Cardiomyocyte Dedifferentiation

Some cardiomyocytes in ARVC/D are characterized by cellular hypertrophy, disruption of sarcomeres, depletion of myofibrils, and T-tubular membrane invaginations of the sarcolemma and sarcoplasmic reticulum. There are also oval nuclei with homoge-nously dispersed chromatin resembling nuclei of fetal cardiomyocytes. These nuclei contain mitochondria of various size and shape with normal cristae (Fig. 6.5a), and often abundant glycogen. The above-

Fig. 6.5 • Features of cardiomyocytes dedifferentiation in ARVC/D heart. a Fragment of cardiomyocyte from ARVC/D heart characterized by oval nuclei exhibiting widespread chromatin,various size mitochondria,vacuoles,no T-tubules and myocytolysis of contractile fibrils. Bar = 2 ^m. b Expression of smooth muscle a-actin in cardiomyocytes in ARVC/D heart at immunostain

Fig. 6.5 • Features of cardiomyocytes dedifferentiation in ARVC/D heart. a Fragment of cardiomyocyte from ARVC/D heart characterized by oval nuclei exhibiting widespread chromatin,various size mitochondria,vacuoles,no T-tubules and myocytolysis of contractile fibrils. Bar = 2 ^m. b Expression of smooth muscle a-actin in cardiomyocytes in ARVC/D heart at immunostain

Fig.6.4 • Electron microscopic images of nuclei of dying cardiomyocytes in ARVC/D hearts. a Apoptotic nuclei (N) with condensed chromatin beneath nuclear membrane. Bar = 2 ^m. b A nucleus protruded from cardiomyocyte with irregular outline of tail segment directed to cell body. Bar = 2 ^m

Fig.6.4 • Electron microscopic images of nuclei of dying cardiomyocytes in ARVC/D hearts. a Apoptotic nuclei (N) with condensed chromatin beneath nuclear membrane. Bar = 2 ^m. b A nucleus protruded from cardiomyocyte with irregular outline of tail segment directed to cell body. Bar = 2 ^m mentioned features are characteristic of dedifferentiated cardiomyocytes [33]. In order to confirm this process in ARVC/D, immunohistochemical staining was performed using antibodies directed against smooth muscle a-actin, a protein that is normally expressed by cardiomyocytes of fetal phenotype and re-expressed by adult cells as adaptation to changes in working conditions of the myocardium. Its positive expression has been observed in cardiomyocytes with myolysis (Fig. 6.5b).

These dedifferentiated cardiomyocytes resemble those occurring in atrial fibrillation [34] or infarction [35]. The biological processes which trigger this cellular remodeling in ARVC/D and further fate of the dedifferentiated cells remain unknown. Several indirect observations have suggested dedifferentiation allows cardiomyocytes to survive for a longer time when stress conditions (e.g., stretching), take place [34,36] and occurs apart from cell death by necrosis or apoptosis [35].

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