Metabolic Mechanisms in Heart Failure

Abstract

Abstract-Although neurohumoral antagonism has successfully reduced heart failure morbidity and mortality, the residual disability and death rate remains unacceptably high. Though abnormalities of myocardial metabolism are associated with heart failure, recent data suggest that heart failure may itself promote metabolic changes such as insulin resistance, in part through neurohumoral activation. A detrimental self-perpetuating cycle (heart failure 3 altered metabolism 3 heart failure) that promotes the progression of heart failure may thus be postulated. Accordingly, we review the cellular mechanisms and pathophysiology of altered metabolism and insulin resistance in heart failure. It is hypothesized that the ensuing detrimental myocardial energetic perturbations result from neurohumoral activation, increased adverse free fatty acid metabolism, decreased protective glucose metabolism, and in some cases insulin resistance. The result is depletion of myocardial ATP, phosphocreatine, and creatine kinase with decreased efficiency of mechanical work. On the basis of the mechanisms outlined, appropriate therapies to mitigate aberrant metabolism include intense neurohumoral antagonism, limitation of diuretics, correction of hypokalemia, exercise, and diet. We also discuss more novel mechanistic-based therapies to ameliorate metabolism and insulin resistance in heart failure. For example, metabolic modulators may optimize myocardial substrate utilization to improve cardiac function and exercise performance beyond standard care. The ultimate success of metabolic-based therapy will be manifest by its capacity further to lessen the residual mortality in heart failure. Key Words: fatty acids Ⅲ glucose Ⅲ heart failure Ⅲ insulin resistance D espite significant therapeutic advances, heart failure (HF) remains a leading cause of morbidity and mortality in developed 1 and increasingly in developing countries, 2 with a 5-year mortality rate of Ϸ50%, which rivals or exceeds that of many cancers. 3 This unacceptably high residual mortality and morbidity has mandated a reevaluation of cardiac biology with the aim to identify novel therapeutic strategies for HF. Because the daily turnover of ATP (Ϸ6 to 35 kg) is very many times that of the myocardial ATP pool, and even the healthy heart only extracts Ϸ25% of energy derivable from substrates, 4 it is not surprising that even subtle variations in the efficiency of energy generation or utilization may have a profound cumulative impact on cellular energy levels. 5 Thus cardiac energetics in particular and metabolism in general represent promising targets for HF therapy. 6 Correspondingly, numerous studies have identified decreased cardiac energy levels and flux as a consistent feature of HF. 6,7 These observations have been reinforced by genomic studies 8 and have focused considerable attention on metabolic modulation as a therapy for HF. 6 Specifically, altered myocardial carbohydrate metabolism and the related state of myocardial insulin resistance (IR), in which given concentrations of...

Experience using high-dose glucose-insulin-potassium (GIK) in critically ill patients

“…A compensatory increase in anaerobic glycolysis occurs, however this is a less efficient producer of ATP compared to aerobic respiration (oxidative phosphorylation). A decrease in oxidative phosphorylation caused by inhibition of the fatty acid transporter, acylpalmitoyltransferase-1 (APT-1), may also result in less oxidation of FFA, thereby increasing plasma levels still further [29]. High levels of FFA have pro-inflammatory and pro-oxidant actions and reduce mitochondrial efficiency [30,31].…”

Role of lipids and lipoproteins in myocardial biology and in the development of heart failure

“…The daily turnover of ATP in the human heart (13 mol or more than 6 kg) is many times higher than the weight of the heart [18]. 145…”

“…The daily turnover of ATP in the human heart (13 mol or more than 6 kg) is many times higher than the weight of the heart [18]. Metabolic homeostasis requires a finetuning of cardiac metabolism of different substrates.…”

Myocardial substrate metabolism in obesity

“…The major function of the electron transport chain is to produce a proton electrochemical potential difference between two compartments that powers ATP synthase to generate ATP, which is used for all cardiac cellular processes. 4 ATP is the heart's only immediate source of energy for contraction, and as both systole and diastole are ATP-consuming processes, 5,6 cardiac ATP demand is very high. To keep up with this demand for continuous and efficient contraction and relaxation, the heart needs to produce around 20 times its own weight in ATP per day.…”

“…5,14 As such, isolating the effects of obesity per se on cardiac metabolism is difficult, but given the ever-increasing incidence of obesity and its links to heart failure 8 and mortality, 15 understanding the alterations of myocardial metabolism that occur in obesity are of great importance and may provide therapeutic options to treat or prevent cardiac dysfunction. This review focuses on the current knowledge of the changes in myocardial metabolism that occur in obesity without established co-morbidities.…”