Metabolism, hypoxia and the diabetic heart

The diabetic heart becomes metabolically remodelled as a consequence of exposure to abnormal circulating substrates and hormones. Fatty acid uptake and metabolism are increased in the type 2 diabetic heart, resulting in accumulation of intracellular lipid intermediates and an increased contribution of fatty acids towards energy generation. Cardiac glucose uptake and oxidation are decreased, predominantly due to increased fatty acid metabolism, which suppresses glucose utilisation via the Randle cycle. These metabolic changes decrease cardiac efficiency and energetics in both humans and animal models of diabetes. Diabetic hearts have decreased recovery following ischemia, indicating a reduced tolerance to oxygen-limited conditions. There is evidence that diabetic hearts have a compromised hypoxia signalling pathway, as hypoxia-inducible factor (HIF) and downstream signalling from HIF are reduced following ischemia. Failure to activate HIF under oxygen-limited conditions results in less angiogenesis, and an inability to upregulate glycolytic ATP generation. Given that glycolysis is already suppressed in the diabetic heart under normoxic conditions, the inability to upregulate glycolysis in response to hypoxia may have deleterious effects on ATP production. Thus, impaired HIF signalling may contribute to metabolic and energetic abnormalities, and impaired collateral vessel development following myocardial infarction in the type 2 diabetic heart.     

Over-nutrition and metabolic cardiomyopathy

Cardiovascular disease, which accounts for the highest morbidity and mortality in the United States, has several major risk factors, including aging and diabetes. Overweight and obesity, especially abdominal obesity, have been increasingly implicated as independent risk factors in the development of cardiovascular disease. Metabolic and/or diabetic cardiomyopathy has been especially associated with excess body weight caused by chronic over-nutrition and high-fat feeding. In the initial stages, obesity is now understood to cause significant dysregulation of cardiac fatty acid and glucose metabolism. These abnormalities are due, in part, to increased oxidative stress, which in turn can cause deleterious effects on intracellular signaling pathways that control cellular growth and proliferation. This increase in oxidative stress is coupled with reduced anti-oxidant species and dysregulation of metabolic signaling pathways. The cardiomyopathy seen with obesity is associated with increased interstitial fibrosis and diastolic dysfunction. Over time, evolving abnormalities include hypertrophy and systolic dysfunction, eventually leading to heart failure.     

Constitutive SIRT1 overexpression impairs mitochondria and reduces cardiac function in mice

Heart failure is associated with a change in cardiac energy metabolism. SIRT1 is a NAD⁺-dependent protein deacetylase, and important in the regulation of cellular energy metabolism. To examine the role of SIRT1 in cardiac energy metabolism, we created transgenic mice overexpressing SIRT1 in a cardiac-specific manner, and investigated cardiac functional reserve, energy reserve, substrate uptake, and markers of mitochondrial function. High overexpression of SIRT1 caused dilated cardiomyopathy. Moderate overexpression of SIRT1 impaired cardiac diastolic function, but did not cause heart failure. Fatty acid uptake was decreased and the number of degenerated mitochondria was increased dependent on SIRT1 gene dosage. Markers of reactive oxygen species were decreased. Changes in morphology and reactive oxygen species were associated with the reduced expression of genes related to mitochondrial function and autophagy. In addition, the respiration of isolated mitochondria was decreased. Cardiac function was normal in transgenic mice expressing a low level of SIRT1 at baseline, but the mice developed cardiac dysfunction upon pressure overload. In summary, the constitutive overexpression of SIRT1 reduced cardiac function associated with impaired mitochondria in mice.     

