Alterations In Myocardial Energy Metabolism Research Articles

Design and therapeutic application of trans‐sodium crocetinate‐loaded cyclodextrin metal–organic frameworks as an enteric preparation for treating chronic heart failure

Chronic heart failure (CHF) arises from structural and functional changes in the myocardial tissue attributable to various etiologies. Crocetin and its derivative trans‐sodium crocetinate (TSC) have exhibited cardioprotective attributes; however, their poor aqueous solubility and bioavailability impede clinical development. This study aimed to construct a cyclodextrin metal–organic frameworks (CDMOFs)‐based oral delivery system to enhance the pharmacokinetic profile and therapeutic efficacy of TSC for CHF treatment. TSC was loaded into the synthesized γ‐CDMOFs via vacuum adsorption. The CDMOFs@TSC formulation was characterized and evaluated in vitro. Pharmacokinetic and pharmacodynamic analyses were performed in beagle dogs and CHF rats induced by coronary artery ligation, respectively. Both TSC and CDMOFs@TSC elicited no discernible toxicity or pathological changes in major organs of rats, providing preliminary evidence for their biosafety. Pharmacokinetic study in beagle dogs demonstrated that CDMOFs@TSC capsules markedly increase the relative oral bioavailability by 198% versus free TSC capsules. In rats afflicted with CHF, the administration of CDMOFs@TSC yielded notable enhancements in cardiac function. Additionally, it precipitated a reduction in biomarkers linked to myocardial injury, manifested anti‐inflammatory and antifibrotic effects, and induced alterations in myocardial energy metabolism. This is the first report of CDMOFs‐based oral delivery to improve the TSC bioavailability and efficacy. The utilization of CDMOFs@TSC resulted in superior therapeutic outcomes in comparison to standalone TSC by optimizing pharmacokinetics and precise targeted delivery. These results highlight the clinical potential of CDMOF as porous carriers to enable oral delivery of natural products for CHF therapy.

Molecular mechanisms of metabolic dysregulation in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM), one of the most serious complications of diabetes mellitus, has become recognized as a cardiometabolic disease. In normoxic conditions, the majority of the ATP production (>95%) required for heart beating comes from mitochondrial oxidative phosphorylation of fatty acids (FAs) and glucose, with the remaining portion coming from a variety of sources, including fructose, lactate, ketone bodies (KB) and branched chain amino acids (BCAA). Increased FA intake and decreased utilization of glucose and lactic acid were observed in the diabetic hearts of animal models and diabetic patients. Moreover, the polyol pathway is activated, and fructose metabolism is enhanced. The use of ketones as energy sources in human diabetic hearts also increases significantly. Furthermore, elevated BCAA levels and impaired BCAA metabolism were observed in the hearts of diabetic mice and patients. The shift in energy substrate preference in diabetic hearts results in increased oxygen consumption and impaired oxidative phosphorylation, leading to diabetic cardiomyopathy. However, the precise mechanisms by which impaired myocardial metabolic alterations result in diabetes mellitus cardiac disease are not fully understood. Therefore, this review focuses on the molecular mechanisms involved in alterations of myocardial energy metabolism. It not only adds more molecular targets for the diagnosis and treatment, but also provides an experimental foundation for screening novel therapeutic agents for diabetic cardiomyopathy.

Energy metabolism in patients with diabetes and heart failure

The heart has a very high energy demand, which is mostly met by mitochondrial oxidative phosphorylation and, to a lesser extent, by glycolysis. In heart failure, there are substantial alterations in myocardial energy metabolism that lead to an “energy-deficient” state. This includes a marked reduction in overall mitochondrial oxidative phosphorylation and an uncoupling between high glycolysis rates and low glucose oxidation, which together contributes to the energy deficit and deteriorates contractile dysfunction. Cardiac ketone oxidation is also increased in heart failure, although it has yet to be determined whether this is an adaptive or maladaptive alteration. Diabetes is a major risk factor for heart failure development. It induces alterations in myocardial energy metabolism and is often associated with ventricular dysfunction. Similar to heart failure, a major change in myocardial energy metabolism in diabetic patients is a reduction in glucose oxidation, which negatively influences cardiac function. In both heart failure and diabetes, a growing body of evidence suggests that targeting myocardial energy metabolism by optimizing cardiac energy substrate preference could be a potential therapeutic approach to improve patient outcomes.

