Inflammation on Endomyocardial Biopsy Predicts Risk of MACE in Undefined Left Ventricular Arrhythmogenic Cardiomyopathy

BACKGROUND Predictors of major adverse cardiovascular events (MACE) in patients with undefined left ventricular arrhythmogenic cardiomyopathy (ULVACM) have not been described. OBJECTIVES The purpose of this study was to investigate the prognostic value of genetic testing and histology in a cohort of ULVACM patients. METHODS We identified 313 patients with ULVACM defined by new-onset ventricular arrhythmia (VA), nonischemic pattern of late gadolinium enhancement limited to the left ventricle (LV), and no severe dilated cardiomyopathy (LV ejection fraction >= 40%) from a retrospective multicenter registry. Patients undergoing next generation sequencing (NGS) for cardiomyopathy genes and endomyocardial biopsy (EMB) were compared with subjects without these studies. The primary endpoint was the occurrence of MACE, defined as the composite of cardiac death, heart transplantation, and malignant VA (ventricular tachycardia, ventricular fibrillation, appropriate implantable cardioverter-defibrillator treatment), at 60 months after clinical presentation. RESULTS Of the whole cohort (age 46 +/- 14 years, 63% men, LV ejection fraction 55% +/- 7%), 160 (51%) and 198 patients (63%), respectively, underwent NGS and EMB. NGS identified pathogenic or likely-pathogenic cardiomyopathy variants (pathogenic variants/likely pathogenic variants) in 25 of 160 cases (16%). EMB showed active myocardial inflammation (AM) in 102 of 198 patients (52%), 47 of whom (46%) received immunosuppressive therapy. After 58-month median follow-up, 93 of 313 patients (30%) experienced MACE. On multivariable analysis, presentation with malignant VA and EMB-proven AM were positively associated with the primary endpoint (HR: 2.8; 95% CI: 1.4-5.5; P = 0.003; and HR: 3.9; 95% CI: 1.9-7.5; P < 0.001, respectively), whereas immunosuppressive therapy showed a reverse association with MACE at 60 months (HR: 0.10; 95% CI: 0.05-0.40; P < 0.001). CONCLUSIONS Presentation with malignant VA or AM associates with MACE in ULVACM patients. (c) 2023 by the American College of Cardiology Foundation.