The diabetic cardiomyopathy

Diabetic cardiomyopathy has been defined as “a distinct entity characterized by the presence of abnormal myocardial performance or structure in the absence of epicardial coronary artery disease, hypertension, and significant valvular disease”. The diagnosis stems from the detection of myocardial abnormalities and the exclusion of other contributory causes of cardiomyopathy. It rests on non-invasive imaging techniques which can demonstrate myocardial dysfunction across the spectra of clinical presentation. The presence of diabetes is associated with an increased risk of developing heart failure, and the 75% of patients with unexplained idiopathic dilated cardiomyopathy were found to be diabetic. Diabetic patients with microvascular complications show the strongest association between diabetes and cardiomyopathy, an association that parallels the duration and severity of hyperglycemia. Metabolic abnormalities (that is hyperglycemia, hyperinsulinemia, and hyperlipemia) can lead to the cellular alterations characterizing diabetic cardiomyopathy (that is myocardial fibrosis and/or myocardial hypertrophy) directly or indirectly (that is by means of renin-angiotensin system activation, cardiac autonomic neuropathy, alterations in calcium homeostasis). Moreover, metabolic abnormalities represent, on a clinical ground, the main therapeutic target in the patients with diabetes since the diagnosis of diabetes is made. Since diabetic cardiomyopathy is highly prevalent in the asymptomatic type 2 diabetic patients, screening for its presence at the earliest stage of development can lead to prevent the progression to chronic heart failure. The most sensitive test is standard echocardiogram, while a less expensive pre-screening method is the detection of microalbuminuria.     

Diabetic cardiomyopathy: concept,heart function,and pathogenesis

The diabetic cardiomyopathy is a disease caused by diabetes and is characterised by the presence of diastolic and/or systolic left ventricular dysfunction. Diabetes may produce metabolic alterations, interstitial fibrosis, myocellular hypertrophy, microvascular disease and autonomic dysfunction. It is thought that all of them may cause cardiomyopathy. Other abnormalities that are usually associated with diabetes such as hypertension, coronary artery disease and nephropathy should be excluded before diagnosing diabetic cardiomyopathy. There is no evidence that diabetic cardiomyopathy alone can produce heart failure. However, subclinical ventricular dysfunction has been described in young asymptomatic diabetic patients without other diseases that could affect the cardiac muscle. In these cases we should consider that diabetes is the only cause of the myocardial disease. More studies are needed to know the natural history of diabetic cardiomyopathy.     

Abnormal Myocardial Dietary Fatty Acid Metabolism and Diabetic Cardiomyopathy

Patients with diabetes are at very high risk of hospitalization and death from heart failure. Increased prevalence of coronary heart disease, hypertension, autonomic neuropathy, and kidney failure all play a role in this increased risk. However, cardiac metabolic abnormalities are now recognized to play a role in this increased risk. Increased reliance on fatty acids to produce energy might predispose the diabetic heart to oxidative stress and ischemic damage. Intramyocellular accumulation of toxic lipid metabolites leads to a number of cellular abnormalities that might also contribute to cardiac remodelling and cardiac dysfunction. However, fatty acid availability from circulation and from intracellular lipid droplets to fuel the heart is critical to maintain its function. Fatty acids delivery to the heart is very complex and includes plasma nonesterified fatty acid flux as well as triglyceride-rich lipoprotein-mediated transport. Although many studies have shown a cross-sectional association between enhanced fatty acid delivery to the heart and reduction in left ventricular function in subjects with prediabetes and diabetes, these mechanisms change very rapidly during type 2 diabetes treatment. The present review focuses on the role of fatty acids in cardiac function, with particular emphasis on the possible role of early abnormalities of dietary fatty acid metabolism in the development of diabetic cardiomyopathy.     