Metabolic remodeling in moderate synchronous versus dyssynchronous pacing-induced heart failure: integrated metabolomics and proteomics study.

Heart failure (HF) is accompanied by complex alterations in myocardial energy metabolism. Up to 40% of HF patients have dyssynchronous ventricular contraction, which is an independent indicator of mortality. We hypothesized that electromechanical dyssynchrony significantly affects metabolic remodeling in the course of HF. We used a canine model of tachypacing-induced HF. Animals were paced at 200 bpm for 6 weeks either in the right atrium (synchronous HF, SHF) or in the right ventricle (dyssynchronous HF, DHF). We collected biopsies from left ventricular apex and performed comprehensive metabolic pathway analysis using multi-platform metabolomics (GC/MS; MS/MS; HPLC) and LC-MS/MS label-free proteomics. We found important differences in metabolic remodeling between SHF and DHF. As compared to Control, ATP, phosphocreatine (PCr), creatine, and PCr/ATP (prognostic indicator of mortality in HF patients) were all significantly reduced in DHF, but not SHF. In addition, the myocardial levels of carnitine (mitochondrial fatty acid carrier) and fatty acids (12:0, 14:0) were significantly reduced in DHF, but not SHF. Carnitine parmitoyltransferase I, a key regulatory enzyme of fatty acid ß-oxidation, was significantly upregulated in SHF but was not different in DHF, as compared to Control. Both SHF and DHF exhibited a reduction, but to a different degree, in creatine and the intermediates of glycolysis and the TCA cycle. In contrast to this, the enzymes of creatine kinase shuttle were upregulated, and the enzymes of glycolysis and the TCA cycle were predominantly upregulated or unchanged in both SHF and DHF. These data suggest a systemic mismatch between substrate supply and demand in pacing-induced HF. The energy deficit observed in DHF, but not in SHF, may be associated with a critical decrease in fatty acid delivery to the ß-oxidation pipeline, primarily due to a reduction in myocardial carnitine content.

Endurance training or beta-blockade can partially block the energy metabolism remodeling taking place in experimental chronic left ventricle volume overload.

BackgroundPatients with chronic aortic valve regurgitation (AR) causing left ventricular (LV) volume overload can remain asymptomatic for many years despite having a severely dilated heart. The sudden development of heart failure is not well understood but alterations of myocardial energy metabolism may be contributive. We studied the evolution of LV energy metabolism in experimental AR.MethodsLV glucose utilization was evaluated in vivo by positron emission tomography (microPET) scanning of 6-month AR rats. Sham-operated or AR rats (n = 10-30 animals/group) were evaluated 3, 6 or 9 months post-surgery. We also tested treatment intervention in order to evaluate their impact on metabolism. AR rats (20 animals) were trained on a treadmill 5 times a week for 9 months and another group of rats received a beta-blockade treatment (carvedilol) for 6 months.ResultsMicroPET revealed an abnormal increase in glucose consumption in the LV free wall of AR rats at 6 months. On the other hand, fatty acid beta-oxidation was significantly reduced compared to sham control rats 6 months post AR induction. A significant decrease in citrate synthase and complex 1 activity suggested that mitochondrial oxidative phosphorylation was also affected maybe as soon as 3 months post-AR.Moderate intensity endurance training starting 2 weeks post-AR was able to partially normalize the activity of various myocardial enzymes implicated in energy metabolism. The same was true for the AR rats treated with carvedilol (30 mg/kg/d). Responses to these interventions were different at the level of gene expression. We measured mRNA levels of a number of genes implicated in the transport of energy substrates and we observed that training did not reverse the general down-regulation of these genes in AR rats whereas carvedilol normalized the expression of most of them.ConclusionThis study shows that myocardial energy metabolism remodeling taking place in the dilated left ventricle submitted to severe volume overload from AR can be partially avoided by exercise or beta-blockade in rats.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2261-14-190) contains supplementary material, which is available to authorized users.

