Loss of Metabolic Flexibility in the Failing Heart

Abstract

To maintain its high energy demand the heart is equipped with a highly complex and efficient enzymatic machinery that orchestrates ATP production using multiple energy substrates, namely fatty acids, carbohydrates (glucose and lactate), ketones and amino acids. The contribution of these individual substrates to ATP production can dramatically change, depending on such variables as substrate availability, hormonal status and energy demand. This “metabolic flexibility” is a remarkable virtue of the heart, which allows utilization of different energy substrates at different rates to maintain contractile function. In heart failure, cardiac function is reduced, which is accompanied by discernible energy metabolism perturbations and impaired metabolic flexibility. While it is generally agreed that overall mitochondrial ATP production is impaired in the failing heart, there is less consensus as to what actual switches in energy substrate preference occur. The failing heart shift toward a greater reliance on glycolysis and ketone body oxidation as a source of energy, with a decrease in the contribution of glucose oxidation to mitochondrial oxidative metabolism. The heart also becomes insulin resistant. However, there is less consensus as to what happens to fatty acid oxidation in heart failure. While it is generally believed that fatty acid oxidation decreases, a number of clinical and experimental studies suggest that fatty acid oxidation is either not changed or is increased in heart failure. Of importance, is that any metabolic shift that does occur has the potential to aggravate cardiac dysfunction and the progression of the heart failure. An increasing body of evidence shows that increasing cardiac ATP production and/or modulating cardiac energy substrate preference positively correlates with heart function and can lead to better outcomes. This includes increasing glucose and ketone oxidation and decreasing fatty acid oxidation. In this review we present the physiology of the energy metabolism pathways in the heart and the changes that occur in these pathways in heart failure. We also look at the interventions which are aimed at manipulating the myocardial metabolic pathways toward more efficient substrate utilization which will eventually improve cardiac performance.

Weight loss enhances cardiac energy metabolism and function in heart failure associated with obesity

“…Insulin resistance causes significant metabolic perturbations in cardiac energy metabolism, which include a decrease in insulin-stimulated glucose oxidation and a decrease in the contribution of glucose oxidation to cardiac ATP production. Accordingly, cardiac insulin resistance can exacerbate the energy deficit seen in heart failure and, as a consequence, exacerbate cardiac dysfunction in the failing heart 32. Indeed, we demonstrate that obese mice with heart failure exhibit a marked increase in insulin resistance, not only in the failing heart, but also in the entire body.…”

“…However, these high rates of fatty acid oxidation that are driven by obesity, in fact further jeopardized cardiac function and hypertrophy in the obese mice with heart failure as compared to non‐obese mice with heart failure. Moreover, obesity exacerbated cardiac insulin resistance in the obese mice with heart failure, which correlates with further attenuation of cardiac insulin signalling, further reduction in insulin‐stimulated glucose oxidation rates and further enhancement of the phosphorylation and acetylation of PDH, both suggested to inhibit its activity . Obesity‐derived cardiac metabolic perturbations did not improve cardiac function, hypertrophy or energy metabolism in the failing heart, which does not support the notion of the “obesity paradox”.…”

“…Importantly, these perturbations in mitochondrial acetylation regulatory enzymes were further aggravated in the HF TAC hearts as compared to the LF TAC hearts (Figure I,J). Taking these data into account, it seems plausible to suggest that the high rates of fatty acid oxidation in the failing heart occur, at least in part, through enhancement of the acetylation of β‐oxidation enzymes, which is shown to increase their activity …”

“…Obesity‐derived cardiac metabolic perturbations did not improve cardiac function, hypertrophy or energy metabolism in the failing heart, which does not support the notion of the “obesity paradox”. This could be explained by the fact that there is a decrease in oxygen availability in the failing heart and that fatty acid oxidation is a less efficient oxygen source of energy (P/O ratio = 2.33) as compared to glucose oxidation (P/O ratio = 2.58) . Therefore, it seems plausible to suggest that obesity‐induced excessively high rates of fatty acid oxidation would jeopardize cardiac function and energy production rather than being cardioprotective.…”

Cardiac metabolic modulation upon low‐carbohydrate low‐protein ketogenic diet in diabetic rats studied in vivo using hyperpolarized 13C pyruvate, butyrate and acetoacetate probes

“…A diabetic heart may develop cardiomyopathy despite the absence of underlying cardiovascular conditions, which can be attributed to its increased preference for fatty acid metabolism . Indeed, heart failure development has also been associated with altered cardiac substrate metabolism . Of note, the role of ketone bodies in cardiometabolic health has also been increasingly appreciated .…”