Alterations in Cardiac Metabolism in Heart Failure

Hallmarks and Regulation of Cardiac Energy Metabolism

Cardiac energy metabolism is essential to maintain cardiac pump function. To enable the heart to beat 100,000 times a day for a lifetime, the heart exhibits a highly regulated and efficient system for adenosine triphosphate (ATP) regeneration, generating up to 6 kg of ATP every day, which is 15- to 20-fold its own weight. Thus the heart is one of the most metabolically active organs, and its prolific capacity for generating energy is underscored by the very high density of mitochondria and their unique patterns of distribution relative to areas of high energy utilization such as sarcomeres (the contractile unit) and the sarcolemma where significant changes in ionic flux occurs. Under physiologic conditions, the heart generates more than 95% of its ATP by oxidative metabolism of energy substrates; 60% to 70% of ATP arises from the oxidation of fatty acids (FAs), and 30% to 40% from the oxidation of glucose and other substrates such as lactate, amino acids, and ketone bodies, depending on their availability in the circulation. Utilization of FAs for ATP regeneration initially requires FA uptake into the cardiomyocyte via fatty acid transporters such as CD36 and the fatty acid transporters (FATP, family of proteins). Following esterification to acyl CoA by acyl-CoA synthetase, they are imported into mitochondria by transient coupling to carnitine via the carnitine palmitoyltransferase (CPT) system. Once imported into mitochondria, acyl Coenzyme A (CoA) is oxidized in the β-oxidation spiral to yield acetyl CoA and flavin adenine dinucleotide (FADH). Utilization of glucose requires sarcolemmal glucose uptake via the classical insulin-responsive glucose transporter 4 (GLUT4) and the constitutive glucose transporter (GLUT1). Recent evidence suggests that some glucose might enter the heart via the sodium-glucose transporter (SGLT1). However, GLUT4, which shuttles to the cell surface with cardiomyocyte contraction, likely accounts for the bulk of myocardial glucose uptake. Upon entering the heart, most of the glucose is metabolized via glycolysis to yield ATP, reduced nicotinamide adenine dinucleotide (NADH), and pyruvate. Additional metabolic branches of glycolysis such as the hexosamine biosynthetic pathway (HBP) or the pentose phosphate pathway (PPP) yield metabolites that play an important role in signal transduction, oxidation-reduction REDOX regulation, and nucleic acid synthesis. Pyruvate is imported into mitochondria via the mitochondrial pyruvate transporter and decarboxylated by pyruvate dehydrogenase (PDH) to acetyl CoA. Acetyl CoA derived from metabolic precursors such as glucose, FAs, and others (e.g., ketones) enters the (tricarboxylic acid) TCA cycle. Oxidation of acetyl CoA in the TCA cycle generates NADH and FADH, which donate electrons to the electron transport chain (ETC), which pumps protons into the mitochondrial intermembrane space to generate the proton-motive force that is dissipated via ATP synthase to ultimately regenerate ATP from adenosine diphosphate (ADP) by the process of oxidative phosphorylation (OXPHOS) ( Fig. 17.1 ).