Regulation of Sarcolemmal Transport of Substrates in the Healthy and Diseased Heart

Introduction Long-chain fatty acids and glucose are the predominant substrates for cardiac metabolic energy production. While in the healthy heart there is a distinctive and very finely tuned balance between the utilization of these metabolic substrates, in chronic cardiac disease this balance is upset to the use of primarily glucose (e.g., cardiac hypertrophy and failure) or primarily fatty acids (e.g., diabetic cardiomyopathy). Cardiac substrate preference is regulated not only at the level of mitochondrial oxidation (Randle cycle) but also at the level of sarcolemmal uptake of substrates. Molecular mechanism of cardiac substrate uptake The latter occurs by translocation of specific substrate transporters, namely fatty acid translocase/CD36 and plasma membrane fatty acid-binding protein (FABPpm) to regulate fatty acid transport, and GLUT4 to regulate glucose transport, from intracellular storage pools to the sarcolemma. Both insulin and cardiac muscle contractions increase the cellular uptake of fatty acids and glucose simultaneously by these mechanisms. Although the signal transduction pathways involved in eliciting substrate transporter trafficking have only partly been disclosed, recent studies indicate the feasibility of selective recruitment of either CD36 or GLUT4 to the sarcolemma, thereby increasing the uptake of a single class of substrates and thus altering the substrate preference of cardiac muscle cells. Concluding remarks As a result, selective modulation of the sarcolemmal localization of fatty acid- and/or glucose transporters holds promise as a therapeutic tool to rectify a disruption of the cardiac substrate balance occurring in chronic cardiac disease.     

Mouse models of mitochondrial dysfunction and heart failure

Mitochondria in the adult mammalian heart have a tremendous capacity for oxidative metabolism, and the conversion of energy by these pathways is critical for proper cardiac function. This review describes mouse models relating mitochondrial metabolism to cardiac function through gain- or loss-of-function approaches that manipulate mitochondrial energy transduction or ATP synthetic pathways. Mouse models of mitochondrial defects are relevant to genetic and acquired forms of human cardiomyopathy. Examples include inborn errors in mitochondrial metabolism or end-stage heart failure. Conversely, chronic reliance on energy production via mitochondrial fatty acid oxidation, such as occurs in the diabetic heart, likely leads to maladaptive sequelae including cellular lipotoxicity and mitochondrial dysfunction. Collectively, these model systems have allowed us to begin to dissect the relationship between mitochondrial metabolism and the development of cardiomyopathy and to define the molecular pathways regulating cardiac mitochondrial number and function.     

Morphological characteristics in diabetic cardiomyopathy associated with autophagy

Diabetic cardiomyopathy, clinically diagnosed as ventricular dysfunction in the absence of coronary atherosclerosis or hypertension in diabetic patients, is a cardiac muscle-specific disease that increases the risk of heart failure and mortality. Its clinical course is characterized initially by diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure from an uncertain mechanism. Light microscopic features such as interstitial fibrosis, inflammation, and cardiomyocyte hypertrophy are observed in diabetic cardiomyopathy, but are common to failing hearts generally and are not specific to diabetic cardiomyopathy. Electron microscopic studies of biopsy samples from diabetic patients with heart failure have revealed that the essential mechanism underlying diabetic cardiomyopathy involves thickening of the capillary basement membrane, accumulation of lipid droplets, and glycogen as well as increased numbers of autophagic vacuoles within cardiomyocytes. Autophagy is a conserved mechanism that contributes to maintaining intracellular homeostasis by degrading long-lived proteins and damaged organelles and is observed more often in cardiomyocytes within failing hearts. Diabetes mellitus (DM) impairs cardiac metabolism and leads to dysregulation of energy substrates that contribute to cardiac autophagy. However, a “snapshot” showing greater numbers of autophagic vacuoles within cardiomyocytes may indicate that autophagy is activated into phagophore formation or is suppressed due to impairment of the lysosomal degradation step. Recent in vivo studies have shed light on the underlying molecular mechanism governing autophagy and its essential meaning in the diabetic heart. Autophagic responses to diabetic cardiomyopathy differ between diabetic types: they are enhanced in type 1 DM, but are suppressed in type 2 DM. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy. Here, we review recent advances in our understanding of the pathophysiology of diabetic cardiomyopathy, paying particular attention to autophagy in the heart, and discuss the therapeutic potential of interventions modulating autophagy in diabetic cardiomyopathy.     

