Gene-elusive arrhythmogenic cardiomyopathy: Roles of sports, inflammation, and beyond

Area of Science:

• Cardiology
• Genetics
• Exercise Physiology

Background:

• Arrhythmogenic cardiomyopathy (ACM) is a primary cause of sudden cardiac death in young adults and athletes.
• Genetic variants in desmosomal proteins are implicated in inherited ACM, but ~33% of patients are gene-elusive.
• Gene-elusive ACM predominantly affects endurance athletes without a family history, suggesting exercise-induced origins.

Purpose of the Study:

• To review the evolving understanding of gene-elusive arrhythmogenic cardiomyopathy.
• To explore mechanical and transcriptional explanations for exercise-induced ACM.
• To examine inflammatory triggers and autoimmune responses in the context of athletic adaptation versus pathologic remodeling.

Main Methods:

• Comprehensive literature review of studies on arrhythmogenic cardiomyopathy, genetics, and exercise physiology.
• Analysis of proposed mechanisms including mechanical stress, transcriptional pathways, and inflammatory/autoimmune responses.
• Discussion of clinical challenges in differentiating physiological adaptation from pathological remodeling in athletes.

Main Results:

• Excessive endurance exercise may induce desmosomal damage in athletes, potentially through polygenic predisposition.
• Chronic exercise stress can lead to upregulation of desmosomal proteins, triggering inflammatory and autoimmune reactions.
• Mechanical and inflammatory effects of exercise may synergize, accelerating cardiac remodeling and arrhythmias.

Conclusions:

• Gene-elusive ACM in athletes may be exercise-induced, involving desmosomal damage and inflammatory pathways.
• Differentiating pathological remodeling from physiological adaptation in athletes remains a critical clinical challenge.
• Further research is needed to elucidate the precise mechanisms and develop diagnostic/therapeutic strategies for exercise-induced ACM.