Calcium as a Key Player in Arrhythmogenic Cardiomyopathy: Adhesion Disorder or Intracellular Alteration?

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease causing sudden death in young individuals.
• Current treatments for ACM lack etiological basis, focusing on symptom management.
• Desmosomal gene mutations are linked to ACM, causing fibro-adipose tissue replacement in the myocardium.

Purpose of the Study:

• To explore the hypothesis that defects in cardiac calcium (Ca2+) handling machinery contribute to ACM pathogenesis.
• To investigate the role of Ca2+ signaling in ACM development, potentially revealing new therapeutic targets.

Main Methods:

• Analysis of Ca2+ handling machinery in cardiomyocytes from a plakophilin-2 deficient mouse model of ACM.
• Examination of ACM-related mutations in genes involved in excitation-contraction coupling (e.g., ryanodine receptor, phospholamban).
• Preliminary assessment using patient-derived induced pluripotent stem cell-derived cardiomyocytes.

Main Results:

• Significant remodeling of the Ca2+ toolkit was observed in ACM model cardiomyocytes.
• ACM-associated mutations affect proteins crucial for excitation-contraction coupling.
• Dysfunctional Ca2+ handling leads to increased sarcoplasmic reticulum Ca2+ release, delayed afterdepolarizations, and impaired contractility.

Conclusions:

• Cardiac Ca2+ handling defects are a potential mechanism underlying ACM.
• Targeting Ca2+ signaling pathways may offer a novel therapeutic strategy for ACM.
• Further research into Ca2+ signaling in ACM is warranted for developing etiological treatments.