Comprehensive quantification of fuel use by the failing and nonfailing human heart

Abstract

The heart consumes circulating nutrients to fuel lifelong contraction, but a comprehensive mapping of human cardiac fuel use is lacking. We used metabolomics on blood from artery, coronary sinus, and femoral vein in 110 patients with or without heart failure to quantify the uptake and release of 277 metabolites, including all major nutrients, by the human heart and leg. The heart primarily consumed fatty acids and, unexpectedly, little glucose; secreted glutamine and other nitrogen-rich amino acids, indicating active protein breakdown, at a rate ~10 times that of the leg; and released intermediates of the tricarboxylic acid cycle, balancing anaplerosis from amino acid breakdown. Both heart and leg consumed ketones, glutamate, and acetate in direct proportionality to circulating levels, indicating that availability is a key driver for consumption of these substrates. The failing heart consumed more ketones and lactate and had higher rates of proteolysis. These data provide a comprehensive and quantitative picture of human cardiac fuel use.

Fig. 1.. Human A-V metabolomics reveal distinct fuel profiles of the heart and leg.

(A) Blood was sampled simultaneously from the radial artery (A), coronary sinus (CS), and femoral vein (FV), and metabolite uptake or release was determined. (B and C) Volcano plot of metabolite abundance in the FV (B) or CS (C) relative to (A). P values were derived from one-sample Wilcoxon test and then Benjamini-Hochberg corrected (P*). Dotted line indicates P* = 0.05. (D and E) Net A-V carbon balance across the leg (D) and heart (E) shown in order of greatest to least average absolute carbon uptake or release.

Fig. 2.. Cardiac nitrogen release reveals net amino acid liberation from proteolysis.

(A) Calculated cardiac sources of free amino acids (uptake from circulation is shown in red, liberation from proteolysis in gray) and released amino acids (shown in blue). Shading is proportional to the quantity of amino acid uptake of secretion. (B) Calculated anaplerotic carbon input from amino acid consumption exceeds carbon released as TCA cycle intermediates. Anaplerotic contribution from lactate through pyruvate carboxylase (PC) could not be determined (dashed lines). All numbers are micromoles of carbon. Non-anaplerotic amino acids (leucine) and amino acids not catabolized in heart (histidine, phenylalanine, and tyrosine) were excluded. PDH, pyruvate dehydrogenase.

Fig. 3.. Comparison of myocardial substrate use in patients with preserved versus reduced ejection fraction.

(A) Calculated substrate-specific contribution to total cardiac oxygen consumption. Average measured myocardial O₂ consumption (ΔO₂) is indicated above each bar. (B) Substrate-specific contribution to cardiac ATP generation in patients with preserved ejection fraction (pEF) versus reduced ejection fraction (rEF). (C) Proportion of total ΔO₂ accounted for by the catabolism of each indicated substrate class in pEF versus rEF. (D) Net amino acid–derived nitrogen release in patients with pEF versus rEF. *P < 0.05 by t test.

Fig. 4.. Cardiac uptake of acetate, ketones, and glutamate primarily depends upon circulating concentrations in pEF and rEF.

(A) Relationship of A-V metabolite gradient (C_V – C_A) with arterial concentration of indicated metabolites by linear regression. (B) C_A versus uptake of indicated metabolites by the heart after adjustment for acetate extraction [(C_CS – C_A)_scaled; see the supplementary data]. *P < 0.05 by analysis of covariance. (C) C_A versus uptake of the indicated metabolites by the leg.