Alterations In Cardiac Energy Metabolism Research Articles

The role of acetylation in obesity-induced cardiac metabolic alterations.

Obesity is a growing public health problem, with its prevalence rate having tripled in the last five decades. It has been shown that obesity is associated with alterations in cardiac energy metabolism, which in turn plays a significant role in heart failure development. During obesity, the heart becomes highly dependent on fatty acid oxidation as its primary source of energy (ATP), while the contribution from glucose oxidation significantly decreases. This metabolic inflexibility is associated with reduced cardiac efficiency and contractile dysfunction. Although it is well recognized that alterations in cardiac energy metabolism during obesity are associated with the risk of heart failure development, the molecular mechanisms controlling these metabolic changes are not fully understood. Recently, posttranslational protein modifications of metabolic enzymes have been shown to play a crucial role in cardiac energy metabolic changes seen in obesity. Understanding these novel mechanisms is important in developing new therapeutic options to treat or prevent cardiac metabolic alteration and dysfunction in obese individuals. This review discusses posttranslational acetylation changes during obesity and their roles in mediating cardiac energy metabolic perturbations during obesity as well as its therapeutic potentials.

Obesity Is a Major Determinant of Impaired Cardiac Energy Metabolism in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a major health problem with limited treatment options. Although optimizing cardiac energy metabolism is a potential approach to treating heart failure, it is poorly understood what alterations in cardiac energy metabolism actually occur in HFpEF. To determine this, we used mice in which HFpEF was induced using an obesity and hypertension HFpEF protocol for 10 weeks. Next, carvedilol, a third-generation β-blocker and a biased agonist that exhibits agonist-like effects through β arrestins by activating extracellular signal-regulated kinase, was used to decrease one of these parameters, namely hypertension. Heart function was evaluated by invasive pressure-volume loops and echocardiography as well as by ex vivo working heart perfusions. Glycolysis and oxidation rates of glucose, fatty acids, and ketones were measured in the isolated working hearts. The development of HFpEF was associated with a dramatic decrease in cardiac glucose oxidation rates, with a parallel increase in palmitate oxidation rates. Carvedilol treatment decreased the development of HFpEF but had no major effect on cardiac energy substrate metabolism. Carvedilol treatment did increase the expression of cardiac β arrestin 2 and proteins involved in mitochondrial biogenesis. Decreasing bodyweight in obese HFpEF mice increased glucose oxidation and improved heart function. This suggests that the dramatic energy metabolic changes in HFpEF mice hearts are primarily due to the obesity component of the HFpEF model. SIGNIFICANCE STATEMENT: Metabolic inflexibility occurs in heart failure with preserved ejection fraction (HFpEF) mice hearts. Lowering blood pressure improves heart function in HFpEF mice with no major effect on energy metabolism. Between hypertension and obesity, the latter appears to have the major role in HFpEF cardiac energetic changes. Carvedilol increases mitochondrial biogenesis and overall energy expenditure in HFpEF hearts.

Body mass index associated differences in cardiac stress energetics in type 2 diabetes

