Understanding myocardial metabolism in the well-perfused, healthy state is important to correctly identify the deranged cardiac metabolism observed in various pathologic states related to type 2 diabetes. These range from rather unspecific diabetic cardiomyopathy and heart failure to outright ischemia. Correcting or improving cardiac substrate utilization in the diabetic heart may even represent an attractive therapeutic option in acute and chronic heart disease related to diabetes. However, assessing the impairment in cardiac substrate utilization by ex-vivo or in-vivo studies is often complex. The heart derives its energy needs primarily from fatty acids, glucose and to a lesser extent ketone bodies and each of these metabolites are not regulated in isolation. Rather, cardiac substrate utilization occurs in response to alterations in energy demand and availability as well as in hormonal milieu. This complex interplay is reflected in the decade long discussions on myocardial insulin resistance and whether the myocardial metabolism is adaptive or maladaptive. Pharmacological improvement of cardiac metabolism is a putative beneficial cardiovascular surrogate effect marker and a challenge of future studies will be to evaluate if therapies that alters myocardial substrate metabolism in e.g. diabetes will translate to lower prevalence of long-term cardiovascular morbidity and mortality.
The healthy heart
ATP must be generated in large quantities to support the viability and contractile function of the myocardium. Most of this energy (>95%) is derived from oxidative phosphorylation in the mitochondria as the anaerobic capacity is limited in the heart. Under normal conditions there is a complete ATP turnover of the myocardial pool approximately every 10 seconds .
Figure 1: In the healthy heart myocardial energy substrate preference varies in a dynamic manner as depicted on the left panel. Mitochondrial fatty acid oxidation is the chief source of energy but the relative contribution of glucose utilization is significant. The substrate plasticity is necessary for constant cellular energy production in diverse physiological and dietary conditions. (Click to enlarge)Free fatty acids (FFAs) and glucose are the primary substrates of myocardial energy metabolism but the substrate preferences in the healthy myocardium are flexible depending on circulating metabolites. For example, lactate can be used in place of glucose e.g. under exercise and ketone bodies may be burned under conditions of stress such as long term starvation. Under normal conditions, a minimum of 60% of the ATP is derived from oxidation of free fatty acids (FFA) and the rest from oxi¬dation of glucose (Figure 1).
Uptake of FFAs is primarily determined by the circulating FFA concentrations, which can vary significantly depending on whether the individual is fed or fasted, under metabolic or ischemic stress or suffers from diabetes. FFAs can be taken up by passive diffusion across the myocardial cell membrane (the so-called “flip-flop”-phenomenon) or by transport proteins (e.g. CD36). Once inside the cardiomyocyte, FFAs enter the mitochondria by CPT1 and undergo beta-oxidation. The products acetyl-CoA, FADH2 and NADH enters the Krebs cycle and the outcome of complete oxidation of 1 mol palmitate is more than 100 mol ATP. Even though the principal energy source of the heart are lipids, maintenance of glucose metabolism is important for cardiac structure and function .
Glucose transporters are divided into two major groups: glucose transporters (GLUT) and sodium-glucose linked transporters (SGLT). Glucose mainly enters myocardial cells via the facilitative glucose transporters, GLUT1 and GLUT4 which approximately account for 40% and 60% of cardiac glucose transporters. Most of the glucose transported across the GLUT1 and GLUT4 into the myocardium is metabolized rapidly and glucose metabolism in the myocardium is estimated to be least 4-fold greater than in skeletal muscles. Only a small fraction is stored as glycogen. GLUT4 is translocated to the plasma membrane by insulin stimulation, increased workload and ischemia while the apparently insulin-insensitive GLUT1 is reported to be responsible for basal cardiac glucose transport. Hence, GLUT 4 translocation represents the main mechanism by which glucose transport into the cardiomyocyte can be increased 10- to 20-fold. In addition to the GLUT protein, SGLT1 mRNA has been reported in human myocardium. SGLT1 is also found in the small intestine and kidney, where it reabsorbs glucose .
