Myocardial Lactate Release Research Articles

Exogenous nitric oxide requires an endothelial glycocalyx to prevent postischemic coronary vascular leak in guinea pig hearts

IntroductionPostischemic injury to the coronary vascular endothelium, in particular to the endothelial glycocalyx, may provoke fluid extravasation. Shedding of the glycocalyx is triggered by redox stress encountered during reperfusion and should be alleviated by the radical scavenger nitric oxide (NO). The objective of this study was to investigate the effect of exogenous administration of NO during reperfusion on both coronary endothelial glycocalyx and vascular integrity.MethodsIsolated guinea pig hearts were subjected to 15 minutes of warm global ischemia followed by 20 minutes of reperfusion in the absence (Control group) and presence (NO group) of 4 μM NO. In further experiments, the endothelial glycocalyx was enzymatically degraded by means of heparinase followed by reperfusion without (HEP group) and with NO (HEP+NO group).ResultsIschemia and reperfusion severely damaged the endothelial glycocalyx. Shedding of heparan sulfate and damage assessed by electron microscopy were less in the presence of NO. Compared with baseline, coronary fluid extravasation increased after ischemia in the Control, HEP, and HEP+NO groups but remained almost unchanged in the NO group. Tissue edema was significantly attenuated in this group. Coronary vascular resistance rose by 25% to 30% during reperfusion, but not when NO was applied, irrespective of the state of the glycocalyx. Acute postischemic myocardial release of lactate was comparable in the four groups, whereas release of adenine nucleotide catabolites was reduced 42% by NO. The coronary venous level of uric acid, a potent antioxidant and scavenger of peroxynitrite, paradoxically decreased during postischemic infusion of NO.ConclusionThe cardioprotective effect of NO in postischemic reperfusion includes prevention of coronary vascular leak and interstitial edema and a tendency to forestall both no-reflow and degradation of the endothelial glycocalyx.

Pacing-Induced Dyssynchrony During Early Reperfusion Reduces Infarct Size

Considering the recent discovery of postconditioning, we investigated whether intermittent dyssynchrony immediately upon reperfusion induces cardioprotection as well. Intermittent dyssynchrony, induced by ventricular pacing, preconditions myocardium. Isolated ejecting rabbit hearts were subjected to 30-min coronary occlusion and 2-h reperfusion. Control, left ventricular (LV) pacing preconditioning (LVPpreC) (3 x 5-min LV pacing), and LV pacing postconditioning (LVPpostC) (10 x 30-s LV pacing during early reperfusion) groups were studied. Mechanical effects of LV pacing were determined using local pressure-length loops (sonomicrometry), whereas effects on myocardial lactate release and coronary flow were assessed from coronary effluent and fluorescent microspheres, respectively. Anesthetized pigs underwent 60-min coronary occlusion and 3-h reperfusion in control and right ventricular (RV) pacing postconditioning groups (RVPpostC) (10 x 30-s RV pacing during early reperfusion). In all hearts, area at risk and infarct size were determined with blue dye and triphenyltetrazolium chloride staining, respectively. Infarct size, normalized to area at risk, was 47.0 +/- 12.3% in control rabbit hearts, but significantly smaller in LVPpreC (17.8 +/- 6.4%) and LVPpostC hearts (17.9 +/- 4.4%). Left ventricular pacing significantly altered regional mechanical work, but did not affect coronary flow or lactate release. In pigs, infarct size was significantly smaller in RVPpostC (9.8 +/- 3.0%) than in control (20.6 +/- 2.2%) animals. Intermittent dyssynchrony during early reperfusion reduces infarct size in 2 different animal models. Dyssynchrony-induced postconditioning cannot be attributed to graded reperfusion but may be induced by modulation of local myocardial workload. Dyssynchrony-induced postconditioning opens new possibilities for cardioprotection in the clinical setting.