Abstract Background Patients with T2D and heart disease have normal body mass index (BMI), suggesting that diabetes and obesity mediate cardiovascular change by different mechanisms. Changes in cardiac energy metabolism in lean diabetic patients during exercise stress have not been previously reported. Objectives We aimed to assess if there are BMI-associated differences in cardiac stress metabolism in patients with T2D. Methods Twenty-five overweight T2D patients (O-T2D) and eleven lean T2D patients (LnT2D), age- and ethnicity-matched and with no other comorbidities were studied. Patients were on oral hypoglycaemics only and were free of diabetes complications. Participants underwent rest and dobutamine stress phosphorus magnetic resonance spectroscopy (31P-MRS) and cardiovascular magnetic resonance (CMR) at 3T for the assessment of myocardial phosphocreatine to ATP ratio (PCr/ATP) as a measure of myocardial energetics, biventricular volumes, rest and stress left ventricular (LV) ejection fraction, global longitudinal shortening, and mitral in-flow E/A ratio for assessment of diastolic function and perfusion. Intravenous Dobutamine was administered at a dose of 10μg/kg/min, increasing at 90 second intervals up to a maximum of 40 μg/kg/min to achieve a target heart rate of 65% of the age-predicted maximal heart rate. Mean rate pressure product (RPP) was recorded at rest and stress. Heart rate was maintained at target for the duration of the 31P-MRS and stress CMR cine, mitral in-flow and perfusion acquisitions. Results The cardiac volumes, systolic or diastolic function and LV mass were similar between LnT2D and O-T2D. Although the O-T2D patients had a numerically lower rest and stress PCr/ATP ratio, this did not reach statistical significance. Resting PCr/ATP was reduced in LnT2D and O-T2D patients similarly. However, LnT2D showed a greater reduction in PCr/ATP (stress PCr/ATP LnT2D 1.51±0.2 vs O-T2D 1.41±0.25, p=0.02) despite similar increases in RPP. Stress myocardial blood flow (MBF) was also significantly lower in the O-T2D patients. There were significant correlations of BMI with LV mass (r=0.35, p=0.03); stress LVEF (r=−0.34, p=0.04); stress MBF stress (r=−0.53, p=0.001) and stress E/A (r=0.46, p=0.01) (figure 1). Conclusions Despite their better stress perfusion and similar glycaemic control, LnT2D show worse metabolic reserve characterised by more significant decrements in energetics in response to hemodynamic stress compared to overweight patients with T2D. Higher BMI correlates inversely with stress myocardial blood flow and with stress left ventricular ejection fraction. The presence of these subtle alterations in measures of stress metabolism and perfusion might signify a distinct metabolic phenotype of “lean diabetic cardiomyopathy”. Future studies are needed to further delineate alterations in cardiac energy metabolism in lean and overweight/obese type 2 diabetes patients, and their role in the development of cardiac dysfunction. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Wellcome TrustBHF

Coronary microvascular dysfunction is only detectable in type 2 diabetes in the presence of obesity

Abstract Background Heart failure (HF) is a leading cardiovascular complication of type 2 diabetes (T2D). Coronary microvascular dysfunction (CMD) precedes HF in diabetes and carries important prognostic information. CMD is also evident in metabolically healthy obese individuals without diabetes or hypertension. Whether diabetes causes CMD in the absence of obesity is uncertain. The interrelation among visceral adiposity and CMD has not been assessed previously. Objectives We sought to better understand the links between visceral and epicardial adipose tissue (VAT and EAT respectively) distribution, insulin resistance with myocardial perfusion, energetics and function in asymptomatic lean (LnT2D) and overweight/obese T2D patients (ObT2D) without cardiovascular disease. Methods 62 participants [27 Ob-T2D, 15 Ln-T2D, and 20 overweight controls] were recruited. Subjects underwent cardiac and abdominal magnetic resonance imaging and 31P-magnetic resonance spectroscopy, for measurements of EAT and VAT areas, rest and adenosine stress myocardial blood flow (MBF), cardiac function and phosphocreatine to ATP ratio (PCr/ATP). Fasting blood samples were taken for plasma homeostasis model assessment of insulin resistance (HOMA-IR) index calculations. Results The biochemical characteristics and multiparametric MR results are given in Table 1 and results of Pearson's regression analysis in the entire study population are given in Table 2. Stress MBF was lowest in ObT2D, while rest MBF was highest in LnT2D. Left ventricular ejection fraction (LVEF) and myocardial PCr/ATP were similarly reduced in diabetes groups. In the absence of obesity, there was no significant increase in VAT, EAT or HOMA-IR in T2D patients compared to controls. BMI and VAT, negatively correlated with LVEF, and strain parameters. PCr/ATP correlated with LVEF, but not HOMA-IR. BMI, EAT and VAT all correlated significantly with HOMA-IR, and HOMA-IR correlated with cardiac functional parameters. There was no association between HOMA-IR and myocardial perfusion. Conclusions In this study CMD was only evident in ObT2D patients, with normal rest and stress MBF in LnT2D patients. Despite normal perfusion and no significant increase in insulin resistance, LVEF and myocardial PCr/ATP were similarly reduced in LnT2D and ObT2D, and PCr/ATP correlated with LVEF. This suggests that alterations in cardiac energy metabolism are mechanistically more relevant for the pathophysiology of diabetic cardiomyopathy in LnT2D patients. In the absence of correlation between insulin resistance and myocardial perfusion, factors like inflammation and altered adipokine profile may play important roles for the pathophysiology of CMD in ObT2D patients. A better understanding of the underlying pathophysiological mechanisms of diabetic cardiomyopathy in LnT2D and ObT2D may help to develop contemporary tailored treatment and prevention strategies to tackle excess heart failure risk. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): BHFWellcome trust Table 1Table 2

