Genetic characterization of a cohort of tachycardia-induced cardiomyopathy

Abstract Introduction Tachycardia-induced cardiomyopathy (TIC) is a clinically common condition, poorly characterized and traditionally considered benign. It has been recently classified within the dilated cardiomyopathy (DCM) spectrum in which the presence of a common genetic substrate is considered. While this classification implies the arrhythmia as the triggering factor on top of a genetic predisposition, genetic characterization of TIC has not been previously reported. Purpose To perform a genetic characterization of tachycardia-induced cardiomyopathy and compare this genetic profile with existing data on dilated cardiomyopathy Methods From October 2022 to October 2024, we prospectively recruited adult patients diagnosed with TIC based on the European Society of Cardiology (ESC) guidelines, excluding those with arrhythmias other than atrial fibrillation or atrial flutter, severe coronary artery disease or significant valvular pathology. Patients were genetically tested using a targeted next-generation sequencing (NGS) wide panel at our institution based on clinical phenotype of dilated cardiomyopathy. The NGS panels included >50 genes related to dilated cardiomyopathy. The interpretation of the pathogenicity of the genetic variants was made by the geneticists of our laboratory following the recommendation of the American College of Medical Genetics. Results We enrolled 45 patients during the study period of whom 40 underwent genetic testing. Among these 40 patients diagnosed with TIC, 4 (10%), were found to carry pathogenic variants associated with DCM. No homozygous or compound heterozygous truncating variants were observed. The detected pathogenic variants affected the following genes: TTN (2 cases), LMNA (1 case), and DES (1 case). Specifically, TTN variants were frameshift mutations, the LMNA variant involved a 122-base pair macrodeletion, and the DES variant was a missense mutation. These findings are consistent with reported pathogenic mutation frequencies in DCM cohorts, where overall mutation rates range from 10-45%, with the most commonly affected genes being TTN (15-25%), LMNA (4-7%), MYH7 (3-4%), RBM20 (2%), and DES (<1%). Conclusions Genetic characterization of patients with TIC revealed DCM-related pathogenic variants in 10% of cases, with TTN, LMNA, and DES as the affected genes. These findings are in accordance with genetic mutation patterns observed in DCM cohorts and, therefore, it supports the hypothesis that TIC is a form of cardiomyopathy within the DCM spectrum, with tachyarrhythmia acting as the precipitating factor.