An overview of the crosstalk between inflammatory processes and metabolic dysregulation during diabetic cardiomyopathy

Metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus are all linked to cardiovascular diseases such as cardiac hypertrophy and heart failure. Diabetic cardiomyopathy in particular, is characterized by structural and functional alterations in the heart muscle of people with diabetes that finally lead to heart failure, and which is not directly attributable to coronary artery disease or hypertension. Several mechanisms have been involved in the pathogenesis of diabetic cardiomyopathy, such as alterations in myocardial energy metabolism and calcium signaling. Metabolic disturbances during diabetic cardiomyopathy are characterized by increased lipid oxidation, intramyocardial triglyceride accumulation, and reduced glucose utilization. Overall changes result in enhanced oxidative stress, mitochondrial dysfunction and apoptosis of the cardiomyocytes. On the other hand, the progression of heart failure and cardiac hypertrophy usually entails a local rise in cytokines in cardiac cells and the activation of the proinflammatory transcription factor nuclear factor (NF)-κB. Interestingly, increasing evidences are arising in the recent years that point to a potential link between chronic low-grade inflammation in the heart and metabolic dysregulation. Therefore, in this review we summarize recent new insights into the crosstalk between inflammatory processes and metabolic dysregulation in the failing heart during diabetes, paying special attention to the role of NF-κB and peroxisome proliferator activated receptors (PPARs). In addition, we briefly describe the role of the AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1) and other pathways regulating cardiac energy metabolism, as well as their relationship with diabetic cardiomyopathy.

[Myocardial lipids and creatine measured by magnetic resonance spectroscopy among patients with heart failure].

Heart failure (HF) is characterized, among other features, by the development of alterations in myocardial energy metabolism, involving a decrease in glucose utilization and increased free fatty acid uptake by cardiomyocytes, associated with decreased deposits of high-energy phosphates (creatine phosphate/creatine transporter). Magnetic resonance (MR) imaging allows a direct and noninvasive assessment of myocardial metabolites. To measure myocardial creatine and lipids by MR spectroscopy among patients with HF. Cardiac MR spectroscopy (1.5 Tesla) with Hydrogen antenna and single voxel acquisition was performed in five patients with non-ischemic heart failure, aged 58 ± 9.7 years, (60% males) and 5 healthy volunteers matched for age and sex. We analyzed the signals of creatine (Cr), lipids (L) and water (W) in the interventricular septum, establishing the water/lipid (W/L) and water/creatine (W/Cr) index to normalize the values obtained. Among patients, left ventricular ejection fraction was 32 ± 6.9%, 60% were in functional capacity II, 60% had hypertension and one was diabetic. Spectroscopic curves showed a depletion of total Cr, evidenced by the W/ Cr index, among patients with heart failure, when compared with healthy controls (1.46 ± 1.21 and 5.96 ± 2.25 respectively, p < 0,05). Differences in myocardial lipid content, measured as the W/L index, were not significant (5.06 ± 2.66 and 1.80 ± 1.62 respectively, p = 0.08). Among patients with heart failure of non-ischemic etiology, there is a depletion of creatine levels measured by MR spectroscopy.

