Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct From Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy

Background: Mutations in desmoplakin (DSP ), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates ofDSP cardiomyopathy have been limited to small case series.Methods: Clinical and genetic data were collected on 107 patients with pathogenicDSP mutations and 81 patients with pathogenic plakophilin 2 (PKP2 ) mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed.Results: DSP andPKP2 cohorts included similar proportions of probands (41% versus 42%) and patients with truncating mutations (98% versus 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present among patients withDSP (55% versus 0% forPKP2 ,P <0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients withDSP versus 40% forPKP2 (P <0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity forDSP cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients withDSP (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients withDSP . Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients withDSP and were strongly associated with LV late gadolinium enhancement (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with late gadolinium enhancement). In 4DSP cases with 18F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. Left ventricle ejection fraction <55% was strongly associated with severe ventricular arrhythmias forDSP cases (P <0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias forPKP2 cases (P <0.001) but was poorly associated forDSP cases (P =0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for bothDSP (80%) andPKP2 (91%) groups (P =non-significant).Conclusions: DSP cardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype-specific approach for diagnosis and risk stratification should be used.