Cardiac Energy Metabolism in Heart Failure.

Alterations in cardiac energy metabolism contribute to the severity of heart failure. However, the energy metabolic changes that occur in heart failure are complex and are dependent not only on the severity and type of heart failure present but also on the co-existence of common comorbidities such as obesity and type 2 diabetes. The failing heart faces an energy deficit, primarily because of a decrease in mitochondrial oxidative capacity. This is partly compensated for by an increase in ATP production from glycolysis. The relative contribution of the different fuels for mitochondrial ATP production also changes, including a decrease in glucose and amino acid oxidation, and an increase in ketone oxidation. The oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in heart failure associated with diabetes and obesity, myocardial fatty acid oxidation increases, while in heart failure associated with hypertension or ischemia, myocardial fatty acid oxidation decreases. Combined, these energy metabolic changes result in the failing heart becoming less efficient (ie, a decrease in cardiac work/O2 consumed). The alterations in both glycolysis and mitochondrial oxidative metabolism in the failing heart are due to both transcriptional changes in key enzymes involved in these metabolic pathways, as well as alterations in NAD redox state (NAD+ and nicotinamide adenine dinucleotide levels) and metabolite signaling that contribute to posttranslational epigenetic changes in the control of expression of genes encoding energy metabolic enzymes. Alterations in the fate of glucose, beyond flux through glycolysis or glucose oxidation, also contribute to the pathology of heart failure. Of importance, pharmacological targeting of the energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac efficiency, decreasing the energy deficit and improving cardiac function in the failing heart.

Metabolic Interventions to Prevent Hypertrophy-Induced Alterations in Contractile Properties In Vitro

(1) Background: The exact mechanism(s) underlying pathological changes in a heart in transition to hypertrophy and failure are not yet fully understood. However, alterations in cardiac energy metabolism seem to be an important contributor. We characterized an in vitro model of adrenergic stimulation-induced cardiac hypertrophy for studying metabolic, structural, and functional changes over time. Accordingly, we investigated whether metabolic interventions prevent cardiac structural and functional changes; (2) Methods: Primary rat cardiomyocytes were treated with phenylephrine (PE) for 16 h, 24 h, or 48 h, whereafter hypertrophic marker expression, protein synthesis rate, glucose uptake, and contractile function were assessed; (3) Results: 24 h PE treatment increased expression of hypertrophic markers, phosphorylation of hypertrophy-related signaling kinases, protein synthesis, and glucose uptake. Importantly, the increased glucose uptake preceded structural and functional changes, suggesting a causal role for metabolism in the onset of PE-induced hypertrophy. Indeed, PE treatment in the presence of a PAN-Akt inhibitor or of a GLUT4 inhibitor dipyridamole prevented PE-induced increases in cellular glucose uptake and ameliorated PE-induced contractile alterations; (4) Conclusions: Pharmacological interventions, forcing substrate metabolism away from glucose utilization, improved contractile properties in PE-treated cardiomyocytes, suggesting that targeting glucose uptake, independent from protein synthesis, forms a promising strategy to prevent hypertrophy and hypertrophy-induced cardiac dysfunction.

