PKP2 mutations cause earlier ACM onset and higher arrhythmic risk, DSP mutations link to LV dysfunction and fibrosis; RV dysfunction predicts major arrhythmias across genotypes.
Does genotype (DSG2, PKP2, or DSP mutations) influence the phenotypic expression and risk of major ventricular arrhythmias in patients with arrhythmogenic cardiomyopathy?
Different desmosomal mutations in arrhythmogenic cardiomyopathy are associated with distinct clinical phenotypes, highlighting the importance of incorporating genetic information into arrhythmic risk stratification.
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Abstract Background mutations in various desmosomal genes have been associated with Arrhythmogenic Cardiomyopathy (ACM). Although recent studies suggest that specific clinical features may be linked to different genetic variants, there is a lack of comparative studies evaluating clinical features and outcomes in matched patients with different desmosomal gene mutations. Purpose to assess the influence of genotype on the phenotypic expression of ACM and to identify potential variables associated with major ventricular arrhythmias (MVA) in patients carrying mutations in the most common disease-related desmosomal gene. Methods we compared the clinical and instrumental features of ACM patients carrying desmoglein-2 (DSG2) mutations (n=80), plakophilin-2 (PKP2) mutations (n=120), and desmoplakin (DSP) mutations (n=110) to investigate phenotypic expression and identify potential variables associated with MVA. Results male sex was more prevalent in the DSG2 and PKP2 cohorts (p=0.004), as was proband status (p=0.009). Patients with PKP2 mutations presented at a significantly younger age (p=0.002). Syncope was more commonly the initial symptom in the DSG2 group (p0.001), whereas chest pain was more frequent in the DSP cohort (p=0.007). The DSG2 group exhibited significantly more severe right ventricular (RV) dilatation (p0.001), while both DSG2 and PKP2 groups showed more pronounced RV dysfunction (p=0.02). In contrast, left ventricular (LV) dilatation and dysfunction were more frequent in the DSP cohort (both p0.001), accompanied by a higher prevalence of fibrosis on Cardiac Magnetic Resonance (CMR) (p0.001). The prevalence of MVA was significantly higher in the PKP2 group (p=0.04), while hot phase episodes were more common in both DSG2 and DSP groups (p=0.013). Different parameters were associated with MVA across the three genetic groups: in the DSG2 cohort, RV dysfunction (p=0.04); in the DSP group, both RV and LV dysfunction (p=0.03); and in the PKP2 group, male sex (p=0.03), more than 500 premature ventricular beats on 24-hour monitoring (p=0.04), RV dysfunction (p0.001), and younger age at presentation (p=0.03). Conclusion different desmosomal mutations are associated with distinct clinical features in ACM. PKP2, the most prevalent ACM-associated gene, is correlated with earlier disease onset and a higher arrhythmic burden. DSP mutations are frequently linked to LV involvement, including both dysfunction and fibrosis as observed on CMR. Hot-phase episodes, traditionally linked to DSP, are also observed in DSG2, which is characterized by a more severe RV phenotype. Despite these genotype-specific differences, RV dysfunction remains a key prognostic marker across all forms of ACM. These findings underscore the importance of incorporating genetic information into the complex framework of arrhythmic risk stratification, highlighting its indispensable role in personalized patient management.RVFAC by Gene and MVA in ARVC LVEF by Gene and MVA in ARVC
Martini et al. (Sat,) reported a other. PKP2 mutations cause earlier ACM onset and higher arrhythmic risk, DSP mutations link to LV dysfunction and fibrosis; RV dysfunction predicts major arrhythmias across genotypes.