Abstract
Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disorder, predisposing to malignant ventricular arrhythmias leading to sudden cardiac death, particularly in young and athletic patients. Pathological features include a progressive loss of myocardium with fibrous or fibro-fatty substitution. During the last few decades, different clinical aspects of ACM have been well investigated but still little is known about the molecular mechanisms that underlie ACM pathogenesis, leading to these phenotypes. In about 50% of ACM patients, a genetic mutation, predominantly in genes that encode for desmosomal proteins, has been identified. However, the mutation-associated mechanisms, causing the observed cardiac phenotype are not always clear. Until now, the attention has been principally focused on the study of molecular mechanisms that lead to a prominent myocardium adipose substitution, an uncommon marker for a cardiac disease, thus often recognized as hallmark of ACM. Nonetheless, based on Task Force Criteria for the diagnosis of ACM, cardiomyocytes death associated with fibrous replacement of the ventricular free wall must be considered the main tissue feature in ACM patients. For this reason, it urges to investigate ACM cardiac fibrosis. In this review, we give an overview on the cellular effectors, possible triggers, and molecular mechanisms that could be responsible for the ventricular fibrotic remodeling in ACM patients.
Highlights
Arrhythmogenic cardiomyopathy (ACM) is a rare genetic cardiac disease, with an incidence estimated in 1:5000 (Corrado et al, 2017), which affects predominantly the right ventricle (RV), left or biventricular forms have been described
The fibrotic molecular mechanisms are known for cardiac diseases but those specific for ACM still need to be investigated in order to uncover therapeutic targets to improve ACM clinical management
The ACM specific cardiac remodeling is characterized by the progressive substitution of ventricular myocardium of patients by non-contractile fibrotic or adipose tissue
Summary
Arrhythmogenic cardiomyopathy (ACM) is a rare genetic cardiac disease, with an incidence estimated in 1:5000 (Corrado et al, 2017), which affects predominantly the right ventricle (RV), left or biventricular forms have been described. In about 50% of ACM patients, a genetic mutation can be identified, mostly in genes coding for cardiac desmosomes. The mode of inheritance is generally autosomic dominant, even if recessive syndromic forms are described (Stadiotti et al, 2019). These different genetic determinants lead to a similar disease phenotype. All forms of ACM are characterized by incomplete penetrance and variable expressivity even in carriers of the same causative mutation
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