Metabolic Signature of Arrhythmogenic Cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a genetic-based cardiac disease accompanied by severe ventricular arrhythmias and a progressive substitution of the myocardium with fibro-fatty tissue. ACM is often associated with sudden cardiac death. Due to the reduced penetrance and variable expressivity, the presence of a genetic defect is not conclusive, thus complicating the diagnosis of ACM. Recent studies on human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) obtained from ACM individuals showed a dysregulated metabolic status, leading to the hypothesis that ACM pathology is characterized by an impairment in the energy metabolism. However, despite efforts having been made for the identification of ACM specific biomarkers, there is still a substantial lack of information regarding the whole metabolomic profile of ACM patients. The aim of the present study was to investigate the metabolic profiles of ACM patients compared to healthy controls (CTRLs). The targeted Biocrates AbsoluteIDQ® p180 assay was used on plasma samples. Our analysis showed that ACM patients have a different metabolome compared to CTRLs, and that the pathways mainly affected include tryptophan metabolism, arginine and proline metabolism and beta oxidation of fatty acids. Altogether, our data indicated that the plasma metabolomes of arrhythmogenic cardiomyopathy patients show signs of endothelium damage and impaired nitric oxide (NO), fat, and energy metabolism.

Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid β-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy

“…The cardiac FA β -oxidation rate was significantly impaired after Dsg2 deletion. This is consistent to a recent finding that ACM patients have a different metabolome compared to healthy controls, and mainly affected beta oxidation of fatty acids 17 . It is also regarded that lipid accumulation in the heart is associated with arrhythmogenicity 39 , 40 , 41 , 42 .…”

“…Impaired energy supply is regarded as the major cause of cardiac dysfunction in ACM patients 17 . The cardiac excitation–contraction coupling consumes the majority of the ATP produced by the mitochondria to fuel incessant activity 18 .…”

Targeting lipid metabolism as a new therapeutic strategy for inherited cardiomyopathies

“…By comparing the transcriptional landscapes between ACM and control human hearts, affected genes were enriched for several metabolic signaling, including mitochondrial dysfunction and oxidative phosphorylation ( 51 ). By comparing the plasma metabolomes between ACM patients and healthy individuals, affected metabolites and lipids further revealed several changed metabolic pathways, including lysine degradation, tryptophan metabolism, and the beta-oxidation of fatty acids ( 52 ). A recent paper compared transcriptional changes in RCM, ischemic heart disease, and valvular heart disease to control human hearts and showed that ATP metabolic processes were enriched by altered genes in RCM but not in the other two heart diseases ( 53 ).…”

Transcriptome Data Analysis of Primary Cardiomyopathies Reveals Perturbations in Arachidonic Acid Metabolism

“…Notably, metabolic impairment is vital in heart failure (13,14). Generally, the heart meets its energy demand by utilizing fatty acids, glucose, amino acid, lactate and ketone bodies, but cardiomyopathies lead to severe metabolic perturbation (15)(16)(17). In cardiovascular research, metabolic explorations have provided new insights (18,19).…”

“…In cardiovascular research, metabolic explorations have provided new insights (18,19). The role of metabolic genes and pathways has been explored in several cardiomyopathy studies to understand the pathophysiological changes involved in the progression of cardiomyopathy (15)(16)(17)(20)(21)(22). These studies have reported a metabolic shift in energy sources during disease progression.…”