Cellular Mechanism and Pathophysiology of ARVC

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C)

ARVD/C refers to a genetically heterogeneous group of cardiomyopathies characterized by progressive degeneration and fibrofatty infiltration of the right ventricular myocardium . Patients are prone to ventricular tachycardia, right heart failure, and sudden death . Mutations in genes encoding for the desmosomal proteins plakoglobin , desmoplakin , and plakophilin-2  have been shown to cause ARVD/C. The molecular mechanisms of arrhythmias in ARVD/C are poorly understood. ARVD2, caused by mutations in the ryanodine receptor (RyR2), is clinically different from other forms of ARVD/C in that ventricular arrhythmias are stereotypically effort-induced .In ARVD2 the leaky ryanodine receptor results in cytosolic Ca²⁺ overload and, consequently, in delayed afterdepolarizations triggering arrhythmias, and may overlap with CPVT.

ARVC occurs in ∼1 in 5,000 individuals and primarily affects adults (Basso et al., 2009). However, ARVC is also an important cause of death among young people, accounting for ∼20% of deaths occurring in individuals under 30 years old (Shen et al., 1995). ARVC is inherited in an autosomal-dominant or recessive pattern in 50% of cases often with incomplete penetrance, so unknown genetic or environmental modifiers are predicted (Basso et al., 2009).

Mutations in proteins that comprise the cardiac desmosome, a junctional complex that mechanically couples neighboring cardiomyocytes to coordinate contractile activity, account for most inherited cases of ARVC (Yang et al., 2006). Disruptions in desmosome stability cause structural and functional alterations and are associated with cardiomyocyte apoptosis (Yamaji et al., 2005). Adipose and fibrotic tissue that replace cardiomyocytes are a hallmark of ARVC, primarily in the right ventricle; however, left ventricular involvement is common in later stages of the disease (Corrado et al., 1997). The right ventricle enlarges as myocyte loss progresses, causing a reduction in blood volume pumped from the heart and arrhythmias.

 A). The action potential of atrial and ventricular myocytes consists of 4 phases (upper part), to which specific ion flows contribute (middle). The long plateau phase (3) and a stable resting phase (4) are characteristic for myocyte action potential. The corresponding electrocardiographic ventricular activity is shown below. Early afterdepolarizations occur during phase 2 / 3 of the action potential, before the ongoing action potential has reached phase 0 (B). Delayed afterdepolarizations occur during phase 4 of the action potential, before the action potential has reached phase 0 (C).

 On the cellular level, three distinct entities causing tachyarrhythmias can be distinguished: automaticity, triggered activity and reentry. One or a combination of these mechanisms occurs in inherited arrhythmias. AP action potential, HCM hypertrophic cardiomyopathy, DCM dilated cardiomyopathy, ARVD/C arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Displayed are transverse tubules of two neighboring cardiomyocytes with the ion channels localized on the sarcolemma of cell 1 and the connecting gap junction connexins to the sarcolemma of cell 2. Shown are the pore regions of the ion channels (α-subunits) through which ions flow across the plasma membrane, and the cytoplasmic β-subunits. Within each subunit, the encoding gene is displayed in italics, the protein in normal font. Differences in disease status are indicated in a box next to the currents. Intranuclear proteins and genes might also interact with ion channels and/or gap junction proteins. Disturbed calcium handling within the sarcomere or sarcoplasmic reticulum underlies distinct arrhythmia causing diseases.

The figure illustrates the location of several intercalated disc proteins associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). Each grey line is a cell membrane, and the area in-between is the cell-to-cell contact area. APC = adenomatous polyposis coli (a tumor suppressor gene that provides a platform for the beta-catenin destruction complex [BDC]); Axin = also part of the BDC that regulates stability of the β-cat in Wnt-signaling pathway; β-cat = beta-catenin; CDH = cadherin; CK1 = casein kinase 1 that targets β-cat for phosphorylation; DSC = desmocollin; DSG = desmoglein; DSP = desmoplakin; Dvl = disheveled [a cytoplasmic protein involved in canonical and noncanonical Wnt-signaling pathways]; GSK3β = glycogen synthase kinase 3 beta and known to phosphorylate β-cat; JUP = junction plakoglobin; LRP5/6 = low-density lipoprotein receptor–related proteins 5 and 6 (transmembrane receptors involved with receptor-mediated endocytosis and transduction of canonical Wnt signals); NF2 = neurofibromin 2 (an upstream molecule of Hippo signaling pathway also known as Merlin [acronym for Moesin-Ezrin-Radixin-like protein], which is a tumor suppressor); PKP-2 = plakophilin-2; PKCα = protein kinase C alpha; Wnt = after Drosophila melanogaster wingless gene.