Role of fatty acid metabolites in the development of myocardial ischemic damage

Hütter, Joachim; Soboll, Sibylle

doi:10.1016/0020-711x(92)90030-5

Cited by 15 publications

(11 citation statements)

References 44 publications

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“…[23][24][25] Consistent with these reports, endogenous triglyceride increased as a result of hypoperfusion. The importance of this approach, using exogenous short chain fatty acids to bypass LCFA utilization, 13 is that if a direct measure of LCFA were performed, we would only demonstrate the known reduction in LCFA oxidation.…”

Section: Discussionsupporting

confidence: 71%

Mitochondrial Preference for Short Chain Fatty Acid Oxidation During Coronary Artery Constriction

et al. 2002

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Background-Reduced fatty acid oxidation in hypoperfused myocardium is believed to result from impaired oxidation in mitochondria. This study suggests another mechanism, that oxidative capacity exceeds regulated entry of long chain fatty acid (LCFA). The ability of myocardium to oxidize fatty acids and metabolize glucose during stenosis was examined in open chest, anesthetized pigs. Methods and Results-The left anterior descending (LAD) coronary artery was infused for 40 minutes (5 mL/min LAD) with [2-13 C] butyrate (4 mmol/L), a short chain fatty acid (SCFA), plus [2-13 C] glucose (10 mmol/L) in either nonischemic controls (nϭ4) or at the end of 5 hours of LAD flow reduction (40%, nϭ7). With LAD constriction, left ventricular wall thickening fell 45Ϯ8% (PϽ0.01). Despite glycolytic production of lactate and alanine, hypoperfused myocardium preferentially oxidized SCFA over endogenous LCFA. SCFA accounted for 63Ϯ4% (meanϮSEM) of carbon units entering oxidation in both ischemic epicardium and endocardium versus only 38Ϯ4% and 40Ϯ6% in respective samples from normal myocardium (PϽ0.002). Unexpectedly, SCFA contributions were elevated in both endocardium and epicardium despite preserved epicardial blood flow versus a 58Ϯ9% drop in endocardial flow (PϽ0.05). No significant oxidation of glucose was evident, indicating that unlabeled fuels were primarily LCFA. Conclusions-Because SCFA bypass LCFA transport into mitochondria, during LAD constriction, mitochondrial capacity to oxidize fatty acid exceeds LCFA entry for oxidation. Importantly, metabolic changes were disassociated from transmural tissue perfusion.

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Section: Discussionsupporting

confidence: 71%

Mitochondrial Preference for Short Chain Fatty Acid Oxidation During Coronary Artery Constriction

et al. 2002

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“…This suggests that mild acidemia and hypoxia leads to accumulation of short-and long-chain acylcarnitines. Accumulation of long-chain acylcarnitines is known as one of the main causes of arrhythmias and cellular damage in ischemic myocardium (21,22). This has also been shown for neonatal rat myocytes (23).…”

Section: Postnatal Changes In Acylcarnitine Profilementioning

confidence: 76%

Postnatal Changes in Neonatal Acylcarnitine Profile

et al. 2001

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Electrospray-tandem mass spectrometry represents a powerful method for detection of inborn errors of fatty acid metabolism. In the present study, it was used to examine neonatal carnitine metabolism, which reflects fatty acid metabolism. In 70 healthy neonates, blood samples were taken from the umbilical cord and by heel-stick puncture in full-term neonates on postnatal d 5. Cord blood specimens were also obtained from 15 preterm and 10 small-for-gestational-age infants. Acylcarnitine concentrations were measured in dried blood spots by electrospray tandem mass spectrometry. Compared with cord blood, the levels of nearly all acylcarnitine species were significantly higher on the postnatal d 5, whereas free carnitine remained unchanged. Total acylcarnitine/free carnitine-ratio increased, whereas the free carnitine/total carnitine-ratio (0.54 Ϯ 0.05; p Ͻ 0.01) further decreased. A reduced availability of free carnitine in the early neonatal period may affect fatty acid oxidation and thus be of potential pathophysiological relevance under conditions with higher energy demands, e.g. in sepsis. Cord blood concentrations of free carnitine, total carnitine, and total acylcarnitines were strongly related to birth weight (p Ͻ 0.01). Lower umbilical artery pH, i.e. mild hypoxia, caused accumulation of mainly long-chain acylcarnitines. This implicates that long-chain acylcarnitines could serve as a parameter of perinatal asphyxia. In utero, the main substrates for fetal metabolism are amino acids and glucose. The human placenta is also permeable to FFA. However, they are mainly stored as triglycerides in adipose tissues and liver because of the constant supply of glucose and amino acids and a low capacity of fetal tissues for FFA oxidation. The cutoff of the nutrient supply in the presuckling period after birth leads to a transient period of starvation. Thus, the newborn infant is entirely dependent on the mobilization of glycogen and fat stores. With the initiation of milk feeding, neonatal metabolism switches to a high-fat diet. Therefore, it is obvious that fatty acid oxidation is very important in the early postnatal period (1).Carnitine plays an important role in oxidation of especially long-chain fatty acids. Carnitine palmitoyltransferases I and II mediate the transport of fatty acid-carnitine esters (acylcarnitines) across the mitochondrial membranes. Carnitine acyltransferases can also be found in peroxisomes (carnitine octanoyltransferase) and endoplasmatic reticulum (microsomal carnitine acyltransferase), although their function is not yet fully understood. In the mitochondrion, carnitine removes excess acyl groups and thus regulates the concentration of free CoA in the mitochondrial matrix (2). Several studies have shown that the carnitine pool in the neonate is limited (1, 3, 4). Tandem mass spectrometry allows quantitative determination of free carnitine and various carnitine esters like acylcarnitines (5, 6).In the present study, we used this technique to investigate the changes in neonatal carnitine and fat...

