Refined diagnostic understanding of arrhythmogenic cardiomyopathy in the modern era from overdiagnosis to diagnostic precision: the evolving diagnostic criteria for arrhythmogenic cardiomyopathy

Background

Arrhythmogenic cardiomyopathy (ACM) is an inherited myocardial disease characterized by ventricular arrhythmias, progressive remodeling, and sudden cardiac death risk. Despite advances in diagnostics, genotype–phenotype correlations remain incompletely understood. Earlier studies often relied on historical cohorts preceding modern diagnostic criteria, resulting in diagnostic uncertainty and limited comparability.

Purpose

To characterize the clinical, electrophysiological, imaging, and genetic features of ACM patients managed at a tertiary referral center and to explore genotype–phenotype associations using the 2020 Padua criteria.

Methods

All patients coded with ICD-10-GM I42.80 (suspected ARVC) at our hospital between 2005 and 2025 were retrospectively screened. Cases were reevaluated according to the 2020 Padua criteria. Demographics, arrhythmic events, ECG, echocardiography, cardiac magnetic resonance (CMR), family history, and genetic results were systematically reviewed. Patients not fulfilling Padua criteria were excluded.

Results

Of 501 patients initially suspected of ARVC, 200 met preliminary ACM criteria; 76 remained indeterminate and 17 were genotype-positive/phenotype-negative. Genetic testing was unavailable or irretrievable in 107 (53%)(Figure 1). Ultimately, 124 fulfilled the Padua criteria. ARVC was the predominant phenotype, with biventricular involvement in 48 (38.7%) and definite arrhythmogenic left ventricular cardiomyopathy (ALVC) in 16 (12.9%) patients. The most frequent major criterion was morpho-functional right ventricular abnormality (n = 113, 56.5%).

Fifty-four patients had positive genetic findings; 47 carried a pathogenic or likely pathogenic (P/LP) variant in an ACM-associated gene. Variants in non-ARVC genes were found in 6% (n = 12). Variant distribution was: PKP2 47% (n = 23), DSP 18.4% (n = 9), DSG2 14.3% (n = 7), and other ARVC genes (DSC2, DES, FLNC) 20.3% (n = 10). Among genotype-positive patients, mean RVEF was 41.3 ± 11.3% and LVEF 51.8 ± 10.8%. Sustained ventricular tachycardia occurred in 28/52 (53.8%), and 33/52 (63.5%) had ICDs.

Conclusions

ACM remains a heterogeneous disease with persistent diagnostic challenges. Earlier studies were limited by overdiagnosis and a predominant right ventricular focus. Applying the 2020 Padua criteria enabled a more precise phenotypic classification and improved diagnostic specificity. Despite clear recommendations, genetic testing was absent in over half of patients, reflecting both historical constraints and ongoing gaps in implementation. Establishing robust genotype–phenotype correlations is essential to improving diagnostic certainty, risk stratification, and personalized patient management. This study contributes to this effort by systematically characterizing a contemporary ACM population under modern diagnostic standards and emphasizing the ongoing need for comprehensive genetic evaluation in clinical practice.Overview of genetic testing outcomes