P62‐positive aggregates are homogenously distributed in the myocardium and associated with the type of mutation in genetic cardiomyopathy

Figures

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  FIGURE 1. Example of heart slice of PLN cardiomyopathy heart divided into 8 regions: 5 regions for the left ventricular free wall (anterior, anterolateral, lateral, posterolateral, posterior), 1 region for the septum and 2 regions for the right ventricle (posterior and anterior). Bottom of figure is anterior part of the heart

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  FIGURE 2. Staining patterns of p62 in cardiomyocytes. A, diffuse staining of the sarcolemma without obvious aggregates. B, perinuclear p62‐positive aggregates. C, p62‐positive aggregates expand into the sarcolemma. D, p62‐positive aggregates occupy almost the complete sarcolemma of the cardiomyocyte. Magnification 400×

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  FIGURE 3. Percentage cardiomyocytes with p62‐positive aggregates per gene and mutation group. A, percentage p62‐positive cardiomyocytes per mutation group in the whole heart. The desmin and phospholamban mutation groups showed significantly higher percentages as compared to the controls and other groups. B, percentage p62‐positive cardiomyocytes per gene in the whole heart. C, percentage p62‐positive cardiomyocytes in right ventricle (RV), septum and left ventricle (LV). In the desmosomal group, the percentage of p62‐positive cardiomyocytes was significantly lower in the RV than in the septum and LV. No difference between RV, septum and LV was observed in the other groups. D, no difference between percentage p62‐positive cardiomyocytes in the trabecular and inner and outer compact layer of the LV was observed

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  FIGURE 4. Hypothesis of pathophysiological mechanism. Proteotoxic stress in desmin and phospholamban cardiomyopathy is present in a relatively high percentage of cardiomyocytes in the myocardium as compared to most other groups of genetic cardiomyopathies. p62 was diffusely present in the myocardium, not related to fibrosis. These findings might suggest that the accumulation of proteotoxic aggregates in the sarcolemma is the first hit in the pathophysiology of desmin and phospholamban cardiomyopathy, making the cell less stable and vulnerable for a second hit such as local mechanical stress