Several modes of regulation adapt cardiac energetics to acute or chronic changes in energy demand. Long-term regulation of cardiac energy metabolism is usually governed by changes in gene expression. For example, transcriptional regulators that regulate genes that encode mitochondrial enzymes of mitochondrial OXPHOS can be induced or repressed by various stimuli that correlate with changes in cardiac substrate metabolism. These transcriptional regulators include nuclear receptors that regulate genes that encode fatty acid oxidation (FAO) enzymes such as peroxisome proliferator activated (PPAR)α, PPARβ/δ, and estrogen related receptor (ERR)α, transcription factors that increase OXPHOS gene expression (transcription factor A of mitochondria [TFAM], nuclear respiratory factors [NRFs], ERRα), and transcriptional coactivators that regulate both the expression of FAO and OXPHOS genes (PPAR gamma coactivator [PGC]-1α, PGC-1β]) ( Table 17.1 ). Thus conditions of FA excess such as obesity and diabetes are associated with increased expression of transcriptional regulators of FAO, whereas heart failure (HF), which is associated with decreased mitochondrial energetics capacity is associated with repression of PGC-1α. Mechanisms that acutely regulate short-term changes in energetics include signaling pathways that drive regulatory pathways via posttranslational mechanisms. One of the best-studied pathways is adenosine monophosphate-activated protein kinase (AMPK) activation, which drives catabolic pathways and inhibits anabolic pathways by phosphorylation of specific metabolic enzymes that regulate glycolysis, glycogen synthesis, and FAO. A second pathway is protein deacetylation of a broad variety of metabolic enzymes, including FAO enzymes, TCA cycle enzymes, PDH, OXPHOS subunits, and the F _O F ₁ -ATPase by a family of NAD ⁺ -dependent deacylases called sirtuins, which links cardiac metabolic capacity with nutrient sensing via NAD ⁺ . Allosteric regulation of metabolic enzymes represents another important mechanism for the short-term regulation of cardiac metabolism. This is classically exemplified by the “Randle cycle,” whereby increased FA utilization inhibits glucose utilization via increased generation of citrate, which inhibits glycolysis, and the reverse Randle cycle, whereby increased malonyl CoA that may occur when glucose utilization is increased in turn allosterically inhibits CPT1 and mitochondrial FA utilization. Cardiac energy metabolism is also acutely regulated by various stress hormones (e.g., catecholamines), cytokines, insulin signaling, changes in workload, or concentrations of metabolic substrates.

Crosstalk Between Cardiac Metabolism and Signaling

Although the main function of myocardial energy substrate metabolism is to generate ATP, metabolic intermediates also serve as signaling molecules. Both glycolysis and mitochondrial energy metabolism generate and consume NADH and thereby participate in the regulation of the NAD ⁺ /NADH ratio, which can be considered an indicator of the cellular energy charge. Accordingly, this ratio increases during energy demand and decreases under conditions of sufficient ATP supply, which in turn regulates the activity of sirtuins, which not only regulate energetics but also cellular senescence, growth, mitochondrial biogenesis, and reactive oxygen species (ROS), among other mechanisms ( see also Chapter 8 ). In addition to entering glycolysis, glucose may also enter other pathways such as the PPP and the HBP. Flux through the HBP generates glucosamine that increases O-GlcNAcylation of many proteins that regulate diverse cellular functions. These include proteins, the modification of which modulates transcription factor activity, epigenetic regulation, cellular Ca ²⁺ homeostasis, cell growth, cell survival, oxidative stress, and mitochondrial function. Flux through the PPP regulates the generation of NADPH, which, as a substrate for NADPH oxidases, serves an important generator of cytosolic ROS. PPP intermediates also maintain the levels of reduced glutathione. Thus PPP flux participates importantly in the regulation of cellular REDOX. The redox state of cells plays important roles in multiple cellular signaling pathways, including oxidative modification of regulatory proteins that includes targets such as phosphatases, protein kinases (A, D, and G), cytokines, mitogen-activated protein kinases, or insulin signaling. In this regard, the activity (i.e., forward or reverse mode) of the mitochondrial nicotinamide nucleotide transhydrogenase (NNT), which transfers electrons between NAD(H) and NADP(H) to balance ATP production and antioxidant capacity, is dependent on metabolic demand and cardiac workload. Another metabolite affecting intracellular signaling is citrate, the conversion of which to acetyl CoA by ATP-citrate lyase may contribute to direct enzyme acetylation by cytosolic acetyltransferases, as well as to nuclear histone acetylation and subsequent epigenetic regulation of gene expression. The examples discussed here are not exhaustive because many additional metabolites, such as succinate, are being identified and may regulate signaling pathways within the heart under basal conditions or in response to stressors such as ischemia/reperfusion.

Significance of Cardiac Energetics for Heart Disease

Impaired cardiac metabolism and energy depletion are well recognized to contribute to cardiac dysfunction and reduced efficiency in terms of energy transfer to contractile work ( see also Chapter 2 ). These changes, which contribute to many cardiac pathologies by impairing ATP-dependent intracellular processes such as myofilament contraction and maintenance of ion homeostasis, have been described in prevalent disorders such as myocardial ischemia reperfusion injury, diabetes-related cardiac dysfunction, cardiac hypertrophy, and HF. In ischemia reperfusion, ATP regeneration is impaired due to limited oxygen and substrate supply and to persistent impairment in OXPHOS and mitochondrial integrity. In cardiac hypertrophy, substrate preference may shift toward a relative increase in glucose utilization, accompanied by early defects in mitochondrial function, whereas in HF, overall mitochondrial oxidative metabolism can be impaired. In diabetes, increased FAO and impaired glucose utilization are associated with impaired mitochondrial ATP generation, mitochondrial uncoupling, and impaired cardiac efficiency that may be characterized by increased myocardial oxygen consumption.

