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

Abstract

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 of DSP cardiomyopathy have been limited to small case series.

Methods: Clinical and genetic data were collected on 107 patients with pathogenic DSP 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 and PKP2 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 DSP (55% versus 0% for PKP2, P<0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients with DSP versus 40% for PKP2 (P<0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity for DSP cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with DSP (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with DSP. Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with DSP 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 DSP 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 DSP cases (P<0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias for PKP2 cases (P<0.001) but was poorly associated for DSP cases (P=0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both DSP (80%) and PKP2 (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.

Keywords: arrhythmogenic right ventricular cardiomyopathy; cardiomyopathy; desmoplakin; desmosome.

Figure 1.. Mutation and population variant locations within DSP.

Mutations present in the study cohort are shown in red for both truncating mutations (except large deletions, see Supplemental Table 2) and for missense mutations. All reported DSP mutations, including from this study, are shown in black. Missense mutations reported in the literature were only included if the allele frequency in the gNomad population was <4×10⁻⁵ (all previously reported variants are included in Supplemental Table 1). The bottom track shows all variants from the gNomad population database with allele frequency >4×10⁻⁵ – these variants are not expected to exert strong pathogenic effects based on tolerance in the general population. DSP truncating mutations are dispersed throughout the gene. In contrast, missense mutations are enriched within the plakophilin/plakoglobin and desmin binding domains as compared to gNomad population variants (70% vs. 39% of variants, odds ratio 3.6 [95% CI, 1.7,7.6], p<0.001).

Figure 2.. Acute Myocardial Injury and Fibrosis Preceding Systolic Dysfunction.

Cardiac magnetic resonance imaging (MRI) was performed in a 19-year-old patient who presented with recurrent episodes of chest pain, troponin elevation, and normal coronary angiography. The MRI revealed extensive left ventricular (LV) late gadolinium enhancement but normal LV systolic function (ejection fraction 60%). Right ventricular function was also normal without focal wall motion abnormalities. A family history of sudden cardiac death (mother and maternal uncle) prompted genetic testing which revealed a pathogenic frameshift mutation in DSP (c.2593_2594dupGA).

Figure 3.. Acute Myocardial Inflammation in a DSP Cardiomyopathy Patient Presenting with Acute Myocardial Injury.

Images were obtained from a 41 year old man with a DSP truncating mutation (p.Arg2284*) following presentation with acute chest pain, troponin elevation, and normal coronary angiography. A) ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) and A’) FDG-PET/CT in the coronal view. B) FDG-PET and B’) FDG-PET/CT in the axial view. Arrowheads indicate areas of inflammation detected by FDG uptake. C-D) Cardiac magnetic resonance (CMR) in the 4-chamber view (C) and short axis view (D) demonstrated late gadolinium enhancement in a subepicardial distribution, including regions corresponding to increased inflammation (arrows). This patient also exhibited reduced left ventricular systolic function with an ejection fraction of 45%.

Figure 4.. Survival Analysis of Severe Ventricular Arrhythmia Outcomes.

A) Desmoplakin mutation carrier survival stratified by normal ventricular function & right ventricular systolic dysfunction vs left ventricular systolic dysfunction groups. B) Plakophilin-2 mutation carrier survival stratified by normal ventricular function and right ventricular systolic dysfunction groups RV: Right ventricle, LV: Left ventricle