risk for this cohort (151). Furthermore, outside the context of a need for pacemaker implantation in LMNA-associated DCM, there are no absolute recommendations for a primary prevention ICD in this cohort (145). Given the lack of randomised controlled trials to support ICD implantation within the broader risk variables identified in LMNA carriers, especially in those without severe ventricular dysfunction, it is currently only considered a reasonable indication from a consensus viewpoint when two or more risk factors are present (153).