Determinaciones de niveles de creatina y lípidos mediante espectroscopia por resonancia magnética en miocardio de pacientes con insuficiencia cardiaca no isquémica

Heart failure (HF) is characterized, among other features, by the development of alterations in myocardial energy metabolism, involving a decrease in glucose utilization and increased free fatty acid uptake by cardiomyocytes, associated with decreased deposits of high-energy phosphates (creatine phosphate/creatine transporter). Magnetic resonance (MR) imaging allows a direct and noninvasive assessment of myocardial metabolites.To measure myocardial creatine and lipids by MR spectroscopy among patients with HF.Cardiac MR spectroscopy (1.5 Tesla) with Hydrogen antenna and single voxel acquisition was performed in five patients with non-ischemic heart failure, aged 58 ± 9.7 years, (60% males) and 5 healthy volunteers matched for age and sex. We analyzed the signals of creatine (Cr), lipids (L) and water (W) in the interventricular septum, establishing the water/lipid (W/L) and water/creatine (W/Cr) index to normalize the values obtained.Among patients, left ventricular ejection fraction was 32 ± 6.9%, 60% were in functional capacity II, 60% had hypertension and one was diabetic. Spectroscopic curves showed a depletion of total Cr, evidenced by the W/ Cr index, among patients with heart failure, when compared with healthy controls (1.46 ± 1.21 and 5.96 ± 2.25 respectively, p < 0,05). Differences in myocardial lipid content, measured as the W/L index, were not significant (5.06 ± 2.66 and 1.80 ± 1.62 respectively, p = 0.08).Among patients with heart failure of non-ischemic etiology, there is a depletion of creatine levels measured by MR spectroscopy.

Myocardial Energetics in Left Ventricular Hypertrophy

The heart carries out its pumping function by converting the chemical energy stored in fatty acids and glucose into the mechanical energy of actin-myosin interaction of myofibrils. Development of congestive heart failure is usually preceded by a period of compensated left ventricular hypertrophy (LVH) and alterations in myocardial bioenergetics have been considered to play an important role in this transition. Myocardial energetic state that is reflected by the ratio of Phosphocreatine to Adenosine Triphosphate (PCr/ATP) is significantly decreased in hearts with LVH. The severity of this abnormality is linearly related to the severity of cardiac hypertrophy as well as left ventricular (LV) dysfunction, and is independent of a persistent myocardial ischemia. The decrease in PCr/ATP is accompanied by a decrease in creatine kinase flux and alterations in substrate utilization in LVH hearts. Moreover, there is a profound heterogeneity in alterations in myocardial energy metabolism in hearts with post-infarction hypertrophy with the most severe abnormality present in the inner layers of the periscar border zone (BZ). This review will discuss various aspects of myocardial energetics in animal models of three different types of LVH (pressure-overload, volume overload and post-infarction) with a brief description of myocardial energetics in humans with LVH.

Effect of pyrrolidine dithiocarbamate on antioxidation of canine myocardium during ichemia/reperfusion injury

To assess the alterations in myocardial energy metabolism and lipid peroxidation during canine cardiopulmonary bypass (CPB), and to investigate the interventional effects of pyrrolidine dithiocarbamate (PDTC) pretreatment. Twelve adult healthy dogs undergoing CPB were randomized into control group (Group C, n=6) and PDTC group(Group P, n=6). In Group P, 30 mg/kg PDTC was administered intravenously before CPB and in Group C animals were given physiological saline instead of PDTC. The contents of adenosine triphosphate (ATP), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), malondialdehyde (MDA) and mitochondrial swelling degree (MSD) of myocardium were determined before CPB, 60 min after aortic cross-clamping (AC) and 60 min after declamping (DC). Hemodynamics was monitored before CPB, 30 min and 60 min after DC. Contents of ATP, SOD and GSH-PX in Group P at 60 min after AC and 60 min after DC were higher than those in Group C (P<0.01). MDA and MSD in Group P at 60 min after AC and 60 min after DC were significantly lower than those in Group C (P<0.01). Hemodynamics of Group P was recovered at 30 min and 60 min after DC. Pretreatment with PDTC is effective in improving antioxidation capacity of myocardium and ameliorates myocardial energy metabolism.

