Acute effects of heparin administration on the ischemic threshold of patients with coronary artery disease

Fragasso, Gabriele; Piatti, Pier Marco; Monti, Lucilla D.; Palloshi, Altin; Lu, Chunzeng; Valsecchi, G.; Setola, Emanuela; Calori, Giliola; Pozza, G.; Margonato, Alberto; Chierchia, Sergio

doi:10.1016/s0735-1097(01)01768-5

Cited by 27 publications

(16 citation statements)

References 42 publications

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“…GIK therapy for acute myocardial infarction was proposed in the 1960s, and several recent trials have shown promise in improving survival (19,21,46). There have also been several studies demonstrating the utility of the fatty acid oxidation inhibitors such as ranolazine and trimetazidine as antiischemic agents (23,52). One of the most commonly proposed mechanisms for the beneficial effects of increasing glucose oxidation at the expense of fatty acid oxidation is that this improves the coupling between glycolysis and glucose oxidation leading to lower accumulation of cellular protons and hence less intracellular acidosis (43,44).…”

Section: Discussionmentioning

confidence: 99%

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Differential modulation of glucose, lactate, and pyruvate oxidation by insulin and dichloroacetate in the rat heart

Lloyd¹,

Brocks²,

Chatham³

2003

American Journal of Physiology-Heart and Circulatory Physiology

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Despite the fact that lactate and pyruvate are potential substrates for energy production in vivo, our understanding of the control and regulation of carbohydrate metabolism is based principally on studies where glucose is the only available carbohydrate. Therefore, the purpose of this study was to determine the contributions of lactate, pyruvate, and glucose to energy production in the isolated, perfused rat heart over a range of insulin concentrations and after activation of pyruvate dehydrogenase with dichloroacetate (DCA). Hearts were perfused with physiological concentrations of [1-13 C]glucose, [U-13 C]lactate, [2-13 C]-pyruvate, and unlabeled palmitate for 45 min. Hearts were freeze clamped, and 13 C NMR glutamate isotopomer analysis was performed on tissue extracts. Glucose, lactate, and pyruvate all contributed significantly to myocardial energy production; however, in the absence of insulin, glucose contributed only 25-30% of total pyruvate oxidation. Even under conditions where carbohydrates represented Ͼ95% of substrate entering the tricarboxylic acid (TCA) cycle, we found that glucose contributed at most 50-60% of total carbohydrate oxidation. Despite being present at only 0.1 mM, pyruvate contributed between ϳ10% and 30% of total acetyl-CoA entry into the TCA cycle. We also found that insulin and DCA not only increased glucose oxidation but also exogenous pyruvate oxidation; however, lactate oxidation was not increased. The differential effects of insulin and DCA on pyruvate and lactate oxidation provide further evidence for compartmentation of cardiac carbohydrate metabolism. These results may have important implications for understanding the mechanisms underlying the beneficial effects of increasing cardiac carbohydrate metabolism. substrate metabolism; carbohydrates; fatty acids THE PREVAILING VIEW of cardiac energy production is that long-chain fatty acids are the primary oxidative energy source, followed to a lesser extent by glucose use, with other substrates such as lactate playing a much smaller role. This is despite the fact that the myocardium is capable of utilizing a wide variety of fuels for oxidative energy production. At rest, circulating lactate concentrations are ϳ1 mM (Table 1) and during moderate exercise can easily reach up to 3-5 mM (37). More than 20 years ago, Drake et al. (20) showed that the uptake of lactate by the heart in vivo is directly proportional to its serum concentration. In addition, it has been shown that in the isolated perfused heart, lactate contributes significantly to acetyl-CoA formation, often contributing more than glucose (9,10,35). In addition, serum pyruvate is typically in the range of 0.1-0.2 mM (Table 1), and, while this is relatively low, pyruvate is readily taken up and oxidized by the heart (36, 40, 45) and thus could contribute significantly to overall oxidative energy production in vivo.There is a resurgence of interest in the regulation of cardiac metabolism, driven, at least in part, by the manipulation of cardiac metabolism as a potential ...

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Section: Discussionmentioning

confidence: 99%

“…For example, drugs such as ranolazine and trimetazidine, which shift the balance from fatty acids to carbohydrate use, appear to be beneficial in the setting of myocardial ischemia (23,52). There has also been renewed interest in the beneficial effects of glucose-insulin-potassium (GIK) infusions in the setting of acute myocardial infarction (19,21,46).…”

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confidence: 99%

Differential modulation of glucose, lactate, and pyruvate oxidation by insulin and dichloroacetate in the rat heart

Lloyd¹,

Brocks²,

Chatham³

2003

American Journal of Physiology-Heart and Circulatory Physiology

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“…It is well known that increased ET-1 levels are present in insulinresistant subjects, in Type 2 diabetic hyperlipidemic patients, and in atherosclerosis and cardiovascular disease (16,20,32). Moreover, in patients with coronary artery disease, a marked increase of ET-1 release was observed during exercise, in the presence of increased FFA levels (11).…”

Section: Effects Of Type 2 Diabetes Mellitus On Myocardial Insulin Rementioning

confidence: 95%

Myocardial insulin resistance associated with chronic hypertriglyceridemia and increased FFA levels in Type 2 diabetic patients

