Myocardial Substrate Metabolism in the Normal and Failing Heart

Abstract

The alterations in myocardial energy substrate metabolism that occur in heart failure, and the causes and consequences of these abnormalities, are poorly understood. There is evidence to suggest that impaired substrate metabolism contributes to contractile dysfunction and to the progressive left ventricular remodeling that are characteristic of the heart failure state. The general concept that has recently emerged is that myocardial substrate selection is relatively normal during the early stages of heart failure; however, in the advanced stages there is a downregulation in fatty acid oxidation, increased glycolysis and glucose oxidation, reduced respiratory chain activity, and an impaired reserve for mitochondrial oxidative flux. This review discusses 1) the metabolic changes that occur in chronic heart failure, with emphasis on the mechanisms that regulate the changes in the expression of metabolic genes and the function of metabolic pathways; 2) the consequences of these metabolic changes on cardiac function; 3) the role of changes in myocardial substrate metabolism on ventricular remodeling and disease progression; and 4) the therapeutic potential of acute and long-term manipulation of cardiac substrate metabolism in heart failure.

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

“…As a reflection of impaired or dysregulated FAO, the elevated plasma LCAC observed may suggest a shared metabolic impairment of the HF clinical syndrome independent of LVEF 13, 53, 54. Given that FAO impairments or dysregulation may result from a variety of mitochondrial insults, further investigation will be needed to identify the causal processes underlying the LCAC elevations reported in this study 12, 83. Given mounting evidence that LCACs are proinflammatory, arrhythmogenic, and induce cell stress, our findings may suggest a benefit for mitochondrial therapies that decrease LCAC production by increasing glucose oxidation, decreasing FAO flux, or improving mitochondrial function by antioxidant activity 63, 64, 65, 66, 67, 68.…”

Modeling the Transition From Decompensated to Pathological Hypertrophy

“…Mitochondrial oxidation of long‐chain fatty acids (FAs) accounts for 60% to 90% of the energy used by the adult heart under normal physiological conditions, with glucose and lactate oxidation providing the remainder 1, 2, 3, 4. The healthy heart is metabolically flexible and can readily switch between energy substrates as dictated by substrate availability, hormonal status, and physiological environment 5.…”

Excitation-contraction coupling and mitochondrial energetics

“…The electrons that travel down the respiratory chain are eventually transferred to O 2 , forming H 2 O. O 2 consumption is respiration. At complex V of the respiratory chain (the F 1 /F 0 -ATPase), Δµ H provides the free energy for the generation of ATP from ADP (oxidative phosphorylation) [45,187]. …”

“…Decreased SR Ca 2+ -ATPase activity is partly compensated by increased expression and activity of the NCX [16,65,93,146,178,190] The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na [58,121,[203][204][205]. During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212] Are defects in EC coupling linked to energy starvation in heart failure?Besides defects in EC coupling, the failing heart is energy-starved [99,187,211]. The total cellular levels of PCr, but also NAD and adenine nucleotides, are reduced in patients with heart failure [11,99,188].…”