Abstract 15649: Pharmacological Inhibition of Aldose Reductase by AT001 Prevents Abnormal Cardiac Energy Metabolism and Improves Heart Function in an Animal Model of Diabetic Cardiomyopathy

Introduction: Diabetic Cardiomyopathy (DCM) is a major cause of death in people with type 2 diabetes (T2D). Alterations in cardiac energy metabolism including increased fatty acid oxidation rates and reduced glucose oxidation rates are key contributing factors to the development of DCM. Studies have shown that Aldose Reductase (AR), an enzyme activated under hyperglycemic conditions, can modulate myocardial glucose and fatty acid oxidation, and promotes cardiac dysfunction. Hypothesis: Pharmacological inhibition of AR using a next-generation inhibitor AT-001, can mitigate DCM in mice by modulating cardiac energy metabolism and improving cardiac efficiency. Methods: Male human AR overexpressing (hAR-Tg) and C57BL/6J (Control) mice were subjected to experimental T2D (high-fat diet [60% kcal from lard] for 10-wk with a single intraperitoneal streptozotocin injection of 75 mg/kg) and treated for the last 3-wk with AT-001 (40mg/kg/day) or vehicle via oral gavage. Cardiac energy metabolism and in vivo cardiac function were assessed via isolated working heart perfusions and ultrasound echocardiography, respectively. Results: AT-001 treatment significantly improved cardiac energetics in a murine model of DCM (hAR-Tg mice with T2D). Particularly, AT-001-treated mice exhibited decreased cardiac fatty acid oxidation rates compared to the vehicle-treated mice (342 ± 53 vs 964 ± 130 nmol/min/g dry wt.). Concurrently, there was a significant decrease in cardiac oxygen consumption in the AT-001-treated compared to the vehicle-treated mice (41 ± 12 vs 60 ± 11 μmol/min/g dry wt.), suggesting increased cardiac efficiency. Furthermore, treatment with AT-001 prevented cardiac structural and functional abnormalities present in DCM, including diastolic dysfunction as reflected by an increase in the tissue Doppler E’/A’ ratio and decrease in E/E’ ratio. Moreover, AT-001 treatment prevented cardiac hypertrophy as reflected by a decrease in LV mass in AT-001-treated mice. Conclusions: AR inhibition with AT-001 prevents cardiac structural and functional abnormalities in a mouse model of DCM, and normalizes cardiac energetics by shifting cardiac metabolism towards a non-diabetic metabolic state.

Cytochrome P450‐Derived Epoxy Lipids of N‐3 PUFAs Protect the Heart From Ischemia‐Reperfusion Injury by Regulating Mitochondrial Sirtuin 3

ObjectiveCytochrome P450 epoxygenases can metabolize dietary n‐3 polyunsaturated fatty acids (n‐3 PUFAs) to epoxy lipids, which have known cardioprotective effects; however, it remains unclear how this cardioprotection occurs. Our recent data demonstrate that cytochrome P450 epoxygenase‐derived metabolites of the n‐3 PUFA docosahexaenoic acid (DHA), 19,20‐epoxydocosapentaenoic acid (19,20‐EDP), exhibit protective effects toward cardiac mitochondria. Maintaining mitochondrial quality is essential to limit myocardial damage following ischemia‐reperfusion (IR) injury. The mitochondrial deacetylase sirtuin 3 (SIRT3) plays a pivotal role in the maintenance of mitochondrial function and cardiac energy metabolism. We hypothesize that the cardioprotective mechanism(s) of 19,20‐EDP against IR injury involve(s) stimulating mitochondrial SIRT3.MethodsLangendorff and isolated working heart perfusions were performed in male and female C57BL/6 mice to assess changes in cardiac function and energy metabolism in response to IR injury. Hearts were perfused with either vehicle, 19,20‐EDP (1 μM) and/or the SIRT3 inhibitor nicotinamide (30 μM) for a 20 min baseline perfusion, following which hearts were subjected to 30 min of global no flow ischemia and 40 min of reperfusion. Glucose and palmitate oxidation rates were measured to detect alterations in cardiac energy metabolism. Mitochondrial fractions were assessed for changes in SIRT3 activity and total lysine acetylation levels. Mitochondrial SIRT3 downstream targets were assessed in human ventricular tissues obtained from individuals with ischemic heart disease (IHD) included in the Human Explanted Heart Program and compared to non‐failing control hearts (NFC) collected from unused transplant donors through the Human Organ Procurement and Exchange Program at the University of Alberta. In addition, mitochondrial respiration was assessed in cardiac fibers isolated from the human tissues.ResultsHearts perfused with 19,20‐EDP demonstrated improved post‐ischemic functional recovery, glucose oxidation and cardiac efficiency compared to control groups. The cardioprotective effects were associated with enhanced mitochondrial SIRT3 activity and reduced global protein acetylation. We observed increased acetylation of the mitochondrial antioxidant superoxide dismutase 2 in tissues obtained from IHD human myocardium suggesting decreased antioxidant capacity. Treatment with 19,20‐EDP also markedly improved mitochondrial respiration in permeabilized human fibers obtained from IHD hearts. Importantly, the cardioprotective effects of 19,20‐EDP was abolished by the SIRT3 inhibitor nicotinamide.ConclusionWe demonstrate that 19,20‐EDP‐mediated cardioprotective mechanisms against IR injury involve preservation of mitochondrial SIRT3 activity, which results in improved cardiac efficiency.

