Phospholamban p.Arg14del cardiomyopathy is characterized by phospholamban aggregates, aggresomes and autophagic degradation

BACKGROUND: The nondesmosomal phospholamban (PLN) p.Arg14del mutation was identified in patients diagnosed with dilated cardiomyopathy (DCM) and/or arrhythmogenic cardiomyopathy (ACM). We aimed to investigate whether this mutation leads to aggregation, aggresome formation and autophagy of mutant PLN protein.

METHODS AND RESULTS: We studied 20 complete heart specimens of PLN p.Arg14del mutation carriers (mean[±SD] age 48±15 years; 55% males), either from autopsies or explants. Gross and microscopic examination showed a biventricular cardiomyopathy with histopathological features of both ACM and DCM, a combination of fibrofatty replacement and interstitial fibrosis. Using immunohistochemistry for PLN, large perinuclear PLN protein aggregates were observed in cardiomyocytes in both ventricles in all examined hearts. The median number of PLN aggregates was 12 per 5mm2 (range 3-48) in right ventricular myocardium and 13 per 5mm(2 ) (range 5-89) in left ventricular myocardium. Using double immunohistochemical staining, co-localization of autophagy markers p62 (sequestosome-1 (SQSTM-1)) and microtubule-associated protein light-chain 3 (LC3) with PLN was observed in all aggregates, suggestive for degradation by selective autophagy. By electron microscopy, the ultrastructural appearance of these PLN-containing aggregates was typical of aggresomes, not surrounded by a membrane and located adjacent to the microtubular organizing centre. PLN aggregates were not found in 10 PLN-negative cases of idiopathic and genetic DCM and in 7 cases of desmosomal ACM.

CONCLUSIONS: Phospholamban p.Arg14del cardiomyopathy is a biventricular cardiomyopathy characterized by large perinuclear PLN protein aggregates with a typical ultrastructural appearance of aggresomes. Immunohistochemistry for PLN appears to be a sensitive and specific marker for this disease. This article is protected by copyright. All rights reserved.