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

Abstract

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