Allele-specific dysregulation of lipid and energy metabolism in early-stage hypertrophic cardiomyopathy

Introduction Hypertrophic cardiomyopathy (HCM) results from pathogenic variants in sarcomeric protein genes that increase myocyte energy demand and lead to cardiac hypertrophy. But whether a common metabolic trait underlies the cardiac phenotype at the early disease stage is unknown. To address this question and define cardiac biochemical pathology in early-stage HCM, we studied two HCM mouse models that express pathogenic variants in cardiac troponin T (TnT) or myosin heavy chain (αMyHC) genes. R92W-TnT+/− and R403Q-MyHC+/− mutant mice show marked differences in cardiac imaging phenotype and mitochondrial function at the early disease stage. Methods We used a combination of echocardiography, transcriptomics, mass spectrometry-based untargeted metabolomics (GC-TOF, HILIC, CSH-QTOF) and computational modeling (CardioNet), to examine cardiac structural and metabolic remodeling, at early disease stage (5 weeks of age) in R92W-TnT+/− and R403Q-MyHC+/− mutant mice. Data from mutants was compared with respective littermate controls (WT). Results Allele-specific differences in cardiac phenotype, gene expression and metabolites were observed at early disease stage. LV diastolic dysfunction was prominent in TnT mutants. Differentially expressed genes in TnT mutant hearts were predominantly enriched in the Krebs cycle, respiratory electron transport, and branched-chain amino acid metabolism. MyHC mutants enriched mitochondrial biogenesis, calcium homeostasis, and liver-X-receptor signaling. Both mutant hearts demonstrated significant alterations in purine nucleoside, trisaccharide levels, dicarboxylic acids, acylcarnitines, phosphatidylethanolamines, phosphatidylinositols, ceramides and triglycerides; 40.4 % of lipids and 24.7 % of metabolites were significantly different in TnT mutants, whereas 10.4 % of lipids and 5.8 % of metabolites were significantly different in MyHC mutants. Both mutants had a lower abundance of unsaturated long-chain acyl-carnitines (18:1, 18:2, 20:1), but only TnT mutants showed enrichment of FA18:0 in ceramide and cardiolipin species. CardioNet predicted impaired energy substrate metabolism and greater phospholipid remodeling in TnT mutants than MyHC-mutants. Conclusions R92W-TnT and R403Q-MyHC mutant hearts demonstrate marked differences in metabolic remodeling, with TnT mutants showing greater derangements than MyHC mutants, at early disease stage. Changes in cardiolipin composition in TnT mutants could underlie impaired mitochondrial function, energy metabolism, diastolic dysfunction, and predispose to energetic stress and ventricular arrhythmias under high workloads such as exercise.