Diabetes-related metabolic perturbations in cardiac myocyte

Although the pathogenesis of diabetic cardiomyopathy is poorly understood, recent evidence implicates perturbations in cardiac energy metabolism. Whereas mitochondrial fatty acid oxidation is the chief energy source for the normal postnatal mammalian heart, the relative contribution of glucose utilization pathways is significant, allowing the plasticity necessary for steady ATP production in the context of diverse physiologic and dietary conditions. In the uncontrolled diabetic state, because of the combined effects of insulin resistance and high circulating fatty acids, cardiac myocytes use fatty acids almost exclusively to support ATP synthesis. Studies using various diabetic rodent models have shown a direct relationship between the chronic drive on myocardial fatty acid metabolism and the development of cardiomyopathy including ventricular hypertrophy and dysfunction. Fatty acids also play a critical role in triggering the development of cellular insulin resistance through derangements in insulin signalling cascade. There are similarities in cardiac dysfunction in animal models and human type 2 diabetes and/or obesity. For instance, obese young women showed increased cardiac fatty acid utilization measured by positron emission tomography and increased myocardial oxygen consumption with reduced cardiac efficiency. Furthermore, accumulation of triglycerides within cardiac myocytes was an early metabolic marker that was associated with increased left ventricular mass. Moreover, data indicate that alterations in cardiac energetics occur early in the pathophysiology of type 2 diabetes and are correlated negatively with the fasting plasma free fatty acid concentrations.     

FAK regulates cardiomyocyte survival following ischemia/reperfusion

Myocyte apoptosis is central to myocardial dysfunction following ischemia/reperfusion (I/R) and during the transition from hypertrophy to heart failure. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase regulates adhesion-dependent survival signals and unopposed FAK activation has been linked to tumor development. We previously showed that conditional myocyte-specific deletion of FAK (MFKO) in the adult heart did not affect basal cardiomyocyte survival or cardiac function but led to dilated cardiomyopathy and heart failure following pressure overload. In the present study, we sought to determine if FAK functions to limit stress-induced cardiomyocyte apoptosis. We reasoned that (I/R), which stimulates robust apoptotic cell death, might uncover an important cardioprotective function for FAK. We found that depletion of FAK markedly exacerbates hypoxia/re-oxygenation-induced cardiomyocyte cell death in vitro. Moreover, deletion of FAK in the adult myocardium resulted in significant increases in I/R-induced infarct size and cardiomyocyte apoptosis with a concomitant reduction in left ventricular function. Finally, our results suggest that NF-κB signaling may play a key role in modulating FAK-dependent cardioprotection, since FAK inactivation blunted activation of the NF-κB survival signaling pathway and reduced levels of the NF-κB target genes, Bcl2 and Bcl-xl. Since the toggling between pro-survival and pro-apoptotic signals remains central to preventing irreversible damage to the heart, we conclude that targeted FAK activation may be beneficial for protecting stress-dependent cardiac remodeling.     

Diabetische Kardiomyopathie

Diabetic cardiomyopathy is a myocardial disease caused by diabetes mellitus unrelated to vascular and valvular pathology or systemic arterial hypertension. Clinical and experimental studies have shown that diabetes mellitus causes myocardial hypertrophy, apoptosis and necrosis, and increases interstitial tissue. The pathophysiology of diabetic cardiomyopathy is incompletely understood and several mechanistical approaches are under debate. Metabolic impairments like hyperglycemia, hyperlipidemia, hyperinsulinemia, and alterations in the cardiac metabolism lead to structural and functional changes which show cellular effects leading to increased oxidative stress, interstitial fibrosis, myocyte death, and disturbances in ion transport and homeostasis. Diastolic dysfunction which consecutively results in systolic dysfunction with increased left ventricular volume and reduced ejection fraction is an early diagnostic parameter. Treatment of diabetic cardiomyopathy does not differ from myocardiopathies of other etiologies and therefore has to follow the appropriate guidelines. Early intervention to reverse metabolic toxicity is the most effective method of prevention.     