MOUSE STRAIN‐SPECIFIC DIFFERENCES IN CARDIAC METABOLIC ENZYME ACTIVITIES OBSERVED IN A MODEL OF ISOPROTERENOL‐INDUCED CARDIAC HYPERTROPHY

1. Alterations in myocardial energy metabolism accompany pressure overload-induced hypertrophy. We previously described a novel model of catecholamine-induced hypertrophy in which A/J mice exhibit more robust cardiac hypertrophy than B6 mice. Accordingly, we assessed the influence of mouse strain on the activities of key myocardial metabolic enzymes and whether there are strain-related metabolic adaptations to short-term, high-dose isoproterenol (ISO) administration. 2. Thirty-nine male mice (19 A/J mice, 20 B6 mice), aged 12-15 weeks, were randomly assigned to receive either ISO (100 mg/kg, s.c.) or vehicle (sterile water) daily for 5 days. On Day 6, all hearts were excised, weighed, freeze clamped and assayed for pyruvate dehydrogenase (PDH), medium chain acyl-CoA dehydrogenase, carnitine palmitoyl transferase I and citrate synthase activities. Plasma fatty acids (FA) were also measured. 3. The ISO-treated A/J mice demonstrated greater percentage increases in gravimetric heart weight/bodyweight ratio than ISO-treated B6 mice (24 vs 3%, respectively; P < 0.001). All enzyme activities were significantly greater in vehicle-treated B6 mice than in A/J mice, illustrating a greater capacity for aerobic metabolism in B6 mice. Administration of ISO reduced PDHa (active form) activity in B6 mice by 47% (P < 0.001), with no significant change seen in A/J mice. Free FA levels were not significantly different between groups; thus, the differences in PDHa were not due to changes in FA. 4. The basal activity of myocardial metabolic enzymes is greater in B6 mice than in A/J mice and ISO alters myocardial PDH activity in a mouse strain-dependent manner. Compared with A/J mice, B6 mice demonstrate less ISO-induced cardiac hypertrophy, but greater activity of key enzymes regulating FA and carbohydrate oxidation, which may protect against the development of hypertrophy. The metabolic adaptations associated with ISO-induced hypertrophy differ from those reported with pressure overload hypertrophy.

Alterations in myocardial energy metabolism induced by the anti-cancer drug doxorubicin

Doxorubicin and other anthracyclines are among the most potent chemotherapeutic drugs for the treatment of acute leukaemia, lymphomas and different types of solid tumours such as breast, liver and lung cancers. Their clinical use is, however, limited by the risk of severe cardiotoxicity, which can lead to irreversible congestive heart failure. There is increasing evidence that essential components of myocardial energy metabolism are among the highly sensitive and early targets of doxorubicin-induced damage. Here we review doxorubicin-induced detrimental changes in cardiac energetics, with an emphasis on the emerging importance of defects in energy-transferring and -signalling systems, like creatine kinase and AMP-activated protein kinase. To cite this article: M. Tokarska-Schlattner et al., C. R. Biologies 329 (2006).

Severe energy deprivation of human hibernating myocardium as possible common pathomechanism of contractile dysfunction, structural degeneration and cell death

