Chronic Inflammatory Cardiomyopathy and Its Overlap with Arrhythmogenic Cardiomyopathy: Long-Term Follow-Up of a Prospective Single-Centre Cohort Study

Abstract Background Chronic Inflammatory Cardiomyopathy (infl-CMP) may overlap with Arrhythmogenic Cardiomyopathy (ACM), a group of conditions with similar ventricular arrhythmic phenotypes and key imaging, electrocardiographic, histopathological, and genetic features. Purpose This single-centre cohort study aimed to assess the role of pathogenic genetic variants of ACM in long-term follow-up of patients with infl-CMP and ventricular arrhythmic phenotype. Methods In this prospective, single-centre study, 24 consecutive patients with suspected infl-CMP and ventricular arrhythmic phenotype were enrolled at our tertiary referral hospital between 2017 and 2022. Baseline demographic and clinical characteristics of the patients were collected. All patients underwent extensive workup, including electrocardiography, echocardiography, cardiac magnetic resonance, and genetic counselling and testing. Endomyocardial biopsy was performed if a definite diagnosis had not been reached after non-invasive diagnostic workup. Patients were classified according to phenotype as ACM (either definite or borderline), as indicated by the 2010 Padua Criteria, and genetically classified as genotype-positive or genotype-negative according to the presence of pathogenic variants for ACM. Long-term follow-up was performed to assess cardiovascular morbidity and mortality. The primary outcome was the occurrence of in-hospital admission for sustained ventricular tachyarrhythmias. Results At admission, 5 (21%) patients presented with syncope, 19 (79%) with high ventricular burden (>25% premature ventricular contractions) or with sustained ventricular tachyarrhythmias. After complete diagnostic work-up, 17 patients (71%) received a diagnosis of either definite or borderline ACM, while the remaining 7 patients (29%) received a diagnosis of infl-CMP. In 18 patients (75.0%), an endomyocardial biopsy was required as part of the diagnostic workup. In our population, the frequency of pathogenic ACM variants was 41% (8 variants in ACM patients and 2 variants in infl-CMP); in particular, pathogenic genetic variants coexisted in 2 patients (1 in the ACM group: PKP2 and KCNE1 mutations; 1 in the infl-CMP group: DSG2 and TMEM43 mutations). At a mean follow-up of 4.37 (SD ±1.77) years, the primary outcome occurred in 8 patients (33%), all identified as borderline or definite ACM (X²=4.94, p=0.026). Notably, sustained ventricular tachyarrhythmias occurred in 25% of genotype-negative and 50% of genotype-positive patients (X²=1.50, p=0.220). Conclusions Criteria-driven diagnosis of ACM was significantly associated with the occurrence of sustained ventricular tachyarrhythmias at long-term follow up. The presence of pathogenic genetic variants of ACM did not clearly stratify the ventricular arrhythmic risk as a single factor in our cohort of patients with ventricular arrhythmic phenotype.