Metabolic Origins of Heart Failure

Abstract

For more than half a century, metabolic perturbations have been explored in the failing myocardium, highlighting a reversion to a more fetal-like metabolic profile (characterized by depressed fatty acid oxidation and concomitant increased reliance on glucose utilization). More recently, alterations in ketone body and amino acid/protein metabolism have been described during heart failure, as well as mitochondrial dysfunction and perturbed metabolic signaling (e.g., acetylation, O-GlcNAcylation). Although numerous mechanisms are likely involved, the current review provides recent advances regarding the metabolic origins of heart failure, and their potential contribution toward contractile dysfunction of the heart.

Keywords: amino acids; fatty acids; glucose; heart failure; ketone bodies.

Graphical abstract

Figure 1

Glucose Contributions to Myocardial Dysfunction During Heart Failure Increased glucose uptake channels carbon into the polyol, PPP, and HBP pathways; this likely contributes to mitochondrial dysfunction, genetic reprogramming, and impaired calcium handling during heart failure. HBP = hexosamine biosynthesis; PPP = pentose phosphate pathway; ROS = reactive oxygen species.

Figure 2

Myocardial Ketone Body Metabolism in the Failing Heart Elevated levels of β-OHB during heart failure provide excess acetyl-CoA for acetylation reactions and inhibit deacetylation at the same time. Increased ketone bodies also likely compete for the oxidation of fatty acids and glucose and potentially activate cell surface receptors. CoA = coenzyme A.

Figure 3

Perturbations in Amino Acid Metabolism During Heart Failure During heart failure, intracardiac branched chain amino acids are increased while taurine levels are decreased, leading to impairments in autophagy, mitochondrial function, and calcium homeostasis. BCAA = branched-chain amino acids; BCKA = branched chain alpha-keto acids; LAT = large neutral amino acid transporter; mTOR = mammalian target of rapamycin; TauT = taurine transporter; TCA = tricarboxylic acid.

Central Illustration

Hypothetical Model for the Metabolic Origins of Heart Failure ADP = adenosine diphosphate; AMP = adenosine monophosphate; AMPK = adenosine monophosphate kinase; ATP = adenosine triphosphate; BCAA = branched-chain amino acids; BCKA = branched chain keto acid; BCKDH = branched chain keto acid dehydrogenase; CoA = coenzyme A; FA = fatty acid; FAO = fatty acid oxidation; KB = ketone body; mTOR = mammalian target of rapamycin.

Figure 4

Increased Circulating Levels of Various Substrates During Heart Failure ANP = atrial natriuretic peptide; BNP = brain natriuretic peptide; FA = fatty acid; FAO = fatty acid oxidation; GLOX = glucose oxidation; KB = ketone body; other abbreviation as in Figure 2.