Basic and translational mechanisms in inflammatory arrhythmogenic cardiomyopathy

Area of Science:

• Cardiology
• Genetics
• Pathology

Background:

• Arrhythmogenic cardiomyopathy (ACM) is a familial, nonischemic heart disease often inherited in an autosomal dominant pattern.
• Early diagnosis is challenging due to incomplete penetrance and variable expressivity, frequently affecting young individuals and athletes.
• Pathogenic variants in desmosomal genes, such as DSC2 and DSG2, are implicated in both autosomal-recessive and autosomal-dominant inheritance patterns.

Approach:

• This review synthesizes current knowledge on ACM pathogenesis, encompassing genetic underpinnings and molecular mechanisms.
• It examines the clinical and pathological phenotypes, including historical perspectives from ARVD to the broader ACM classification.
• The review also covers basic and translational research on inflammation's role and ongoing clinical trials for disease prevention.

Key Points:

• ACM, historically known as arrhythmogenic right ventricular dysplasia (ARVD), is now recognized as a primary cardiomyopathy with diverse subtypes (ARVC, ALVC, biventricular ACM).
• Fibrofatty replacement of the myocardium is a key pathological feature, evolving from earlier theories of congenital absence.
• Genetic factors, particularly desmosomal gene variants, play a crucial role in ACM development and inheritance.

Conclusions:

• Understanding the complex interplay of genetics, inflammation, and myocardial changes is crucial for diagnosing and managing ACM.
• Further research and clinical trials are essential to develop effective strategies for preventing ACM onset and progression.
• The evolving classification of ACM highlights the need for comprehensive diagnostic and therapeutic approaches across all subtypes.