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Branched-chain amino acids in cardiovascular disease

Abstract

Research conducted in the past 15 years has yielded crucial insights that are reshaping our understanding of the systems physiology of branched-chain amino acid (BCAA) metabolism and the molecular mechanisms underlying the close relationship between BCAA homeostasis and cardiovascular health. The rapidly evolving literature paints a complex picture, in which numerous tissue-specific and disease-specific modes of BCAA regulation initiate a diverse set of molecular mechanisms that connect changes in BCAA homeostasis to the pathogenesis of cardiovascular diseases, including myocardial infarction, ischaemia–reperfusion injury, atherosclerosis, hypertension and heart failure. In this Review, we outline the current understanding of the major factors regulating BCAA abundance and metabolic fate, highlight molecular mechanisms connecting impaired BCAA homeostasis to cardiovascular disease, discuss the epidemiological evidence connecting BCAAs with various cardiovascular disease states and identify current knowledge gaps requiring further investigation.

Key points

  • Branched-chain amino acids (BCAAs) — isoleucine, leucine and valine — are essential amino acids that have a crucial role in metabolic homeostasis through nutrient signalling.

  • High circulating concentrations of BCAAs are a hallmark of metabolic disorders, including obesity, insulin resistance and type 2 diabetes mellitus.

  • Mechanisms underlying the association between BCAAs and cardiovascular disease (CVD) are still being defined, but include activation of the serine/threonine protein kinase mTOR, mitochondrial dysfunction, shifts in cardiac substrate utilization and platelet activation.

  • Epidemiological studies have also shown that high plasma BCAA concentrations identify individuals with heart failure, coronary artery disease or hypertension and predict adverse events in these populations.

  • In some other populations (such as African American individuals without CVD and frail elderly individuals), high plasma BCAA concentrations predict improved cardiovascular outcomes.

  • Areas for future research include the roles of tissue-specific BCAA metabolism and inter-organ BCAA metabolic crosstalk in various CVD states and the roles of impaired BCAA metabolism in vascular function and atherosclerosis.

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Fig. 1: Major sources and sites of BCAA supply and utilization.
Fig. 2: Potential mechanisms connecting dysregulated BCAA metabolism with CVD.

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Acknowledgements

The authors are supported by NIH grants K08HL135275 (R.W.M.) and R01HL160689 (R.W.M.), American Diabetes Association Pathway to Stop Diabetes Award 1-16-INI-17 (P.J.W.), the Edna and Fred L. Mandel Jr. Foundation (R.W.M.) and the Duke School of Medicine Strong Start Award (R.W.M.).

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McGarrah, R.W., White, P.J. Branched-chain amino acids in cardiovascular disease. Nat Rev Cardiol (2022). https://doi.org/10.1038/s41569-022-00760-3

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