Arrhythmogenic cardiomyopathy (ARVC/ACM), now classified as arrhythmogenic cardiomyopathy in WHO 2022, most commonly results from mutations in which molecular complex, and what is the mechanistic link between these mutations and the fibro-fatty replacement of the myocardium?
- A Desmosomal protein mutations (plakophilin-2, desmoplakin, desmoglein-2) impair mechanical coupling at the intercalated discs; stressed cardiomyocytes lose desmoglein-mediated Wnt/β-catenin suppression of adipogenesis, transdifferentiating into adipocytes and fibroblasts ✓
- B Sarcomeric mutations (MYH7, MYBPC3) disrupt mechanical coupling, causing myocyte death and fibro-fatty infiltration similar to dilated cardiomyopathy
- C Lamin A/C nuclear envelope mutations cause cardiomyocyte loss preferentially in the right ventricle due to lower wall stress in the right compared to left ventricle
- D SCN5A sodium channel mutations cause ventricular arrhythmias, and repeated ischemia from arrhythmia-mediated hemodynamic compromise leads to fibro-fatty scar formation
Explanation
ARVC is predominantly caused by mutations in desmosomal proteins: plakophilin-2 (PKP2, most common in European populations), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2), and junction plakoglobin (JUP). The mechanistic link to fibro-fatty replacement involves two pathways: (1) impaired mechanical coupling at intercalated discs leading to cardiomyocyte death under hemodynamic stress; (2) loss of desmosomal junction plakoglobin disrupts its inhibitory signalling on β-catenin nuclear translocation (Wnt pathway), releasing nuclear β-catenin-mediated transcriptional programs that activate adipogenic transcription factors (PPARγ) — causing cardiomyocyte-to-adipocyte transdifferentiation. Sarcomeric mutations cause HCM/DCM not ARVC. Lamin mutations cause ARVC-DCM overlap but are not the primary mechanism.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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