Clinical characteristics and risk stratification of desmoplakin cardiomyopathy

Abstract

Aims Desmoplakin (DSP) cardiomyopathy is an increasingly recognized form of arrhythmogenic cardiomyopathy. With a genotype-specific approach, we characterized the diagnosis, natural history, and risk for ventricular arrhythmia and heart failure in DSP cardiomyopathy. Methods and results We followed 91 individuals [45 probands, 34% male, median age 27.5 years (interquartile interval 20.0–43.9)] with pathogenic or likely pathogenic DSP variants for a median of 4.3 years. Regarding the ventricular involvement, left predominance was most common (n = 22, 28%) followed by bi-ventricular in 12 (15%) and right predominance in 5 (6%). Myocardial injury (chest pain, elevated troponin, normal coronary angiogram) occurred in 20 (22%) individuals. Incidence rates of sustained ventricular arrhythmia and heart failure (ventricular dysfunction ± symptoms) were 5.9 [95% confidence interval (CI): 3.9–9.1] and 6.7 (95% CI: 4.5–9.8) per 100 person-years, respectively. In univariate regression, myocardial injury was associated with sustained ventricular arrhythmia [hazard ratio (HR) 2.53, 95% CI: 1.05–6.11] and heart failure (HR 7.53, 95% CI: 3.10–18.26). After adjustment, left ventricular ejection fraction <35% and right ventricular dysfunction were prognostic for sustained ventricular arrhythmia while proband status and myocardial injury were prognostic for heart failure (all P < 0.05). The sensitivity of the arrhythmogenic right ventricular cardiomyopathy Task Force Criteria in diagnosing left dominant disease was 0.73; 5/22 (23%) of patients with sustained ventricular arrhythmias did not meet these criteria. Conclusion DSP cardiomyopathy affects both ventricles and carries high risk for ventricular arrhythmia and heart failure. Myocardial injury is associated with worse disease outcomes. Both diagnosis and risk stratification of DSP cardiomyopathy need refinement.

Cardiovascular Characteristics of Patients with Genetic Variation in Desmoplakin (DSP)

“…In addition, we report substantial utilization of therapies related to the treatment of malignant ventricular arrhythmias and heart failure including, secondary prevention ICD implantation, appropriate ICD shocks, ventricular arrhythmia ablation, and heart transplantation. Our observations support recent work from Wang et al, derived from a single center prospective registry of ARVC [31], which demonstrated that individuals with disease-causing variants in DSP were at high risk for sustained ventricular arrhythmia and heart failure. Importantly, the three individuals in our cohort who underwent secondary prevention ICD implantation had LVEFs above the guideline recommended primary prevention ICD implantation threshold of <35%.…”

“…Current knowledge regarding clinical phenotypes and outcomes of desmoplakin cardiomyopathies is largely based on published reports of small populations [ 5 ], including (1) large cohorts of individuals with ARVC [ 11 – 13 , 15 , 17 , 18 , 24 ], (2) other cardio-myopathy cohorts with fewer than 10 probands [ 25 – 28 ], and (3) single family/single DSP variant cohorts [ 29 , 30 ]. Our study is one of the larger single-center descriptions of the clinical characteristics of DSP cardiomyopathy and aligns with recent work describing the distinctive presentation and course of this disease and the importance of molecular diagnosis for appropriate detection and risk stratification [ 8 , 31 ].…”

Histopathological Features and Protein Markers of Arrhythmogenic Cardiomyopathy

“…Notably, DSP variants have been increasingly linked to biventricular or left-dominant ACM. In fact, a recent report, suggested that patients bearing pathogenic DSP variants manifest with a disease distinct from ACM or DCM, termed desmoplakin cardiomyopathy ( 37 , 38 ).…”

“…Patients carrying mutations in PKP2 gene often present LV involvement at advanced stages of the disease while mutations in DSG2 and DSC are often associated to biventricular forms of ACM. Mutations in DSP ( 37 , 38 ) and more recently in DSG2 ( 39 ) genes have been associated to left-dominant forms of the disease.…”

Prognostic Cardiac Magnetic Resonance Markers of Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy for Predicting Heart Failure Outcomes

“…Our finding could be supported by a recent study of DSP cardiomyopathy (one subtype of ACM) that showed the LV involvement including LV LGE was also not related to VT events. 22 Considering the nature of ACM, a heterogeneous disease, it is thought that the genetic backgrounds and clinical courses of each study may be different. Nevertheless, it is meaningful that we showed that CMR markers (LGE, native T1, ECV, and T2 mapping) were associated with HF‐related outcomes in patients with ACM.…”