Monti¹,

Landoni²,

Setola³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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dial insulin resistance associated with chronic hypertriglyceridemia and increased FFA levels in Type 2 diabetic patients. Am J Physiol Heart Circ Physiol 287: H1225-H1231, 2004. First published May 6, 2004; 10.1152/ajpheart.00629.2003.-We evaluated the influence of chronic hypertriglyceridemia and endothelial dysfunction on myocardial glucose uptake (MGU) in Type 2 diabetic patients without coronary heart disease. Patients were divided into two groups according to fasting triglyceride (TG) levels: 5.4 Ϯ 1.1 and 1.5 Ϯ 0.3 mmol/l for high-and normal-TG groups, respectively. Five subjects were assigned to the high-TG group and 11 to the normal-TG group. Age, gender, body mass index, systolic and diastolic blood pressure, glucose, insulin, HbA1c, cholesterol, and HDL cholesterol were similar in the two groups, whereas free fatty acid (FFA) levels were higher in the high-TG group basally and at the end of the clamp. Furthermore, five healthy subjects were subjected to the same protocol and used as the control group. MGU was assessed by using 18 F-labeled 2-fluoro-2-deoxy-D-glucose under hyperglycemic-hyperinsulinemic conditions. Basal endothelin-1 and nitric oxide levels were significantly higher in the high-TG group than in the normal-TG and control groups, and cGMP and maximal postischemic vasodilation were significantly decreased in the high-TG group compared with the normal-TG and control groups. However, significant alterations were found in the same parameters in the normal-TG group compared with the control group. By the end of the hyperglycemic clamp, in the high-TG group, MGU was ϳ40 and 65% of that in the normal-TG and control groups. MGU negatively correlated with TG, FFA, and endothelin-1, whereas a positive correlation was found with cGMP and maximal postischemic vasodilation. In conclusion, increased TG and FFA levels are risks, in addition to Type 2 diabetes mellitus, for myocardial insulin resistance, endothelial dysfunction, and alteration of nitric oxide/cGMP levels. triglycerides; myocardial glucose uptake; positron emission tomography study; endothelium; free fatty acid FOR MANY YEARS, hypertriglyceridemia was considered a marker of cardiovascular disease only in certain subjects, such as women (5, 12) and patients with Type 2 diabetes (10). The association between triglycerides (TGs), independently of HDL cholesterol levels, and definite cardiovascular disease, such as myocardial infarction or angina, was found in some studies (5) and denied in others, in which the simultaneous association of high TG and low HDL cholesterol was necessary to predict cardiovascular risk (8). This apparent discrepancy is probably related to the fact that it is quite difficult to match for duration and degree of cardiovascular disease in different populations, and, when cardiovascular disease is established, some factors might have lost their primary pathogenic significance. Hypertriglyceridemia occurs frequently in patients with coronary heart disease (CHD) and in survivors of myocardial infarction (5), and, durin...

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“…6 This has been the focus of many studies, leading to the development of putative fatty acid oxidation inhibitors such as trimetazidine and ranolazine for the treatment of ischemic disease. 7,8 Their protective effects are typically attributed to increased glucose oxidation and decreased fatty acid oxidation. 6 -8 Despite the continuing interest in GIK therapy and the apparent efficacy of trimetazidine and ranolazine, there is no consensus about the mechanisms underlying their beneficial effects.…”

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confidence: 99%

Impact of High Glucose/High Insulin and Dichloroacetate Treatment on Carbohydrate Oxidation and Functional Recovery After Low-Flow Ischemia and Reperfusion in the Isolated Perfused Rat Heart

Wang¹,

Lloyd²,

Chatham³

2005

Circulation

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Background-It is believed that increasing cardiac glucose metabolism in the setting of ischemia and reperfusion is protective because of the resulting decrease in fatty acid oxidation, which improves cardiac efficiency and increases glucose oxidation relative to glycolysis; however, these conclusions are based primarily on studies in which glucose is the only carbohydrate provided. The goal of this study was to examine the effect of stimulating myocardial carbohydrate use either by increasing glucose and insulin levels or by using dichloroacetate on the response to ischemia and reperfusion in hearts perfused with physiological concentrations of lactate and pyruvate plus glucose and fatty acids. Methods and Results-Metabolic fluxes were determined in hearts from male Sprague-Dawley rats perfused with 13 C-labeled substrates using 13 C/ 1 H-NMR isotopomer analysis after 30 minutes of low-flow ischemia (0.3 mL/min) and 60 minutes of reperfusion. Measurements were made under control conditions: 5 mmol/L glucose, 1 mmol/L lactate, 0.1 mmol/L pyruvate, 0.3 mmol/L palmitate, and 50 U/mL insulin plus dichloroacetate 5 mmol/L or glucose and insulin increased to 30 mmol/L and 1000 U/mL, respectively. Dichloroacetate increased carbohydrate oxidation and the ratio of glucose oxidation to glycolysis but did not improve functional recovery or cardiac efficiency; however, elevated glucose and insulin levels improved functional recovery and cardiac efficiency but did not increase carbohydrate oxidation or the ratio of glucose oxidation to glycolysis. Conclusions-These data support the notion that increasing myocardial glucose use is beneficial in the setting of ischemia and reperfusion; however, the protective effect appears not to be mediated by shifting the balance between carbohydrate and fatty acid oxidation.

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Acute effects of heparin administration on the ischemic threshold of patients with coronary artery disease

Cited by 27 publications

References 42 publications

Differential modulation of glucose, lactate, and pyruvate oxidation by insulin and dichloroacetate in the rat heart

Differential modulation of glucose, lactate, and pyruvate oxidation by insulin and dichloroacetate in the rat heart

Myocardial insulin resistance associated with chronic hypertriglyceridemia and increased FFA levels in Type 2 diabetic patients

Impact of High Glucose/High Insulin and Dichloroacetate Treatment on Carbohydrate Oxidation and Functional Recovery After Low-Flow Ischemia and Reperfusion in the Isolated Perfused Rat Heart

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