Malonyl CoA Decarboxylase Inhibition Improves Cardiac Function Post-Myocardial Infarction

Alterations in cardiac energy metabolism after a myocardial infarction contribute to the severity of heart failure (HF). Although fatty acid oxidation can be impaired in HF, it is unclear if stimulating fatty acid oxidation is a desirable approach to treat HF. Both immediate and chronic malonyl coenzyme A decarboxylase inhibition, whichdecreases fatty acid oxidation, improved cardiac function through enhancing cardiac efficiency in a post-myocardial infarction rat that underwent permanent left anterior descending coronary artery ligation. The beneficial effects of MCD inhibition were attributed to a decrease in proton production due to an improved coupling between glycolysis and glucose oxidation.

Quercetin Prevents Diastolic Dysfunction Induced by a High-Cholesterol Diet: Role of Oxidative Stress and Bioenergetics in Hyperglycemic Rats.

Alterations in cardiac energy metabolism play a key role in the pathogenesis of diabetic cardiomyopathy. Hypercholesterolemia associated with bioenergetic impairment and oxidative stress has not been well characterized in the cardiac function under glycemic control deficiency conditions. This work aimed to determine the cardioprotective effects of quercetin (QUE) against the damage induced by a high-cholesterol (HC) diet in hyperglycemic rats, addressing intracellular antioxidant mechanisms and bioenergetics. Quercetin reduced HC-induced alterations in the lipid profile and glycemia in rats. In addition, QUE attenuated cardiac diastolic dysfunction (increased E:A ratio), prevented cardiac cholesterol accumulation, and reduced the increase in HC-induced myocyte density. Moreover, QUE reduced HC-induced oxidative stress by preventing the decrease in GSH/GSSG ratio, Nrf2 nuclear translocation, HO-1 expression, and antioxidant enzymatic activity. Quercetin also counteracted HC-induced bioenergetic impairment, preventing a reduction in ATP levels and alterations in PGC-1α, UCP2, and PPARγ expression. In conclusion, the mechanisms that support the cardioprotective effect of QUE in rats with HC might be mediated by the upregulation of antioxidant mechanisms and improved bioenergetics on the heart. Targeting bioenergetics with QUE can be used as a pharmacological approach to modulate structural and functional changes of the heart under hypercholesterolemic and hyperglycemic conditions.

Cardiac Hypertrophy in Neonates With Congenital Heart Disease Delays Maturational Alterations in Cardiac Energy Metabolism by Modifying Myocardial Acetylation Control

Cardiac Hypertrophy in Neonates With Congenital Heart Disease Delays Maturational Alterations in Cardiac Energy Metabolism by Modifying Myocardial Acetylation Control

Acetylation Control Contributes to Maturational Alterations in Cardiac Energy Metabolism in the Newborn Heart

Acetylation Control Contributes to Maturational Alterations in Cardiac Energy Metabolism in the Newborn Heart

Cardiac fatty acid oxidation in heart failure associated with obesity and diabetes