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“…Hü tter and Soboll (15) have also speculated that the increase in oxygen consumption evoked by LC fatty acids in the intact heart is related to futile cycles such as extramitochondrial ␤-oxidation or uncoupling of oxidative phosphorylation. The latter effect, uncoupling, is thought to involve cyclic mitochondrial influx of fatty acid (R-COOH) and efflux of its anionic (R-COO Ϫ ) form (27,31).…”

Section: Discussionmentioning

confidence: 99%

Long-chain fatty acids increase basal metabolism and depolarize mitochondria in cardiac muscle cells

Ray

Noll

Daut

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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The effects of long-chain (LC) fatty acids on rate of heat production (heat rate) and mitochondrial membrane potential (⌬⌿) of intact guinea pig cardiac muscle were investigated at 37°C. Heat rate of ventricular trabeculae was measured with microcalorimetry, and ⌬⌿ was monitored in isolated ventricular myocytes with either JC-1 or tetramethylrhodamine ethyl ester (TMRE). Methyl-␤-cyclodextrin was used as fatty acid carrier. Application of 400 M oleate or linoleate increased resting heat rate by ϳ30% and ϳ25%, respectively. When LC fatty acid was supplied as sole metabolic substrate, resting heat rate was decreased by 3-mercaptopropionic acid. In TMRE-loaded myocytes, neither 40-80 M oleate nor 40 M linoleate affected ⌬⌿. At a higher concentration (400 M) both oleate and linoleate increased TMRE fluorescence by ϳ20% of maximum, obtained using 2,4-dinitrophenol (100 M), indicating a depolarization of the inner mitochondrial membrane. We conclude that LC fatty acids, at sufficiently high concentration, increase heat rate and decrease ⌬⌿ in intact cardiac muscle, consistent with a protonophoric uncoupling action. These effects may contribute to the high metabolic rate after reperfusion of postischemic myocardium. mitochondrial membrane potential; microcalorimetry IN CARDIAC MUSCLE, the resting (basal) level of metabolism is extraordinarily high, accounting for 25-30% of the metabolic rate of mechanically active muscle (3,4,9,12,22,29). Although the origin of this high resting metabolic rate is unknown, it has been shown to be sensitive to metabolic substrate (4, 9). This is well illustrated with pyruvate, which has been shown to increase resting rate of heat production (4) and oxygen consumption (9) of isolated cardiac muscle preparations.In isolated mitochondrial preparations, long-chain (LC) fatty acids have been shown convincingly to uncouple oxidative phosphorylation (27,31). Whether this uncoupling action manifests in intact cardiac muscle is not known (14,35). This unresolved issue is important because LC fatty acids are the major metabolic substrates of the heart and, furthermore, they are known to accumulate in high concentrations during ischemia (6, 33). The aims of the present study were to determine the effects of LC fatty acids on both resting heat rate and mitochondrial membrane potential (⌬⌿) of intact cardiac muscle. METHODS Isolation of trabeculae and microcalorimetry.Guinea pigs (200-300 g) were anesthetized with 3-4% isoflurane in oxygen and then decapitated with a guillotine. The heart was rapidly excised and perfused with dissecting solution containing (mM) 105 NaCl, 15 KCl, 2 CaCl 2, 1 MgCl2, 1 NaH2PO4, 24 NaHCO3, 20 2,3-butanedione monoxime, and 10 glucose. The solution was equilibrated with 95% O2-5% CO2, and the pH was 7.4. The right ventricle was opened, and free running trabeculae (diameter Ͻ400 m) were excised and subsequently transferred to the calorimeter. These preparations were shown recently to be composed chiefly of myocytes accompanied by parallel perimysial collagen fibers (13). Af...

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Role of fatty acid metabolites in the development of myocardial ischemic damage

Cited by 15 publications

References 44 publications

Mitochondrial Preference for Short Chain Fatty Acid Oxidation During Coronary Artery Constriction

Mitochondrial Preference for Short Chain Fatty Acid Oxidation During Coronary Artery Constriction

Postnatal Changes in Neonatal Acylcarnitine Profile

Long-chain fatty acids increase basal metabolism and depolarize mitochondria in cardiac muscle cells

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