Abstract
BACKGROUND: Desmoplakin (DSP) cardiomyopathy, caused by variants in the gene DSP, is a unique subtype of cardiomyopathy distinct from typical dilated or arrhythmogenic right ventricular cardiomyopathies. Specific diagnostic and disease staging criteria have yet to be developed for DSP cardiomyopathy. OBJECTIVE: Utilizing a large cohort of DSP cardiomyopathy patients and their genotype-positive family members, this study aims to develop diagnostic and disease staging criteria for DSP cardiomyopathy. METHODS: Patients from the DSP-ERADOS Network with complete rhythm monitoring, electrocardiogram and cardiac magnetic resonance imaging were enrolled. Diagnostic criteria were assessed in initially-presenting patients (probands) and their genotype-positive family members. Early disease criteria (with preserved left ventricular ejection fraction, LVEF) were integrated into standard LVEF-based classifications. Diagnostic and staging criteria were assessed by time-event analyses (major ventricular arrhythmia and heart failure events). RESULTS: A total of 605 patients with complete diagnostic testing were included (mean age 40 yr, 60% female, 40% probands). The most prevalent disease features in probands were premature ventricular contractions (PVCs) >500/24hr (66%), nonsustained ventricular tachycardia (NSVT, 29%), LV late gadolinium enhancement (LGE, 53%), and reduced LVEF (44%). The presence of any one of these features was 97% sensitive for diagnosis (along with a DSP pathogenic variant) and were therefore considered as diagnostic criteria. Using these criteria, 77% of genotype-positive family members were considered clinically affected. Isolated right ventricular (RV) involvement occurred in only 0.7%. The absence of diagnostic criteria identified a low-risk group (composite event rate 0.8%/year, p<0.001). Integration of these criteria into LVEF-based classification improved identification of composite arrhythmia/heart failure events (early: diagnostic criteria with LVEF ≥50%, HR 2.7, p=0.04; intermediate: LVEF 41-49%, HR 3.7, p=0.009; advanced: LVEF ≤40% HR 10.3, p<0.001). LGE was mostly subepicardial (87%). Circumferential (ring-like) LGE was more frequent in intermediate or advanced vs early disease (66% vs 48%, p<0.001). CONCLUSION: This study identifies genotype-specific diagnostic and disease staging criteria for DSP cardiomyopathy that improve identification of risk for both heart failure and sustained ventricular arrhythmias. This work highlights how gene-specific criteria may be used to refine diagnosis and staging for cardiomyopathy subtypes - a critical step as gene-targeted treatments move toward clinical trials.