Obesity and diabetes are major public health problems, and are linked to the development of heart failure. Emerging data highlight the importance of alterations in cardiac energy metabolism as a major contributor to cardiac dysfunction related to obesity and diabetes. Increased rates of fatty acid oxidation and decreased rates of glucose utilization are two prominent changes in cardiac energy metabolism that occur in obesity and diabetes. This metabolic profile is probably both a cause and consequence of a prominent cardiac insulin resistance, which is accompanied by a decrease in both cardiac function and efficiency, and by the accumulation of potentially toxic lipid metabolites in the heart that can further exaggerate insulin resistance and cardiac dysfunction. The high cardiac fatty acid oxidation rates seen in obesity and diabetes are attributable to several factors, including: 1) increased fatty acid supply and uptake into the cardiomyocyte, 2) increased transcription of fatty acid metabolic enzymes, 3) decreased allosteric control of mitochondrial fatty acid uptake and fatty acid oxidation, and 4) increased post-translational acetylation control of various fatty acid oxidative enzymes. Emerging evidence suggests that therapeutic approaches aimed at switching the balance of cardiac energy substrate preference from fatty acid oxidation to glucose use can prevent cardiac dysfunction associated with obesity and diabetes. Modulating acetylation control of fatty acid oxidative enzymes is also a potentially attractive strategy, although presently this is limited to precursors of nicotinamide adenine or nonspecific activators of deacetylation such as resveratrol. This review will focus on the metabolic alterations in the heart that occur in obesity and diabetes, as well as on the molecular mechanisms controlling these metabolic changes. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.

Cardiac energy metabolic alterations in pressure overload-induced left and right heart failure (2013 Grover Conference Series).

Pressure overload of the heart, such as seen with pulmonary hypertension and/or systemic hypertension, can result in cardiac hypertrophy and the eventual development of heart failure. The development of hypertrophy and heart failure is accompanied by numerous molecular changes in the heart, including alterations in cardiac energy metabolism. Under normal conditions, the high energy (adenosine triphosphate [ATP]) demands of the heart are primarily provided by the mitochondrial oxidation of fatty acids, carbohydrates (glucose and lactate), and ketones. In contrast, the hypertrophied failing heart is energy deficient because of its inability to produce adequate amounts of ATP. This can be attributed to a reduction in mitochondrial oxidative metabolism, with the heart becoming more reliant on glycolysis as a source of ATP production. If glycolysis is uncoupled from glucose oxidation, a decrease in cardiac efficiency can occur, which can contribute to the severity of heart failure due to pressure-overload hypertrophy. These metabolic changes are accompanied by alterations in the enzymes that are involved in the regulation of fatty acid and carbohydrate metabolism. It is now becoming clear that optimizing both energy production and the source of energy production are potential targets for pharmacological intervention aimed at improving cardiac function in the hypertrophied failing heart. In this review, we will focus on what alterations in energy metabolism occur in pressure overload induced left and right heart failure. We will also discuss potential targets and pharmacological approaches that can be used to treat heart failure occurring secondary to pulmonary hypertension and/or systemic hypertension.

Sweet as sugar: excessive glucose metabolism in the failing heart.

