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Arrhythmogenic Cardiomyopathy
Acknowledgments
This work has been supported by TRANSAC, University of Padua Strategic Project CPDA133979/13, Padua, Italy; Registry for Cardio-cerebro-vascular Pathology, Veneto Region, Venice, Italy; Target Project, Regional Health System, Venice, Italy; PRIN Ministry of Education, University and Research 2010BWY8E9_004, Rome, Italy; University Research Grant CPDA144300, Padua, Italy.
Arrhythmogenic cardiomyopathy (AC) is a rare, genetically determined cardiomyopathy featured by progressive myocardial dystrophy with fibrofatty replacement afflicting the right ventricle (RV), left ventricle (LV), or both. AC shows an age-related penetrance, manifesting with palpitations, syncope, or cardiac arrest usually in adolescence or young adulthood, and represents one of the major causes of sudden death in the young and athletes. It is caused mostly by heterozygous or compound heterozygous mutations in genes encoding proteins of the desmosomal complex (approximately 50% of probands). Cases with a recessive trait of inheritance have been reported, either associated or not with skin/hair abnormalities. The estimated prevalence of AC in the general population ranges from 1:2000 to 1:5000. AC affects more frequently males than females (up to 3:1), despite a similar prevalence of carrier status, and becomes clinically overt most often in the second to fourth decade of life.
Pathologic Findings
AC is a “structural” cardiomyopathy characterized by the replacement of the ventricular myocardium by fibrofatty tissue. Myocardial atrophy occurs progressively with time, starts from the epicardium, and eventually extends down to reach the endocardium as to become transmural. This entity should not be confused with Uhl disease, a congenital heart defect in which the RV myocardium fails to develop during embryonic life. The gross pathognomonic features of AC consist of RV aneurysms, whether single or multiple, located in the so-called triangle of dysplasia (ie, inflow, apex, and outflow tract). Cases with isolated or predominant LV involvement are not so rare. Indeed, up to 76% of the AC hearts studied at post mortem revealed an LV involvement, usually limited to the subepicardium or midmural layers of the posterolateral free wall. Hearts with end-stage disease and congestive heart failure show usually multiple RV aneurysms, thinning of the RV free wall, and huge chamber dilatation, with a high prevalence of biventricular involvement, whereas the ventricular septum is mostly spared.
Histologic examination reveals islands of surviving myocytes, interspersed with fibrous and fatty tissue. Fatty infiltration of the RV is not a sufficient morphologic hallmark of AC 12 and replacement-type fibrosis and myocyte degenerative changes should be always searched for. Myocyte necrosis is seldom evident and may be associated with inflammatory infiltrates. Myocardial inflammation has been reported in up to 75% of hearts at autopsy. An apoptotic mechanism of myocyte death has been also demonstrated in humans. Rather than being a continuous ongoing process, disease progression may occur through periodic “acute bursts” of an otherwise stable disease, as to mimic “infarct-like” myocarditis or simulate myocardial infarction. In a desmoglein-2 transgenic animal model, spontaneous myocyte necrosis was demonstrated to be the key initiator of myocardial injury, triggering progressive myocardial damage, followed by an inflammatory response. The detection of viral genomes in humans led to the possibility of an infective viral etiology, but it is most likely that either viruses are innocent bystanders or that myocardial cell degeneration may serve as a milieu favoring viral settlement.
Pathogenesis of Arrhythmogenic Cardiomyopathy
Transgenic animal models that mimic the human AC phenotype (mice and zebrafish) and induced pluripotent stem cells (iPSCs) from affected patients are useful tools to explore how the mechanical and/or functional disruption of cell junctions by mutant desmosomal proteins leads to cardiomyocyte death and subsequent repair with fibrous and adipose tissue.
Abnormal Cell-Cell Adhesion
Even before the discovery of desmosomal genes in AC, electron microscopy studies, demonstrating intercalated disc disruption, first raised the hypothesis of an abnormal cell-cell adhesion in disease pathogenesis. However, more recent studies point to the possible role of mutant desmosomal proteins in intracellular signaling rather than adhesion remodeling, as initially assumed.
Abnormal Intercellular Junction Proteins and Intracellular Signaling
The role of mutant desmosomal proteins in the intracellular signaling was first demonstrated in a Desmoplakin (DSP)-deficient mouse model, with the Wnt signaling pathway suppression leading to adipogenesis as a consequence of the abnormal distribution of intercalated disc proteins. More recent studies in different experimental models further support this hypothesis, showing an additional suppression of the canonical Wnt signaling leading due to aberrant activation of the Hippo kinase cascade pathway, which resulted into phosphorylation and cytoplasmic retention of yes associated protein (YAP) leading to enhanced myocyte death and fibroadipogenesis as a consequence of β-catenin and junctional plakoglobin (JUP) cytoplasmic sequestration.
However, cellular reprogramming of patient-derived somatic cells (ie, dermal fibroblasts) into iPSCs from AC patients with plakophilin-2 (PKP2) mutations, demonstrated that the abnormal JUP nuclear translocation and decreased β-catenin activity is insufficient to reproduce the pathologic phenotype in standard conditions and only the induction of an adult-like metabolism in a lipogenic milieu coactivated peroxisome proliferator-activated receptor (PPAR)-γ pathway with lipogenesis, apoptosis, and calcium-handling deficit.
It is noteworthy that transgenic experimental animal models and iPSC-derived cardiomyocytes demonstrated only abnormal “lipogenesis,” but not adipocyte formation or sudden death. Thus cells other than cardiomyocytes must be involved in the abnormal adipogenesis and fibrosis, which is also an essential feature of AC phenotype. A role of cardiac mesenchymal stromal cells as a source of adipocytes in AC has been recently advanced.
Gap Junction and Ion Channel Remodeling
Desmosomes, gap junctions, and sodium channels act as a functional triad in which changes in the composition of one constituent can affect the function and integrity of the others. Recent studies demonstrated diminished connexin-43 expression at intercellular junctions of most AC human myocardial specimens and reduced cardiac sodium current in experimental models of AC. These findings led to the hypothesis that life-threatening ventricular arrhythmias could occur in AC patients, even preceding the structural abnormalities (prephenotypic stage) due to electrical uncoupling and reduced sodium current prevention. However, it remains to be proven in humans.
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