Pacing-Induced Dys-Synchrony Preconditions Rabbit Myocardium Against Ischemia/Reperfusion Injury

Because increased mechanical load induces preconditioning (PC) and dys-synchrony increases loading in late-activated regions, we investigated whether dys-synchrony induced by ventricular pacing (VP) at normal heart rate leads to cardioprotection. Isolated working rabbit hearts were subjected to 35 minutes of global ischemia and 2 hours of reperfusion. Seven hearts underwent VP PC (3 periods of 5 minutes VP at the posterior left ventricular [LV] wall), 7 hearts underwent ischemic preconditioning (IPC) (3 periods of 5 minutes of global ischemia), and 9 hearts served as control (C). LV pressure and sonomicrometry were used to assess global hemodynamics and segment work (SW) and end-diastolic segment length (EDSL) in anterior and posterior LV myocardium. Myocardial release of lactate and expression of proBNP mRNA were determined to gain insight in molecular processes involved in VP PC (*P<0.05). Infarct size (triphenyl tetrazolium chloride staining) was 18.3+/-13.0% in group C, and was uniformly reduced in the VP PC and IPC groups (1.8+/-0.8%*, and 3.5+/-3.1%*, respectively; and not significant between VP PC and IPC). LV posterior wall pacing (VP PC group) increased EDSL (by 6.3+/-5.8%*) and SW (to 335+/-207%*) in the LV anterior wall, whereas posterior wall SW decreased to negative values (-23+/-63%*). LV pacing did not significantly change lactate release and coronary flow but significantly increased proBNP mRNA expression in both anterior and posterior myocardium as compared with controls. Intermittent dys-synchrony is equally cardioprotective as "classical" IPC. Stretch-mediated signaling is a more likely trigger for VP PC than ischemia. VP PC is potentially applicable in cardiac surgery.

Blood Cardioplegia Provides Superior Protection in Infant Cardiac Surgery

We hypothesized that blood cardioplegia preserves myocardial metabolism and function more effectively than St Thomas' crystalloid cardioplegia in infant cardiac surgery. Thirty infants with atrioventricular septal defects were randomly allocated to either blood or crystalloid intermittent cold (4 degrees C) cardioplegia. Arterial and coronary sinus blood was analyzed for lactate and oxygen. Cardiac output (thermodilution) and left ventricular function (echocardiography) were evaluated. The lactate concentration in coronary sinus blood early after bypass was significantly higher after crystalloid cardioplegia than after blood cardioplegia (2.1 +/- 0.3 vs 1.3 +/- 0.1 mmol/L, p = 0.006), with a significant myocardial release of lactate after crystalloid but not after blood cardioplegia. Oxygen extraction (arterial-coronary sinus O2 content) was higher early after crystalloid cardioplegia (3.02 +/- 0.13 vs 2.35 +/- 0.22 mmol/L, p = 0.01), possibly reflecting a difference in oxygen debt. The cardiac index was higher after blood cardioplegia (4.9 +/- 0.3 vs 4.0 +/- 0.3 L/min(-1)/m(-2), p = 0.04) and echocardiographic grading of left ventricular function was better (4.1 +/- 0.17 vs 3.5 +/- 0.22 arbitrary units, p = 0.046). This study indicates that blood cardioplegia preserves myocardial metabolism and function more effectively than crystalloid cardioplegia in infant cardiac surgery. The clinical significance of this finding is uncertain, but the more than 20% increase in cardiac index in the critical phase during weaning from bypass may be advantageous.

Early postoperative function of the heart after coronary artery bypass grafting is not predicted by myocardial necrosis and glutathione-associated oxidative stress

Background To investigate whether cardioplegia-related myocardial necrosis, lactate and glutathione release are predictive for early postoperative cardiac function after coronary artery bypass grafting (CABG). Methods Twelve patients with stabile angina scheduled for elective CABG were included. Myocardial release of troponin I (Tn I), creatine kinase MB isoenzyme mass (CK-MB), oxidized glutathione (GSSG) and lactate in blood were measured before cardioplegia, and up to 20 min thereafter. Cardiac function was assessed for 12 postoperative hours. Results Release of Tn I and CK-MB peaked at 20 min (− 14.5 ± 24.1 ng/ml and − 23.9 ± 30.6 ng/ml, respectively) and lactate at 1 min of reperfusion (− 1.5 ± 0.6 mmol/l). Significant GSSG release occurred at 5 min, with concomitant increase of glutathione redox ratio. The changes were not correlated to ischemic time. Cardiac index was increased after CPB and remained higher than preoperative value until the first postoperative morning. No correlations between postcardioplegic heart function and markers of tissue injury were found. Conclusions The extent of myocardial reversible and irreversible injury does not predict early postoperative contractile function of the heart.

