Retained Metabolic Flexibility of the Failing Human Heart

Abstract

BACKGROUND: The failing heart is traditionally described as metabolically inflexible and oxygen starved, causing energetic deficit and contractile dysfunction. Current metabolic modulator therapies aim to increase glucose oxidation by increasing oxygen efficiency of adenosine triphosphate production, with mixed results. METHODS: To investigate metabolic flexibility and oxygen delivery in the failing heart, 20 patients with nonischemic heart failure with reduced ejection fraction (left ventricular ejection fraction 34.9±9.1) underwent separate infusions of insulin+glucose infusion (I+G) or Intralipid infusion. We used cardiovascular magnetic resonance to assess cardiac function and measured energetics using phosphorus-31 magnetic resonance spectroscopy. To investigate the effects of these infusions on cardiac substrate use, function, and myocardial oxygen uptake (MV o 2 ), invasive arteriovenous sampling and pressure–volume loops were performed (n=9). RESULTS: At rest, we found that the heart had considerable metabolic flexibility. During I+G, cardiac glucose uptake and oxidation were predominant (70±14% total energy substrate for adenosine triphosphate production versus 17±16% for Intralipid; P =0.002); however, no change in cardiac function was seen relative to basal conditions. In contrast, during Intralipid infusion, cardiac long-chain fatty acid (LCFA) delivery, uptake, LCFA acylcarnitine production, and fatty acid oxidation were all increased (LCFA 73±17% of total substrate versus 19±26% total during I+G; P =0.009).Myocardial energetics were better with Intralipid compared with I+G (phosphocreatine/adenosine triphosphate 1.86±0.25 versus 2.01±0.33; P =0.02), and systolic and diastolic function were improved (LVEF 34.9±9.1 baseline, 33.7±8.2 I+G, 39.9±9.3 Intralipid; P <0.001). During increased cardiac workload, LCFA uptake and oxidation were again increased during both infusions. There was no evidence of systolic dysfunction or lactate efflux at 65% maximal heart rate, suggesting that a metabolic switch to fat did not cause clinically meaningful ischemic metabolism. CONCLUSIONS: Our findings show that even in nonischemic heart failure with reduced ejection fraction with severely impaired systolic function, significant cardiac metabolic flexibility is retained, including the ability to alter substrate use to match both arterial supply and changes in workload. Increasing LCFA uptake and oxidation is associated with improved myocardial energetics and contractility. Together, these findings challenge aspects of the rationale underlying existing metabolic therapies for heart failure and suggest that strategies promoting fatty acid oxidation may form the basis for future therapies.

RETRACTED: GIPC1 remodels lipid metabolism by transporting DECR1 into mitochondria against ferroptosis during dilated cardiomyopathy (DCM)

“…Especially, 60-90% of the energy necessary for contractile function was provided from mitochondrial fatty acid β-oxidation (FAO), which required a series of enzymes, transporters, and facilitating proteins 9,10 . DECR1, also known as 2,4-dienoyl-CoA reductase, is a key enzyme involved in the auxiliary pathway of FAO, which catalyzes the rate-limiting step during polyunsaturated fatty acids (PUFAs) β-oxidation 11,12 .…”

Myocardial sodium–glucose cotransporter 2 expression and cardiac remodelling in patients with severe aortic stenosis: The BIO‐AS study

“…33 This energy imbalance might trigger increased SGLT2 expression, precipitating a metabolic shift from primarily lipid-based to carbohydrate-based metabolism, resulting in reduced ATP synthesis and functional inefficiency. 36 In this context, our study reveals that in patients with LF-LG AS, GLUT4, and NHE1 levels are elevated, causing a plausible increase in intracellular concentrations of glucose, sodium, and a reduction in H + levels. The described structural and metabolic perturbations might promote: (i) metabolic shift by upregulating PPAR-γ while downregulating PPAR-α expression, favouring carbohydrate over lipid metabolism; (ii) fibrosis and cardiac remodelling, as suggested by tissue TGF-β 37 and collagen over-expression, and by increased levels of circulating galectin-3, and sST2; (iii) inflammation, by rising GDF-15 and phosphorylated NF-κB(S276) (active form) levels, subsequently increasing IL-6 gene expression;…”

Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial

“…We chose this as IC because a peroral meal intake is known to increase cardiac function per se. 44 Although this approach allowed a direct comparison of hemodynamic responses to KE, it did not account for a true placebo effect. The study intervention was not weight adjusted, but KE dosing induced significant ketosis in all participants, underscoring its high bioavailability.…”