Figure 2: Myocardial perfusion, FFA- and glucose metabolism assessed by PET in a healthy woman during insulin clamp. The homogenously perfused left ventricle metabolizes both FFA and glucose even in the presence of rather significant insulinemia. (Click to enlarge)Ketone bodies (β-hydroxybutyrate, acetoacetate and acetone) are produced in the liver during fasting and are subsequently secreted to peripheral tissues (skeletal muscle, the heart and the brain) where they are taken up by MCTs. Acetoacetate and β-hydroxybutyrate are extracted and oxidized in a concentration-dependent manner and are transformed into acetyl-CoA which enter Krebs cycle resulting in the production of ATP in the myocardial mitochondria. Elevated plasma ketone bodies are thought to inhibit the uptake and oxidation of FFA, glucose and lactate in most tissues , although this is still a matter of debate. The energy-sensing enzyme AMPK plays a pivotal role in regulation of myocardial metabolism and is activated in response to either metabolic (e.g. increased AMP/ATP ratio) or hormonal status, e.g. the incretin hormone glucagon-like peptide-1 is thought to activate AMPK. AMPK increases glucose metabolism, inactivates lipid generation and serves as an important switch ensuring sufficient
Figure 3: Relative glucose metabolism assessed by 18F-FDG PET during a hyperinsulinaemic-euglycemic clamp (viability - top) in a patient with ischemic heart disease and T2D. Rest myocardial perfusion was assessed by 82Rb-PET (Rest perfusion - bottom). Yellow colors signify high relative perfusion or FDG uptake. Despite hyperinsulinaemia (~20 fold increased from fasting conditions), FDG-uptake was markedly reduced (blue areas) in perfused areas of the left ventricle indicating an almost exclusive preference for fatty acid oxidation. (Click to enlarge)myocardial ATP via a non-oxidative pathway during reduced oxygen supply.
Due to the inaccessibility of the heart, quantification of myocardial metabolism is often assessed in experimental models of isolated perfused hearts or in cell cultures. These setups enable assessment of changes in glucose or FFA utilization in response to various carefully selected challenges (increased hormones, ischemia etc.). This approach is primarily limited by its inherent non-physiological properties and static experimental conditions. By contrast, the use of Positron Emission Tomography (PET) imaging allows quantification of cardiac fatty acid and glucose metabolism in-vivo in humans (Figure 2) and even enables researchers to study acute and complex responses to pharmacological treatment, changes in substrate availability and alterations in cardiac energy demand. The most commonly used PET tracer is the glucose analogue [18F]fluorodeoxyglucose (FDG), which competes with endogenous glucose for GLUTs and phosphorylation by hexokinase. FDG is trapped in glucose consuming cells as the analogue differs from “cold” glucose due to the substitution of a hydroxyl group for the positron-emitting radioactive isotope fluorine-18. The hydroxyl group is required to further metabolize glucose to glucose-6-phosphate and the FDG metabolites are therefore irreversibly trapped in cells until decay. This results in intense radiolabeling of tissues with high glucose metabolism (Figure 3).
The diabetic heart
The main cause of morbidity and mortality in type 2 diabetes mellitus (T2D) remains cardiovascular disease . However, the impact of tight blood glucose control on macrovascular disease are disappointing . The highly debated concept of diabetic cardiomyopathy was introduced in 1972 by Rubler et. al. and describes diabetes-associated structural and functional changes of the myocardium independent of hypertension or manifest coronary artery disease. The diabetes-associated changes are amplified by these co-morbidities, which increase the risk of developing left ventricular hypertrophy, heart failure and myocardial damage in relation to ischemia. Several mechanisms have been proposed in the pathogenesis of diabetic cardiomyopathy and the early changes of myocardial metabolism may precede clinically manifest cardiac dysfunction .
