ArticleCardiovascular diabetology2019
Impaired branched chain amino acid oxidation contributes to cardiac insulin resistance in heart failure.
Article in Cardiovascular diabetology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers.
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Who cites it
119 citing papers in PubMed.
- A randomized placebo-controlled clinical trial for pharmacological activation of BCAA catabolism in patients with type 2 diabetes.Nature communications · 2022Trial
- The Gut Microbiota-Metabolite-Host Axis in Cardiometabolic Diseases: Bridging Bench to Bedside.Cardiovascular drugs and therapy · 2026Review
- Cardiac fibrosis: mechanistic insights and translational advances.Molecular biomedicine · 2026Review
- BCKDK protects against obesity-induced cardiac remodelling and dysfunction by alleviating mitochondrial oxidative stress and ROS-driven MAPK signalling.Redox biology · 2026Article
- A Slc5a6-deficient mouse model reveals metabolically driven cardiomyopathy with therapeutic potential for vitamin-based intervention.JCI insight · 2026Article
- Association Between Serum Leucine and NT-proBNP Levels in Relation to Fragmented QRS: A Multiomic Analysis of the HOZUGAWA Cohort.Nutrients · 2026Article
- Dynamic [Research square · 2026Article
- Defects in auxiliary fuel oxidation and mitochondrial pyruvate transport mark transition to overt heart failure in Tgαq*44 mice.Journal of translational medicine · 2026Article
- Microbial Metabolite 4EPS Inhibits AT1R to Reduce Blood Pressure and Aortic Aneurysm Outcome.Hypertension (Dallas, Tex. : 1979) · 2026Article
- BCAA Metabolic Dyshomeostasis in Cardiovascular Disease: Pathogenic Mechanisms and Intervention.American journal of cardiovascular drugs : drugs, devices, and other interventions · 2026Review
- Biomarkers of Cardiac Metabolic Flexibility in Health, HFrEF and HFpEF.International journal of molecular sciences · 2026Review
- Research progress on metabolic abnormalities in myocardial hypertrophy.Frontiers in cardiovascular medicine · 2026Review
- Metabolic reprogramming in cardiac fibrosis: mechanisms, crosstalk, and therapeutic interventions.Frontiers in physiology · 2026Review
- Integrated bioinformatic and in vivo analysis confirms the cardioprotective role of OPA1.BMC cardiovascular disorders · 2025Article
- Early branched-chain amino acid reduction delays the onset of cognitive decline in a mouse model of Alzheimer's disease.Journal of Alzheimer's disease : JAD · 2025Article
- Integrated multi-omics mapping of mitochondrial dysfunction and substrate preference in Barth syndrome cardiac tissue.EMBO molecular medicine · 2025Article
- Empagliflozin enhances metabolic efficiency and improves left ventricular hypertrophy in a hypertrophic cardiomyopathy mouse model.European heart journal · 2025Article
- Cardiac intermediary metabolism in heart failure: substrate use, signalling roles and therapeutic targets.Nature reviews. Cardiology · 2025Review
- Left ventricular myocardial molecular profile of human diabetic ischaemic cardiomyopathy.EMBO molecular medicine · 2025Article
- Role of branched chain amino acid metabolism on aging.Biogerontology · 2025Review
59 more citing papers are in PubMed but not listed here.
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17 authors.
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Abstract
backgroundBranched chain amino acids (BCAA) can impair insulin signaling, and cardiac insulin resistance can occur in the failing heart. We, therefore, determined if cardiac BCAA accumulation occurs in patients with dilated cardiomyopathy (DCM), due to an impaired catabolism of BCAA, and if stimulating cardiac BCAA oxidation can improve cardiac function in mice with heart failure.
methodFor human cohorts of DCM and control, both male and female patients of ages between 22 and 66 years were recruited with informed consent from University of Alberta hospital. Left ventricular biopsies were obtained at the time of transplantation. Control biopsies were obtained from non-transplanted donor hearts without heart disease history. To determine if stimulating BCAA catabolism could lessen the severity of heart failure, C57BL/6J mice subjected to a transverse aortic constriction (TAC) were treated between 1 to 4-week post-surgery with either vehicle or a stimulator of BCAA oxidation (BT2, 40 mg/kg/day).
resultEchocardiographic data showed a reduction in ejection fraction (54.3 ± 2.3 to 22.3 ± 2.2%) and an enhanced formation of cardiac fibrosis in DCM patients when compared to the control patients. Cardiac BCAA levels were dramatically elevated in left ventricular samples of patients with DCM. Hearts from DCM patients showed a blunted insulin signalling pathway, as indicated by an increase in P-IRS1ser636/639 and its upstream modulator P-p70S6K, but a decrease in its downstream modulators P-AKT ser473 and in P-GSK3β ser9. Cardiac BCAA oxidation in isolated working hearts was significantly enhanced by BT2, compared to vehicle, following either acute or chronic treatment. Treatment of TAC mice with BT2 significantly improved cardiac function in both sham and TAC mice (63.0 ± 1.8 and 56.9 ± 3.8% ejection fraction respectively). Furthermore, P-BCKDH and BCKDK expression was significantly decreased in the BT2 treated groups.
conclusionWe conclude that impaired cardiac BCAA catabolism and insulin signaling occur in human heart failure, while enhancing BCAA oxidation can improve cardiac function in the failing mouse heart.
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