ObjectivesWe tested the hypothesis that severe alterations in myocardial energy metabolism play an important role in the pathophysiology of human hibernating myocardium (HHM). BackgroundIt is well established that a disturbed myocardial energy metabolism results in impairments of contractile performance, structure and viability. All of these are important characteristics of HHM. MethodsIn 16 patients with documented coronary artery disease and impaired left ventricular function, HHM was preoperatively detected by thallium-201 scintigraphy, radionuclide ventriculography and low-dose dobutamine echocardiography. These regions were validated as HHM by their recovery of contractile function three months following revascularization. During open-heart surgery, transmural biopsies were removed from the hibernating areas and analyzed both biochemically and morphologically. These findings were compared to normal human myocardium. All metabolite contents given were normalized for the degree of fibrosis (control: 9.8 ± 0.5%; HHM: 28.1 ± 3.0%; p < 0.05), providing myocellular contents. ResultsIn HHM, decreased contents (μmol/g wet weight) in adenosine triphosphate (ATP) (control: 4.17 ± 0.26; HHM: 1.72 ± 0.25; p < 0.001), creatine phosphate (5.67 ± 0.70 vs. 0.84 ± 0.13; p < 0.001) and creatine (27.6 ± 3.19 vs. 11.2 ± 1.56; p < 0.0001) were found, but contents in lactate (2.22 ± 0.26 vs. 25.38 ± 3.53; p < 0.001), purine bases (0.58 ± 0.09 vs. 1.26 ± 0.13; p < 0.001) and protons (pH units: 7.199 ± 0.01 vs. 6.59 ± 0.07; p < 0.001) were increased. Levels in adenosine diphosphate, adenosine monophosphate and inorganic phosphate remained unchanged. Energy depletion in HHM was reflected by decreases in the free energy of ATP hydrolysis and in energy charge. ConclusionsThese data confirm our hypothesis that HHM is energy-depleted myocardium, exhibiting signs of chronic reduction in resting blood flow and a downregulation of energy turnover. The alterations in energy metabolism observed may become operative in triggering and maintaining contractile dysfunction, continuous tissue degeneration and cardiomyocyte loss.

Differential responses to chronic hypoxia and dietary restriction of aerobic capacity and enzyme levels in the rat myocardium.

Chronic exposure of mammals to hypoxia induces a state of anorexia. We aimed to determine the role played by diet restriction in the alterations of myocardial energy metabolism occurring under chronic hypoxia in order to detect the specific effects of hypoxia per se. Adult female rats were exposed to normobaric hypoxia (FiO2 = 0.10) for three weeks; pair-fed rats, kept under normoxic conditions, received the same amount of food as hypoxic rats. The oxidative capacity of myocardial ventricles and some skeletal muscles was evaluated using permeabilized fibers. Several metabolic enzyme activities were measured on extracts from myocardium and soleus. Diet restriction increased the activity of lactate dehydrogenase in both ventricles while it augmented phosphofructokinase and pyruvate kinase activities only in the left ventricle and depressed the respiratory rate in the right ventricle only. Hypoxia per se induced a rise in hexokinase activity in all studied oxidative muscles and a fall of hydroxy-acyl CoA-dehydrogenase activity in both myocardial ventricles. The respiratory rate and the citrate synthase activities were unaffected by hypoxia. We conclude that chronic hypoxia per se leads to specific alterations in myocardial metabolism that could favor the use of exogenous glucose at the expense of free fatty acids without any change in the oxidative capacity.

Heart failure: is there an energy deficit contributing to contractile dysfunction?

Alterations in myocardial energy metabolism have been demonstrated in both animal experiments and clinical observations. Whether these changes contribute to heart failure has been a longstanding and controversial issue. I. The creatine kinase (CK) system and the high energy phosphates under physiological conditions and in acute heart failure: 1. According to in vivo and in vitro experiments the myocardial creatine/creatine phosphate (Cr/CP) system is directly linked to mitochondrial oxidative phosphorylation via the mitochondrial CK. 2. The shift in the mass action ratio of the CK reaction with increasing myocardial oxygen consumption enables marked stimulation of mitochondrial respiratory function via the Cr/CP system with almost maintained free energy of the adenosine triphosphate/adenosine diphosphate (ATP/ADP) system. 3. In acute heart failure the depressed myocardial content mainly of CP can be considered as an adaptive mechanism related to increased oxygen demands. II. The CK system and the high energy phosphates in chronic heart failure: 1. The alterations observed in the CK system in chronic heart failure cannot be interpreted in terms of an "energy deficit" (i.e., the excess of what is spent over what is received on energy). 2. "Energy reserve" (i.e., energy kept back for future use, to fill an emergency) is markedly reduced in heart failure. 3. Under steady state conditions decreased "energy reserve" cannot be expected to contribute to heart failure. Under stress conditions, however, this mechanism is manifest by reducing contractile reserve. 4. The mechanisms by which decreased "energy reserve" induces depression of contractile reserve is not elucidated. III. Heart failure related to alterations in energy metabolism (mitochondrial diseases, stunned, and hibernating myocardium): 1. The phenotype of mitochondrial diseases is predominantly determined by neurological disorders and myopathies. Therefore, the patients are rarely referred to a cardiologist, although the cardiac involvement may ultimately determine the patients' prognosis. 2. Stunned and hibernating myocardium are characterized by prolonged contractile dysfunction in the presence of reversibly damaged myocardium. The underlying mechanisms and its triggers are unknown. 1. The reduced energy reserve in heart failure may be considered to contribute to the progression of the disease. 2. As an alternative, however, it can likewise represent a mechanism to protect the endangered myocardium from overload.

