Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy

Abstract

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disorder characterized by myocardial fibro-fatty replacement and an increased risk of sudden cardiac death (SCD). Originally described as a right ventricular (RV) disease, ACM is increasingly recognized as a biventricular entity. We evaluated pathological, genetic, and clinical associations in a large SCD cohort. Methods: We investigated 5205 consecutive cases of SCD referred to a national cardiac pathology center between 1994 and 2018. Hearts and tissue blocks were examined by expert cardiac pathologists. Following comprehensive histological evaluation, 202 cases (4%) were diagnosed with ACM. Of these, 15 (7%) were diagnosed ante-mortem with dilated cardiomyopathy (DCM)(n=8) or ACM (n=7). Prior symptoms, medical history, circumstances of death, and participation in competitive sport were recorded. Post-mortem genetic testing was undertaken in 24/202 (12%). Rare genetic variants were classified according to American College of Medical Genetics and Genomics (ACMG) criteria. Results: Of 202 ACM decedents (35.4±13.2 years; 82% male), 157 (78%) reported no prior cardiac symptoms. Forty-one decedents (41/202; 20%) were participants in competitive sport. The adjusted odds of dying during physical exertion were higher in males than females (OR 4.58; 95% CI 1.54-13.68; p=0.006) and in competitive athletes compared with non-athletes (OR 16.62; 95% CI 5.39-51.24; pConclusions: SCD due to ACM affects males predominantly, most commonly occurring during exertion in athletic individuals in the absence of prior reported cardiac symptoms. LV involvement is observed in the vast majority of SCD cases diagnosed with ACM at autopsy. Current Task Force criteria may fail to diagnose biventricular ACM prior to death.