Contractile function of the heart after cardioplegia is not determined by the extent of myocardial necrosis and lactate release

1North Estonian Regional Hospital, Tallinn; 2University of Tartu, Clinic of Anaesthesiology and Intensive Care, Estonia

Intermittent Warm Blood Cardioplegia Induces the Expression of Heat Shock Protein-72 by Ischemic Myocardial Preconditioning

Objective: Recent studies have demonstrated that the induction of heat shock protein-72 (HSP72) by different stimuli preserves the heart function after cardioplegic arrest. Based on these findings, we investigated whether intermittent warm blood cardioplegia would induce changes in the myocardial expression of HSP72. Methods: Forty patients scheduled for aortocoronary bypass were randomly assigned to receive either cold or warm intermittent blood cardioplegia. In all patients HSP72 and HSP72 mRNA were assayed in biopsies from the right atrium at baseline, and during the reperfusion period. Plasma CK-MB and troponin-T, and myocardial oxygen extraction and lactate release were also measured. Results: In both groups, myocardial expression of HSP72 increased throughout the reperfusion period, but the values of HSP72 band lengths were significantly higher in the warm group. Correspondingly, HSP72 mRNA levels increased progressively in both groups, with significant difference between groups observed in biopsies at the reperfusion. Warm blood cardioplegia was associated with lower levels of CK-MB and troponin-T. Myocardial oxygen extraction and lactate release were higher during intermittent warm cardioplegia, indicating a more profound ischemic anaerobic metabolism in the warm group. Conclusions: Intermittent warm blood cardioplegia induces an increased expression of HSP72 and it is associated with a better myocardial protection, by a mechanism involving a variant of the classical ischemic preconditioning model.

Intermittent warm blood cardioplegia induces the expression of heat shock protein-72 by ischemic myocardial preconditioning

Objective: Recent studies have demonstrated that the induction of heat shock protein-72 (HSP72) by different stimuli preserves the heart function after cardioplegic arrest. Based on these findings, we investigated whether intermittent warm blood cardioplegia would induce changes in the myocardial expression of HSP72. Methods: Forty patients scheduled for aortocoronary bypass were randomly assigned to receive either cold or warm intermittent blood cardioplegia. In all patients HSP72 and HSP72 mRNA were assayed in biopsies from the right atrium at baseline, and during the reperfusion period. Plasma CK-MB and troponin-T, and myocardial oxygen extraction and lactate release were also measured. Results: In both groups, myocardial expression of HSP72 increased throughout the reperfusion period, but the values of HSP72 band lengths were significantly higher in the warm group. Correspondingly, HSP72 mRNA levels increased progressively in both groups, with significant difference between groups observed in biopsies at the reperfusion. Warm blood cardioplegia was associated with lower levels of CK-MB and troponin-T. Myocardial oxygen extraction and lactate release were higher during intermittent warm cardioplegia, indicating a more profound ischemic anaerobic metabolism in the warm group. Conclusions: Intermittent warm blood cardioplegia induces an increased expression of HSP72 and it is associated with a better myocardial protection, by a mechanism involving a variant of the classical ischemic preconditioning model.

Dexmedetomidine decreases perioperative myocardial lactate release in dogs.