Microvascular heart disease in diabetes mellitus.

betic patients have an increased risk of developing heart failure independent of serum cholesterol, systolic blood pressure and age [1]. Diabetic patients have a markedly adverse course following myocardial infarction, with high rates of post-infarct failure and death [2, 3], and there is a significant association between dilated cardiomyopathy and a history of diabetes mellitus [4, 5]. Such studies have established the presence of a myocardial disorder in diabetic patients, distinct from macrovascular coronary disease and hypertension, which has led to the concept of diabetic cardiomyopathy. Diabetic cardiomyopathy may be defined as myocardial disease in diabetic patients unrelated to the presence of macrovascular atheromatous coronary artery stenosis. It has non-specific morphological and functional characteristics which include myocyte hypertrophy [6], interstitial fibrosis, arteriolar thickening, capillary microaneurysms and reduced capillary density [7–9], and abnormalities of left ventricular function with alterations in systolic and particularly diastolic function [10, 11]. The development of diabetic cardiomyopathy is likely to be multifactorial; putative mechanisms include stiffening and loss of ventricular compliance due to increased myocardial fibrosis, microvascular dysfunction, structural changes in collagen, alterations in myocardial energy metabolism, and structural changes to the sarcolemmal and contractile protein of the muscle itself. This review will concentrate on the possible relationship between microvascular dysfunction in diabetes and diabetic cardiomyopathy. Coronary microvascular function

Effect of glibenclamide on ischemic canine myocardium with glucose infusion

Glibenclamide, an ATP-sensitive K (K ATP) channel blocker, worsens the ischemia-induced metabolic derangement in the heart through inhibition of K ATP channels. We examined whether the hypoglycemic effect of glibenclamide was involved in the worsening of myocardial energy metabolism during ischemia. Pentobarbital-anesthetized dogs were subjected to 15-min ligation of the left anterior descending coronary artery. Either vehicle (dimethyl sulfoxide, DMSO) or glibenclamide (1 mg/kg) was injected i.v. 10 min before the ligation. In half of the animals given glibenclamide, glucose was continuously infused at 3 mg/kg per min immediately after glibenclamide injection. Glibenclamide increased the serum insulin level and decreased the blood glucose level. Glucose infusion completely abolished the hypoglycemia due to glibenclamide. Glibenclamide enhanced the decrease in ATP and total adenine nucleotides and increase in tissue lactate caused by ischemia. Glucose infusion did not cancel the augmentation of ischemia-induced alterations of myocardial energy metabolism caused by glibenclamide. These results suggest that K ATP channels directly play an important role in endogenous mechanisms of myocardial protection against ischemic damage.

Hyperthyroidism increases adenosine transport and metabolism in the rat heart.

