Abstract
Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder characterized by structural and electrical cardiac abnormalities, including myocardial fibro-fatty replacement. Its pathological ventricular substrate predisposes subjects to an increased risk of sudden cardiac death (SCD). ACM is a notorious cause of SCD in young athletes, and exercise has been documented to accelerate its progression. Although the genetic culprits are not exclusively limited to the intercalated disc, the majority of ACM-linked variants reside within desmosomal genes and are transmitted via Mendelian inheritance patterns; however, penetrance is highly variable. Its natural history features an initial “concealed phase” that results in patients being vulnerable to malignant arrhythmias prior to the onset of structural changes. Lack of effective therapies that target its pathophysiology renders management of patients challenging due to its progressive nature, and has highlighted a critical need to improve our understanding of its underlying mechanistic basis. In vitro and in vivo studies have begun to unravel the molecular consequences associated with disease causing variants, including altered Wnt/β-catenin signaling. Characterization of ACM mouse models has facilitated the evaluation of new therapeutic approaches. Improved molecular insight into the condition promises to usher in novel forms of therapy that will lead to improved care at the clinical bedside.
Highlights
Arrhythmogenic CardiomyopathyArrhythmogenic cardiomyopathy (ACM) is a rare form of heart disease characterized by fibro-fatty replacement of ventricular myocardium [1]
Studies have shown that ACM is responsible for 3–10% of sudden cardiac deaths (SCD) worldwide among individuals less than 40 years of age, with studies in Italy attributing over 20% of SCD cases to ACM in young athletes [4,5,6]
This review focuses on our current knowledge of the genetics underlying ACM and the mechanisms leading to disease onset and progression
Summary
Arrhythmogenic cardiomyopathy (ACM) is a rare form of heart disease characterized by fibro-fatty replacement of ventricular myocardium [1]. Encompassing cardiomyopathies associated with a high risk of ventricular arrhythmias, ACM is a general term that includes multiple subtypes. The most common subtype of ACM is arrhythmogenic right ventricular cardiomyopathy (ARVC); left and biventricular dominant forms of the disease are well documented [3,14,15,16], including lamin types A/C (LMNA) and phospholamban (PLN) cardiomyopathies [17,18]. Due to the absence of a single test that can confirm the condition, its diagnosis can be challenging This has necessitated the development of task force criteria in an effort to standardize ACM diagnosis. This review focuses on our current knowledge of the genetics underlying ACM and the mechanisms leading to disease onset and progression. Current disease models of ACM and environmental factors shown to contribute to disease development and progression will be discussed, followed by a review of recent studies examining promising future therapeutics
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