糖尿病心肌病的能量代谢紊乱

随着糖尿病发病率逐年上升,糖尿病心肌病也引起了人们越来越多的关注。然而,对于糖尿病导致的心肌损害,其分子机制现在仍未被阐明。糖尿病心肌病的发病受多种因素的影响,包括钙离子平衡失调、肾素．血管紧张素系统的激活、氧化应激的增加、心肌代谢底物改变以及线粒体损伤等。本文就糖尿病心肌病的能量代谢紊乱作一综述。     

Diabetic cardiomyopathy: the search for a unifying hypothesis

Although diabetes is recognized as a potent and prevalent risk factor for ischemic heart disease, less is known as to whether diabetes causes an altered cardiac phenotype independent of coronary atherosclerosis. Left ventricular systolic and diastolic dysfunction, left ventricular hypertrophy, and alterations in the coronary microcirculation have all been observed, although not consistently, in diabetic cardiomyopathy and are not fully explained by the cellular effects of hyperglycemia alone. The recent recognition that diabetes involves more than abnormal glucose homeostasis provides important new opportunities to examine and understand the impact of complex metabolic disturbances on cardiac structure and function.     

Alterations in mitochondrial function as a harbinger of cardiomyopathy: Lessons from the dystrophic heart

While compelling evidence supports the central role of mitochondrial dysfunction in the pathogenesis of heart failure, there is comparatively less information available on mitochondrial alterations that occur prior to failure. Building on our recent work with the dystrophin-deficient mdx mouse heart, this review focuses on how early changes in mitochondrial functional phenotype occur prior to overt cardiomyopathy and may be a determinant for the development of adverse cardiac remodelling leading to failure. These include alterations in energy substrate utilization and signalling of cell death through increased permeability of mitochondrial membranes, which may result from abnormal calcium handling, and production of reactive oxygen species. Furthermore, we will discuss evidence supporting the notion that these alterations in the dystrophin-deficient heart may represent an early “subclinical” signature of a defective nitric oxide/cGMP signalling pathway, as well as the potential benefit of mitochondria-targeted therapies. While the mdx mouse is an animal model of Duchenne muscular dystrophy (DMD), changes in the structural integrity of dystrophin, the mutated cytoskeletal protein responsible for DMD, have also recently been implicated as a common mechanism for contractile dysfunction in heart failure. In fact, altogether our findings support a critical role for dystrophin in maintaining optimal coupling between metabolism and contraction in the heart.     

Metabolic Abnormalities in the Diabetic Heart

Congestive heart failure is a major health problem in the diabetic. Diabetics have a high incidence of heart disease, including an increased incidence and severity of congestive heart failure than the non-diabetic. Progression to heart failure after an acute myocardial infarction is also more frequent in diabetics then non-diabetics. While atherosclerosis and ischemic injury are important contributing factors to this high in incidence of heart failure, another important factor is diabetes-induced changes within the heart itself. A prominent change that occurs in the diabetic is a switch in cardiac energy metabolism. Increases in fatty acid oxidation accompanied by decreases in glucose metabolism can result in the myocardium becoming almost entirely reliant on fatty acid oxidation as a source of energy. This switch in energy metabolism contributes to congestive heart failure by increasing the severity of injury following an acute myocardial infarction, and by having direct negative effects on contractile function. This paper will review the evidence linking alterations in energy metabolism to alterations in contractile function in the diabetic.     

肥胖、脂毒性与心力衰竭

肥胖中脂肪组织扩张到最大限度后脂质溢出,非脂肪组织如心脏等也出现了脂质累积。心脏由最初代偿性改变,而后出现脂毒性状态,最终出现收缩功能不全。非酯化脂肪酸的过度供应加上代谢失调（包括脂肪酸不充分的氧化）导致线粒体功能不全是发病过程中的一个重要环节。