Defects in the Proteome and Metabolome in Human Hypertrophic Cardiomyopathy

Abstract

BACKGROUND: Defects in energetics are thought to be central to the pathophysiology of hypertrophic cardiomyopathy (HCM); yet, the determinants of ATP availability are not known. The purpose of this study is to ascertain the nature and extent of metabolic reprogramming in human HCM, and its potential impact on contractile function. METHODS: We conducted proteomic and targeted, quantitative metabolomic analyses on heart tissue from patients with HCM and from nonfailing control human hearts. RESULTS: In the proteomic analysis, the greatest differences observed in HCM samples compared with controls were increased abundances of extracellular matrix and intermediate filament proteins and decreased abundances of muscle creatine kinase and mitochondrial proteins involved in fatty acid oxidation. These differences in protein abundance were coupled with marked reductions in acyl carnitines, byproducts of fatty acid oxidation, in HCM samples. Conversely, the ketone body 3-hydroxybutyrate, branched chain amino acids, and their breakdown products, were all significantly increased in HCM hearts. ATP content, phosphocreatine, nicotinamide adenine dinucleotide and its phosphate derivatives, NADP and NADPH, and acetyl CoA were also severely reduced in HCM compared with control hearts. Functional assays performed on human skinned myocardial fibers demonstrated that the magnitude of observed reduction in ATP content in the HCM samples would be expected to decrease the rate of cross-bridge detachment. Moreover, left atrial size, an indicator of diastolic compliance, was inversely correlated with ATP content in hearts from patients with HCM. CONCLUSIONS: HCM hearts display profound deficits in nucleotide availability with markedly reduced capacity for fatty acid oxidation and increases in ketone bodies and branched chain amino acids. These results have important therapeutic implications for the future design of metabolic modulators to treat HCM.

Targeting lipid metabolism as a new therapeutic strategy for inherited cardiomyopathies

“…Besides these two major metabolic processes, enhanced ketone body metabolism is also shown in DCM and HCM (56,57). Interestingly, suppressed oxidative metabolism, amino acid metabolism, pentose phosphate pathway, and nucleotide metabolism are observed in DCM (58)(59)(60)(61), whereas they are all elevated in HCM (19,(62)(63)(64)(65). A recent study further examined the metabolic alterations in DCM and HCM hearts as compared to non-failing control hearts at the global transcriptional level and demonstrated impaired metabolic signaling of fatty acids, carbohydrates, and amino acids in both DCM and HCM hearts (66).…”

Applications of multi‐omics analysis in human diseases

“…Additionally, there has a quantifiable correlation between metabolomics and other omics (genomics, transcriptomics, proteomics, etc. ), such as mRNA count can predict metabolite level, 36 gut bacteria has a correlation with amino acids level in patients with fibromyalgia, 37 the expressions of creatine kinase and mitochondrial protein are consistent with acylcarnitine and acetyl‐CoA in human hypertrophic cardiomyopathy 38 . Moreover, the Human Metabolome Database (https://hmdb.ca/) is a free database containing detailed information of small molecule metabolites in the human body that can be used for metabolomics research, 39 and the corresponding metabolites analysis can be performed by MetaboAnalyst 5.0 (https://www.metaboanalyst.ca/, a free platform for metabolomics analysis) 40 .…”

Lipid overload - a culprit for hypertrophic cardiomyopathy?

“…However, increased contractility and the resulting higher energy demand must be supported by efficient metabolism. Inefficient energy utilization has been shown to cause energetic stress and adverse remodeling [11] . Two recent multi-omics studies have shown that energy metabolism is impaired in the heart of HCM patients [12,13] .…”

“…Inefficient energy utilization has been shown to cause energetic stress and adverse remodeling [ 11 ] . Two recent multi-omics studies have shown that energy metabolism is impaired in the heart of HCM patients [ 12 , 13 ] . In particular, increased levels of free fatty acids and reduced acylcarnitines, with broadly downregulated gene expression and protein reduction across fatty acids transport, activation, and β-oxidation, suggest a severely depressed fatty acid metabolism associated with HCM, similar to what have been reported in the advanced heart failure.…”

“…The observed lipid accumulation in cTnI R186Q knockin hearts is most likely a result of enhanced fatty acid synthesis, rather than the impaired or slowed breakdown of fatty acids, as the proteins involved in the fatty acid β-oxidation pathway were overall unchanged. Interestingly, human studies on HCM hearts with both sarcomeric and non-sarcomeric variants did not reveal accumulation of triacylglyceride, i.e., lipid droplets [ 12 , 13 ] . Further previous animal models, including those with other cTnI variant transgenic models, which recapitulated phenotypic HCM, did not reveal a fatty acid accumulation phenotype [ 14 ] .…”