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

<jats:sec> <jats:title>Background:</jats:title> <jats:p> Mutations in desmoplakin ( <jats:italic>DSP</jats:italic> ), 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 of <jats:italic>DSP</jats:italic> cardiomyopathy have been limited to small case series. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p> Clinical and genetic data were collected on 107 patients with pathogenic <jats:italic>DSP</jats:italic> mutations and 81 patients with pathogenic plakophilin 2 ( <jats:italic>PKP2</jats:italic> ) mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed. </jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> <jats:italic>DSP</jats:italic> and <jats:italic>PKP2</jats:italic> 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 with <jats:italic>DSP</jats:italic> (55% versus 0% for <jats:italic>PKP2</jats:italic> , <jats:italic>P</jats:italic> <0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients with <jats:italic>DSP</jats:italic> versus 40% for <jats:italic>PKP2</jats:italic> ( <jats:italic>P</jats:italic> <0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity for <jats:italic>DSP</jats:italic> cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with <jats:italic>DSP</jats:italic> (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with <jats:italic>DSP</jats:italic> . Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with <jats:italic>DSP</jats:italic> 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 4 <jats:italic>DSP</jats:italic> 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 for <jats:italic>DSP</jats:italic> cases ( <jats:italic>P</jats:italic> <0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias for <jats:italic>PKP2</jats:italic> cases ( <jats:italic>P</jats:italic> <0.001) but was poorly associated for <jats:italic>DSP</jats:italic> cases ( <jats:italic>P</jats:italic> =0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both <jats:italic>DSP</jats:italic> (80%) and <jats:italic>PKP2</jats:italic> (91%) groups ( <jats:italic>P</jats:italic> =non-significant). </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p> <jats:italic>DSP</jats:italic> 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. </jats:p> </jats:sec>