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Fibrosis in Arrhythmogenic Cardiomyopathy: The Phantom Thread in the Fibro-Adipose Tissue
Angela Serena Maione1, Chiara Assunta Pilato1, Michela Casella2
1Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino IRCCS, Milan, Italy.
Insights
Arrhythmogenic cardiomyopathy (ACM) involves inherited heart dysfunction leading to sudden death. This review focuses on understanding the molecular mechanisms driving cardiac fibrosis in ACM, a key pathological feature.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disorder causing malignant ventricular arrhythmias and sudden cardiac death, especially in young individuals.
- Pathological hallmarks include progressive myocardial loss with fibrous or fibro-fatty substitution.
- While genetic mutations, often in desmosomal genes, are found in 50% of ACM patients, the underlying molecular mechanisms remain unclear.
Purpose of the Study:
- To review the cellular effectors, potential triggers, and molecular mechanisms responsible for ventricular fibrotic remodeling in arrhythmogenic cardiomyopathy.
- To shift focus towards understanding cardiac fibrosis as the primary tissue feature in ACM, as per Task Force Criteria.
Main Methods:
- Literature review of studies investigating ACM pathogenesis.
- Analysis of molecular mechanisms related to cardiomyocyte death and fibrotic replacement.
- Examination of cellular pathways implicated in ventricular remodeling.
Main Results:
- Previous research has primarily focused on adipose substitution in ACM, overlooking the significance of fibrosis.
- Cardiomyocyte death and subsequent fibrous replacement are critical features of ACM.
- Several molecular mechanisms and cellular effectors are proposed to drive fibrotic remodeling in ACM.
Conclusions:
- Understanding the molecular basis of cardiac fibrosis in ACM is crucial for diagnosis and treatment.
- Further research into the triggers and pathways of fibrotic remodeling is warranted.
- This review synthesizes current knowledge on ACM cardiac fibrosis, highlighting key areas for future investigation.
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.
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