Heart failure (HF) is a leading cause of death and disability worldwide, estimated to affect nearly 5 million people alone in the USA [1]. In the past 2 decades, a multitude of research has illustrated the importance of alterations in cardiac energy metabolism in the pathogenesis of HF [2], resulting in the concept that the failing heart may be ‘an engine out of fuel’ [3]. Indeed, reductions in myocardial fatty acid oxidation rates are frequently observed in the failing heart [4,5], whereas glycolytic metabolism is markedly enhanced [4,6], in order to provide a way for the heart to meet its energy requirements in the face of reduced oxidative ATP production. In the current issue of the Journal of Molecular and Cellular Cardiology, Pereira and colleagues [7] have elucidated the role of the cardiac myocyte glucose transporter 1 (GLUT1) in the failing heart, and its contribution to the alterations in cardiac energy metabolism that accompany HF progression. Pereira and colleagues demonstrated that GLUT1 expression is increased in the heart 4 weeks following transverse aortic constriction (TAC), which positively correlated with a significant increase in glycolysis rates during aerobic isolated working heart perfusions. This metabolic phenotype was ameliorated in mice with a cardiac-specific deletion of GLUT1 (GLUT1). However, GLUT1 mice exhibited a similar adaptive response to TAC-induced HF, as the decline in left ventricular (LV) function (ejection fraction [EF] and fractional shortening), progression of cardiac hypertrophy, decrease in vascularity and expression of HF markers (Nppa and Nppb mRNA expression) were similar in GLUT1 mice and their control littermates. These seminal findings add to the growing body of evidence demonstrating a marked increase in nonoxidative glucose metabolism as a significant source of energy for the failing heart. Bing and colleagues noted in 1964 that myocardial samples from patients who died from congestive HF exhibited a significant increase in activity of the glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase [8], whereas Bishop and Altschuld observed in 1970 that muscle-type lactate dehydrogenase expression and lactate production were elevated in LV extracts from dogs with HF secondary to heartworm infection [9]. Furthermore, isolated working heart perfusions from rats subjected to abdominal aortic constriction also demonstrated a significant increase in glycolytic rates when perfused either aerobically or during lowflow ischemia [10,11], while myocardial glucose uptake rates were more than doubled in a canine model of rapid right ventricular pacing [4]. The increased glycolysis rates observed in the failing heart have been proposed to be an adaptive “...future efforts may be better served in trying to understand how to improve oxidative metabolism and/or the efficiency of mitochondrial oxidation ... as a means to improving cardiac metabolism and subsequent left ventricular function during heart failure progression.”

Malonyl CoA: A promising target for the treatment of cardiac disease

Alterations in cardiac energy metabolism are an important contributor to the high incidence and severity of heart disease in the world. These alterations can include an impairment of the production of ATP necessary to meet the high energy demands of the heart, as well as adverse switches in energy substrate preference by the heart. With regard to this latter point, evidence suggests that a decrease in cardiac efficiency, caused by a rise in cardiac fatty acid oxidation and/or an increase in the uncoupling of glycolysis from glucose oxidation, impairs cardiac function and is a contributing factor to cardiac disease. In support of this concept, therapeutic strategies that modulate these metabolic pathways and increase cardiac efficiency produce beneficial results in the setting of heart disease. One such strategy is to increase cardiac malonyl CoA levels, an important inhibitor of mitochondrial fatty acid uptake. This includes malonyl CoA decarboxylase (MCD) inhibition that results in increased cardiac malonyl CoA levels, decreased cardiac fatty acid oxidation rates, and improved cardiac efficiency. Preclinical studies have shown that MCD inhibition can improve cardiac function in various forms of heart disease. Here, we focus on the importance of malonyl CoA in the regulation of cardiac energy metabolism and function in the normal and diseased heart and discuss the evidence that suggests that inhibition of fatty acid oxidation especially via regulation of malonyl CoA, through MCD inhibition, is a promising strategy to treat cardiac disease. © 2014 IUBMB Life, 66(3):139-146, 2014.

Cardiac Insulin Resistance: It's Sweeter Than You Think

Obesity is increasing at an epidemic rate in our society and is a significant risk factor for cardiovascular diseases such as coronary artery disease and heart failure. Indeed, approximately 11% and 14% of heart failure cases are attributed to underlying obesity in men and women, respectively (1). Furthermore, obesity increases one’sriskforinsulinresistanceandtype2diabetesmellitus (T2DM), and each of these conditions may significantly impact cardiac energy metabolism. Because alterations in cardiac energy metabolism have been demonstrated to contribute to cardiac dysfunction in obesity and T2DM (2), there has recently been a significant research effort to betterunderstandhowobesityandinsulinresistanceaffect cardiacmetabolism,andwhetherthesemetabolicchanges can be targeted to improve cardiac function. In numerous animal models of obesity and insulin resistance, including chronic high-fat feeding, db/db mice, and ob/ob mice, myocardial fatty acid oxidation rates are elevated while

