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Multi-Omics Approach Profiling Metabolic Remodeling in Early Systolic Dysfunction and in Overt Systolic Heart Failure.

ABSTRACT: Metabolic remodeling plays an important role in the pathophysiology of heart failure (HF). We sought to characterize metabolic remodeling and implicated signaling pathways in two rat models of early systolic dysfunction (MOD), and overt systolic HF (SHF). Tandem mass tag-labeled shotgun proteomics, phospho-(p)-proteomics, and non-targeted metabolomics analyses were performed in left ventricular myocardium tissue from Sham, MOD, and SHF using liquid chromatography-mass spectrometry, n = 3 biological samples per group. Mitochondrial proteins were predominantly down-regulated in MOD (125) and SHF (328) vs. Sham. Of these, 82% (103/125) and 66% (218/328) were involved in metabolism and respiration. Oxidative phosphorylation, mitochondrial fatty acid β-oxidation, Krebs cycle, branched-chain amino acids, and amino acid (glutamine and tryptophan) degradation were highly enriched metabolic pathways that decreased in SHF > MOD. Glycogen and glucose degradation increased predominantly in MOD, whereas glycolysis and pyruvate metabolism decreased predominantly in SHF. PKA signaling at the endoplasmic reticulum-mt interface was attenuated in MOD, whereas overall PKA and AMPK cellular signaling were attenuated in SHF vs. Sham. In conclusion, metabolic remodeling plays an important role in myocardial remodeling. PKA and AMPK signaling crosstalk governs metabolic remodeling in progression to SHF.

SUBMITTER: Chaanine AH

PROVIDER: S-EPMC8745344 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Despite advances in pharmacologic therapy and devices, patients with heart failure (HF) continue to have significant rehospitalization rates and risk prediction remains challenging. We sought to explore the value of a multi-biomarker panel [including NT-proBNP, high-sensitivity cardiac troponin T (hs-TnT), and ST2] on top of clinical assessment for long-term prediction of recurrent hospitalizations in HF. METHODS AND RESULTS:NT-proBNP, hs-TnT, and ST2 (suppression of tumorigenicity-2) levels were measured in 891 consecutive ambulatory HF patients. The independent association between the multi-biomarker panel and recurrent hospitalizations was assessed through a multivariable negative binomial regression and expressed as incidence rates ratios. McFadden pseudo-R2 and goodness-of-fit measures were also used. The total number of unplanned hospitalizations [all-cause, cardiovascular (CV)-, and HF-related] were selected as the primary endpoints. At a mean follow-up of 4.2?±?2.1?years, 1623 all-cause hospitalizations in 498 patients (55.9%), 710 CV-related hospitalizations in 331 patients (37.2%), and 444 HF-related hospitalizations in 214 patients (24.1%) were registered. The crude incidence of all-cause, CV-, and HF-related recurrent hospitalizations was significantly higher for patients with the multi-biomarker panel above the cut-point (hs-TnT?>?14?ng/L, NT-proBNP?>?1000?ng/L, and ST2?>?35?ng/mL) (all P?<?0.001). For all-cause, CV-, and HF-related recurrent hospitalizations, the McFadden R2, Akaike information criterion, and Bayesian information criterion supported the superiority of incorporating the multi-biomarker panel into a clinical predictive model. CONCLUSION:A multi-biomarker approach based on NT-proBNP, hs-TnT, and ST2 better identifies HF patients at risk for recurrent hospitalizations as compared to approaches entailing just one or two of these biomarkers. Elucidation of new biophysiological predictors for recurrent hospitalizations may identify patient profiles for focused intervention.

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Multi-Omics Approach Profiling Metabolic Remodeling in Early Systolic Dysfunction and in Overt Systolic Heart Failure.

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