It is still unclear whether cardiomyocytes are as insulin resistant as peripheral myocytes in patients with insulin resistance and T2D. Recent research suggests that obesity causes cardiac insulin resistance primarily by inhibiting cardiac glucose oxidation whereas glucose uptake and glycolysis is unaltered . In contrast to this, outright high-fat feeding decreases myocardial glucose uptake, glycolysis, and oxidation .
Patients with T2D have elevated circulating FFAs and derive most of their myocardial energy demands from increased beta-oxidation of FFAs. By contrast, glucose oxidation is reduced even in the presence of hyperglycemia , a phenomenon termed “metabolic inflexibility” (Figure 1). This inability of the diabetic heart to oxidize glucose is associated with increased myocardial oxygen consumption, since oxidation of glucose results in (calculated) 11% greater ATP production per mole of oxygen consumed than oxidation of fatty acids. It is also associated with decreased left ventricular mechanical efficiency. The increased demand of oxygen by the diabetic heart renders it susceptible to more widespread hypoxia and damage during ischemic events – and these occur more frequently in diabetics due to the increased prevalence of coronary artery disease.
Numerous explanations have been put forward in an attempt to explain this shift in cardiac substrate utilization by the diabetic heart. The most prevalent point towards decreased glucose uptake, increased uptake of FFAs, decreased insulin signaling, and activation of transcriptional pathways .
The earliest changes observed in the hearts of obese rodents are reduced content and translocation of the insulin dependent GLUT4 in the myocardial sarcolemma. This results in reduced rates of glucose uptake and subsequently in reduced glycolysis and glucose oxidation (Figure 3). By contrast, FFA uptake facilitated by CD36 translocated to the membrane is increased leading to increased fatty acid oxidation . This is in accordance with observations in models of T2D where reduced translocation of GLUT1 and GLUT4 is observed in the heart . The proposed mechanisms of myocardial insulin resistance include dyslipidemia and lipotoxity, mitochondrial dysfunction, inflammation and endoplasmatic reticulum stress . Despite increased FFA oxidation, FFA uptake frequently exceeds the mitochondrial oxidative capacity and any excess fatty acids taken up results in intracellular accumulation of lipid derived metabolites. Accumulation of lipids and lipid intermediates in the heart has been demonstrated to be associated with systolic and diastolic dysfunction . Obesity further aggravates cardiac function, since adipocytes secrete inflammatory cytokines that may decrease myocardial glucose metabolism. It is also speculated that FFA oxidation increases generation of mitochondrial and cytosolic reactive oxygen species causing endoplasmatic reticulum stress. Generation of FFA-associated reactive oxygen species leads to uncoupling of mitochondria, which reduces mitochondrial ATP production. This mitochondrial uncoupling contributes to increased oxygen consumption and demand without a concomitant increase in ATP production. The result is decreased cardiac efficiency .
Pharmacological manipulation of myocardial energetics
The idea of improving the energetics in the heart can be tracked back to 1962 where Sodi-Pallares published results on glucose, insulin and potassium treatment of evolving myocardial infarctions . The general idea was to suppress FFA production and subsequent metabolism by the heart while at the same time increasing glucose uptake and metabolism. Results from the DIGAMI-1 study and others revealed significant benefits of this regime, however these promising data could not be repeated in the DIGAMI-2 and CREATE-ECLA studies. Recently metformin, DPP-4 inhibitors and the GLP-1 analogues have been suggested as potential rectifiers of the decreased myocardial glucose metabolism in diabetic patients, but reports are conflicting and should be evaluated with careful scrutiny .
In summary, although the shift from a healthy and balanced cardiac metabolism of glucose and fatty acids towards T2D and exclusive cardiac oxidation of fatty acids is associated with adverse effects, it is still unclear whether this is an adaptive mechanism (e.g. to prevent lipid accumulation) or is purely maladaptive and caused by increased availability of substrate . Further studies involving in-vivo measurement of cardiac fatty acid and glucose metabolism by PET in patients with T2D may well shed light on this.
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