Recent work has revealed important sex differences in cardiac metabolism in healthy subjects and in individuals with cardiac dysfunction or high-risk conditions such as diabetes. Myocardial oxygen consumption (MVO ₂ ) and myocardial FA utilization (MFAU) are higher in healthy females relative to males and may be related to estrogen. These differences persisted in individuals with type 2 diabetes (T2D) and in those with HF with preserved ejection fraction (HFpEF) ( see also Chapters 11 and 39 ). Myocardial blood flow (MBF) rates were higher in women with HFpEF, and MBF was correlated with better event-free survival. Despite lower rates of MFAU, diabetic men exhibited greater impairment in diastolic relaxation. In a study of normal, obese, and T2D subjects, diabetes and obesity reduced glucose utilization, but sex also had a powerful effect on glucose utilization, with levels of glucose utilization being lower in females. Because glucose uptake and metabolism rates were relatively low in nonobese women, they were not markedly different from those in obese and T2DM women. Thus the potentially detrimental effects of obesity and diabetes on myocardial glucose metabolism appear to be more pronounced in men than women.

The relevance of altered myocardial metabolism for disease development and progression is underpinned by a number of clinical trials that investigated the effects of specific metabolic interventions, in particular in HF. Some of these trials have yielded promising results despite small patient numbers, including improvements in ejection fraction (EF), HF symptoms, and HF hospitalization, although data from large randomized controlled clinical trials investigating hard clinical end points are lacking to date. Finally, a number of metabolic cardiomyopathies have been described in which a single mutation or enzyme deficiency may lead to cardiac failure, likely due to impairment in cardiac energetics, further emphasizing the direct relationship between myocardial energy metabolism and HF development. These defects include systemic carnitine deficiency, malonyl carboxylase deficiency, deficiency of FAO enzymes, and inherited mutations in mitochondrial (mtDNA). This chapter will review mechanisms, diagnostic approaches, and potential therapeutic strategies related to metabolic dysfunction in the failing heart.

Energy Depletion in the Failing Heart

Continuous cardiac pump function requires the regeneration of large amounts of ATP. Energy depletion is a well-established characteristic of HF irrespective of its etiology. When directly examined, energy deprivation in failing human hearts is characterized by a reduction in the phosphocreatine (PCr)/ATP ratio. The PCr shuttle transfers ATP from mitochondria to myofilaments and transfers ADP back to the mitochondria for rephosphorylation. PCr receives its phosphate group from ATP by the creatine kinase reaction, which favors ATP synthesis over PCr synthesis by approximately 100-fold. Thus, when ATP demand outweighs ATP availability, the PCr/ATP ratio declines first and represents a sensitive and powerful index of the energetic state of the heart. In HF patients, PCr/ATP was found to be reduced, and the magnitude of this reduction correlates with New York Heart Association (NYHA) functional class, systolic and diastolic function, and mortality. In addition, mitochondrial respiratory capacity and rates of ATP synthesis are markedly decreased in HF patients, both in ischemic and nonischemic dilated cardiomyopathy. An unresolved question remains as to whether impaired cardiac energetics are cause or consequence of HF. There is a large body of evidence particularly from animal studies that support a causal role, between energy depletion and the pathophysiology of HF. However, cardiac mitochondria isolated from failing hearts at the time of left ventricular assist device (LVAD) implantation might not reveal intrinsic defects, and metabolomics analysis reveals improved mitochondrial metabolism after ventricular unloading, suggesting that some degree of mitochondrial plasticity might exist in failing hearts. It is also noteworthy that animal studies that directly seek to increase mitochondrial biogenesis in HF models might not necessarily improve ventricular function in the face of ongoing hemodynamic stress. Thus it is likely that the mitochondrial changes associated with HF might reflect both an adaptive response and a direct contributor to ventricular dysfunction.