G Protein–Coupled Receptor Kinase 2 Activity Impairs Cardiac Glucose Uptake and Promotes Insulin Resistance After Myocardial Ischemia

Alterations in cardiac energy metabolism downstream of neurohormonal stimulation play a crucial role in the pathogenesis of heart failure. The chronic adrenergic stimulation that accompanies heart failure is a signaling abnormality that leads to the upregulation of G protein-coupled receptor kinase 2 (GRK2), which is pathological in the myocyte during disease progression in part owing to uncoupling of the β-adrenergic receptor system. In this study, we explored the possibility that enhanced GRK2 expression and activity, as seen during heart failure, can negatively affect cardiac metabolism as part of its pathogenic profile. Positron emission tomography studies revealed in transgenic mice that cardiac-specific overexpression of GRK2 negatively affected cardiac metabolism by inhibiting glucose uptake and desensitization of insulin signaling, which increases after ischemic injury and precedes heart failure development. Mechanistically, GRK2 interacts with and directly phosphorylates insulin receptor substrate-1 in cardiomyocytes, causing insulin-dependent negative signaling feedback, including inhibition of membrane translocation of the glucose transporter GLUT4. This identifies insulin receptor substrate-1 as a novel nonreceptor target for GRK2 and represents a new pathological mechanism for this kinase in the failing heart. Importantly, inhibition of GRK2 activity prevents postischemic defects in myocardial insulin signaling and improves cardiac metabolism via normalized glucose uptake, which appears to participate in GRK2-targeted prevention of heart failure. Our data provide novel insights into how GRK2 is pathological in the injured heart. Moreover, it appears to be a critical mechanistic link within neurohormonal crosstalk governing cardiac contractile signaling/function through β-adrenergic receptors and metabolism through the insulin receptor.

Improved cardiac metabolism and activation of the RISK pathway contributes to improved post-ischemic recovery in calorie restricted mice

Recent evidence has suggested that activation of AMP-activated protein kinase (AMPK) induced by short-term caloric restriction (CR) protects against myocardial ischemia-reperfusion (I/R) injury. Because AMPK plays a central role in regulating energy metabolism, we investigated whether alterations in cardiac energy metabolism contribute to the cardioprotective effects induced by CR. Hearts from control or short-term CR mice were subjected to ex vivo I/R and metabolism, as well as post-ischemic functional recovery was measured. Even in the presence of elevated levels of fatty acids, CR significantly improved recovery of cardiac function following ischemia. While rates of fatty acid oxidation or glycolysis from exogenous glucose were similar between groups, improved functional recovery post-ischemia in CR hearts was associated with high rates of glucose oxidation during reperfusion compared to controls. Consistent with CR improving energy supply, hearts from CR mice had increased ATP levels, as well as lower AMPK activity at the end of reperfusion compared to controls. Furthermore, in agreement with the emerging concept that CR is a non-conventional form of pre-conditioning, we observed a significant increase in phosphorylation of Akt and Erk1/2 at the end of reperfusion. These data also suggest that activation of the reperfusion salvage kinase (RISK) pathway also contributes to the beneficial effects of CR in reducing post-ischemia contractile dysfunction. These findings also suggest that short-term CR improves post-ischemic recovery by promoting glucose oxidation, and activating the RISK pathway. As such, pre-operative CR may be a clinically relevant strategy for increasing ischemic tolerance of the heart.

Metabolismo energético del corazón y sus proyecciones en el tratamiento de la insuficiencia cardíaca

It is unknown why heart failure progresses even when patients are treated with the best therapy available. Evidences suggest that heart failure progression is due to loss of neurohumoral blockade in advanced stages of the disease and to alterations in myocardial metabolism induced, in part, by this neurohumoral activation. Alterations in cardiac energy metabolism, especially those related to substrate utilization and insulin resistance, reduce the efficiency of energy production, causing a heart energy reserve deficit. These events play a basic role in heart failure progression. Therefore, modulation of cardiac metabolism has arisen as a promissory therapy in the treatment of heart failure. This review describes myocardial energy metabolism, evaluates the role of impaired energy metabolism in heart failure progression and describes new therapies for heart failure involving metabolic intervention.