Arrhythmogenic Right Ventricular Cardiomyopathy

Cardiology section

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiac condition that typically emerges in adulthood, affecting the myocardium, the muscular wall of the heart. It leads to the progressive breakdown of a portion of the myocardium, elevating the risk of abnormal heartbeats (arrhythmias) and sudden death. While initially asymptomatic, ARVC may manifest with sensations of

chest fluttering or pounding (palpitations), light-headedness, and fainting (syncope), particularly during strenuous physical activity. As the condition progresses, individuals may also experience shortness of breath and abnormal swelling in the legs or abdomen. In advanced stages, severe damage to the myocardium may culminate in heart failure.

ABOUT ARVC

UNDERSTANDING Arrhythmogenic Right Ventricular Cardiomyopathy

Delving Deeper into Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

ARVC can be attributed to mutations in at least 13 genes, many of which fall under the category of desmosomal genes. These genes encode instructions for constructing components of cellular structures known as desmosomes, crucial for connecting heart muscle cells and fortifying the myocardium while facilitating signaling between adjacent cells.

Mutations in desmosomal genes compromise the functionality of desmosomes, leading to the detachment and demise of myocardial cells, especially under stress conditions such as intense physical activity. The impact is primarily observed in the myocardium surrounding the right ventricle, one of the heart's lower chambers. The damaged myocardium is gradually replaced by fat and scar tissue, causing the right ventricle walls to stretch and impede effective blood pumping. Additionally, these changes disrupt the electrical signals governing heartbeat, increasing the risk of arrhythmias. While desmosomal genes are predominant, mutations in non-desmosomal genes can also contribute to ARVC, affecting various functions such as cell signaling, providing structural stability to heart muscle cells, and maintaining a normal heart rhythm. Researchers are actively investigating the mechanisms through which mutations in non-desmosomal genes lead to ARVC.

Key genes associated with ARVC include:

PKP2 (Plakophilin-2)

Mutations in the PKP2 gene are the most common cause of ARVC, accounting for approximately 40-60% of cases. PKP2 encodes plakophilin-2, a protein that is involved in maintaining the structural integrity of cardiac desmosomes, which are cell-cell junctions critical for maintaining the integrity of cardiac tissue. Mutations in PKP2 disrupt desmosome function, leading to cell detachment and fibrofatty replacement of myocardium, characteristic features of ARVC.

DSP (Desmoplakin)

Mutations in the DSP gene are also associated with ARVC, although less frequently than PKP2 mutations. DSP encodes desmoplakin, another protein involved in desmosome structure and function. Mutations in DSP can disrupt desmosome assembly and integrity, leading to cell detachment and myocardial fibrofatty replacement, contributing to the development of ARVC.

DSG2 (Desmoglein-2)

Mutations in the DSG2 gene have also been associated with ARVC, particularly in cases with predominant left ventricular involvement. DSG2 encodes desmoglein-2, another component of the desmosome complex. Mutations in DSG2 can disrupt desmosome function, leading to cell detachment and myocardial fibrofatty replacement, similar to mutations in PKP2, DSP, and DSC2.

DSC2 (Desmocollin-2)

Mutations in the DSC2 gene have been implicated in ARVC, particularly in cases with predominant left ventricular involvement. DSC2 encodes desmocollin-2, a protein that is part of the desmosome complex. Mutations in DSC2 can impair desmosome function, leading to cell detachment and myocardial fibrofatty replacement, similar to mutations in PKP2 and DSP.

JUP (Junction Plakoglobin)

Mutations in the JUP gene, which encodes junction plakoglobin (also known as γ-catenin), have been implicated in a subset of ARVC cases. Junction plakoglobin is a component of the desmosome complex and plays a role in cell-cell adhesion and signaling. Mutations in JUP can disrupt desmosome function, leading to cell detachment and myocardial fibrofatty replacement, contributing to the development of ARVC.

These genes play critical roles in maintaining the structural integrity of cardiac tissue, particularly in the right ventricle, and mutations in these genes can lead to the pathological changes observed in ARVC.

Genetic testing can help identify mutations associated with ARVC and guide clinical management and treatment decisions for affected individuals and their families. Early detection and intervention are essential for preventing or mitigating the serious complications associated with ARVC, including arrhythmias and sudden cardiac death.