Key result
Mitochondrial dysfunction may contribute to arrhythmogenic cardiomyopathy pathogenesis by depleting ATP and increasing reactive oxygen species, leading to altered calcium handling and fibrosis.
Why the study?
A potential role of mitochondrial dysfunction in arrhythmogenic cardiomyopathy pathology is unclear and mitochondrial biology in the arrhythmogenic cardiomyopathy heart remains understudied.
Mitochondrial dysfunction may serve as a critical substrate for arrhythmogenesis and structural remodeling in arrhythmogenic cardiomyopathy, offering a potential target for future therapeutic interventions.
Mitochondrial pathways merit experimental testing as potential ACM targets; leaves open causal timing and clinical relevance.
Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease, associated with ventricular arrhythmias, fibrofatty replacement of the myocardial mass and an increased risk of sudden cardiac death (SCD). Malignant ventricular arrhythmias and SCD largely occur in the pre-clinical phase of the disease, before overt structural changes occur. To prevent or interfere with ACM disease progression, more insight in mechanisms related to electrical instability are needed. Currently, numerous studies are focused on the link between cardiac arrhythmias and metabolic disease. In line with that, a potential role of mitochondrial dysfunction in ACM pathology is unclear and mitochondrial biology in the ACM heart remains understudied. In this review, we explore mitochondrial dysfunction in relation to arrhythmogenesis, and postulate a link to typical hallmarks of ACM. Mitochondrial dysfunction depletes adenosine triphosphate (ATP) production and increases levels of reactive oxygen species in the heart. Both metabolic changes affect cardiac ion channel gating, electrical conduction, intracellular calcium handling, and fibrosis formation; all well-known aspects of ACM pathophysiology. ATP-mediated structural remodeling, apoptosis, and mitochondria-related alterations have already been shown in models of PKP2 dysfunction. Yet, the limited amount of experimental evidence in ACM models makes it difficult to determine whether mitochondrial dysfunction indeed precedes and/or accompanies ACM pathogenesis. Nevertheless, current experimental ACM models can be very useful in unraveling ACM-related mitochondrial biology and in testing potential therapeutic interventions.
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Opbergen et al. (2019) conducted a review in Arrhythmogenic Cardiomyopathy (ACM). Mitochondrial dysfunction was evaluated. Mitochondrial dysfunction may contribute to arrhythmogenic cardiomyopathy pathogenesis by depleting ATP and increasing reactive oxygen species, leading to altered calcium handling and fibrosis.
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