Hyperthyroidism induces a number of metabolic and physiological changes in the heart including hypertrophy, increase in inotropic status, and alterations of myocardial energy metabolism. The effects of hyperthyroidism on adenosine metabolism which is intimately involved in the control of many aspects of myocardial energetics, have not been clarified. The aim of this study was thus to evaluate the potential role of adenosine in the altered physiology of the hyperthyroid heart. Transport of adenosine was studied in cardiomyocytes isolated from hyperthyroid and euthyroid rats. Activities of different enzymes of purine metabolism were studied in heart homogenates and concentrations of nucleotide and creatine metabolites were determined in hearts freeze-clamped in situ. Both transport of adenosine into cardiomyocytes and the rate of intracellular phosphorylation were higher in the hyperthyroid rat. At 10 microM concentration, adenosine transport rates were 275 and 197 pmol/min/mg protein in hyperthyroid and euthyroid cardiomyocytes respectively whilst rates of adenosine phosphorylation were 250 and 180 pmol/min/mg prot. An even more pronounced difference was observed if values were expressed per number of cells due to cardiomyocyte enlargement. Hyperthyroidism was associated with a 20% increase in adenosine kinase, 30% decrease in membrane 5'-nucleotidase and 15% decrease in adenosine deaminase activities measured in heart homogenates. In addition there was a substantial depletion in the total creatine pool from 63.7 to 41.6 mumol/g dry wt, a small decrease in the adenylate pool (from 27.2 to 24.3 mumol/g dry wt) and an elevation of the guanylate pool (from 1.22 to 1.36). These results show that adenosine transport and phosphorylation capacity is enhanced in hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholism and Myocardial Energy Metabolism

A review of the effects of chronic ethanol consumption on myocardial energy metabolism in animal models reveals that alterations in cardiac function are not accompanied by changes in the levels of the high-energy metabolites, ATP, and creatine phosphate. There are minor alterations in mitochondrial ultrastructure and function that appear to be accentuated by lowered nutrient intake. Observations to date indicate that, in animal models, there is an interaction between chronic ethanol consumption and caloric deprivation in eliciting alterations in myocardial energy metabolism. Furthermore, ethanol-related ultrastructural changes and depressed mitochondrial function are much more demonstrable in liver than in heart, suggesting strongly that the myocardium is less susceptible to the deleterious effects of alcohol than is the liver.

The relationship between oxygen radical generation and impairment of myocardial energy metabolism following post-ischemic reperfusion

Oxygen radical toxicity has been implacated in the pathogenesis of myocardial reperfusion injury. In the present study we sought to document the existence of a precise temporal relationship between the time course of free radical generation and the time course of alterations of myocardial energy metabolism during early reperfusion. Rabbit hearts perfused within the bore of a 31-Phosphorous NMR spectrometer were subjected to 30 min of total global ischemia at 37°C. At reflow, 12 control hearts received a bolus of normal perfusate and 12 hearts recombinant human superoxide dismutase (h-SOD) as a 60,000 IU bolus followed by a 100 IU/ml infusion for 15 min. Ischemia resulted in similar depletion of tissue ATP and phosphocreatine (PCr) in the two groups. During the first minute of reflow, recovery of PCr was similar in both groups. However, PCr recovery arrested in control hearts after 2 min, at 63% of baseline, and averaged 64 ± 4% after 45 min of reperfusion. In contrast, h-SOD treated hearts recovered 86.7% of baseline PCr content after 2 min, 102% after 10 min of reperfusion ( P<0.001), and 93 ± 6.4% at the end of the 45 min of reflow ( P<0.01). The time course of free radical formation during reperfusion was assessed by EPR spectroscopy using both the frozen tissue and the spin trapping methodologies. In control hearts, peak generation of oxygen radicals was reached after 20 s of reflow. h-SOD treatment decreased concentrations of the oxygen-centered radicals in myocardial tissue and of the radical-adducts in the coronary effluent by approximately 80%. Thus, in reperfused hearts peak oxygen radical generation is followed by the occurrence of alterations in the recovery of high energy phosphate metabolism. Both events were largely prevented by administration of h-SOD at reflow. These results provide strong support for a link between oxygen free radical generation and post-ischemic reperfusion injury.