The sympatholytic effect of the alpha(2)-adrenergic agonist dexmedetomidine may decrease emergence-related myocardial ischemic load in patients. However, a direct measure of myocardial ischemia, such as myocardial lactate release, is difficult to obtain in patients. Therefore, we studied mongrel dogs and measured myocardial lactate release, myocardial oxygen supply, hemodynamic variables, and neurohumoral indices of the stress response. After the induction of a standardized degree of borderline myocardial ischemia, either dexmedetomidine (dexmed group, n = 9) or normal saline (control group, n = 9) was infused. Measurements were repeated at the end of the anesthetic period and every 10 min during the 90-min emergence period. In the dexmed group, the cumulative emergence-related lactate release was 46% less than in the control group (95% confidence interval, 20%-80%; P = 0.02). Simultaneously, dexmedetomidine increased the endo-/epicardial blood flow ratio by 35% (control group, 0.4 +/- 0.1; dexmed group, 0.6 +/- 0.1; P = 0.03). These antiischemic effects of dexmedetomidine were accompanied by reduced plasma concentrations of norepinephrine (126 versus 577 pg/mL) and epinephrine (158 versus 1909 pg/mL) and a slower heart rate (123 +/- 6 versus 160 +/- 10 bpm, dexmed versus control). The antiischemic effect of dexmedetomidine started before emergence, as evidenced by a decreased prevalence of myocardial lactate release at that time (zero of eight dogs in the dexmed group and four of seven dogs in the control group had lactate release before emergence; P = 0.03). Dexmedetomidine decreases plasma catecholamines and heart rate during emergence from anesthesia. In dogs with a coronary stenosis, these sympatholytic effects decrease myocardial lactate release and, therefore, minimize emergence-related myocardial ischemia.

Cardiac performance as a function of intracellular oxygen tension in buffer-perfused hearts.

Critical intracellular myocardial oxygen tension was determined by optical spectroscopic measurement of myoglobin oxygen saturation in crystalloid-perfused guinea pig hearts. Accurate end-point determinations of the maximally oxygenated and deoxygenated myoglobin were made. Hearts were subjected to a steady decrease in perfusate oxygen tension while left ventricular developed pressure, maximal left ventricular dP/dt, myocardial oxygen consumption, lactate release, and adenosine release were measured as indices of myocardial function. Intracellular myoglobin was found to be only 72% saturated under baseline conditions with an arterial oxygen tension of >600 mmHg at 37 degrees C. Baseline intracellular oxygen tension was 6.3 mmHg. Myocardial oxygen consumption was decreased by 10% when the oxygen tension fell to 5.7 mmHg, and cardiac contraction decreased 10% when oxygen tension was 4.1 mmHg. Adenosine release and, finally, lactate release began to increase at sequentially lower oxygen tensions. The present results indicate that the buffer-perfused guinea pig heart at 37 degrees C has an intracellular oxygen tension just above the threshold for impaired function.

Metabolic changes and myocardial injury during cardioplegia: a pilot study

Background. The timing, nature, and severity of both increased cardiac troponin I (cTn-I) levels and myocardial injury during ischemic arrest with cardioplegia are unknown. To define them more accurately, we studied myocardial metabolic activity and the release of markers of myocardial cell injury into the coronary sinus before, during, and after cardioplegia. Methods. We simultaneously measured creatine kinase, creatine kinase-MB, cTn-I, lactate, phosphate, and blood gases in coronary sinus and systemic arterial blood from 12 patients before cardiopulmonary bypass, after removal of the aortic cross-clamp, and after discontinuation of cardiopulmonary bypass. We also measured coronary sinus flow and transmyocardial fluxes of all analytes and calculated myocardial oxygen consumption, myocardial carbon dioxide production, and myocardial energy expenditure. Results. Myocardial lactate release increased 10-fold after removal of the aortic cross-clamp ( p = 0.012) and was accompanied by a surge in myocardial phosphate uptake ( p = 0.056). These events were associated with only partial cardioplegia-induced suppression of myocardial oxygen consumption ( p = 0.0047), myocardial carbon dioxide production ( p = 0.0022), and myocardial energy expenditure ( p = 0.0029). Simultaneously, coronary sinus cTn-I levels increased from a mean of 0.76 to 2.43 ng/mL after removal of the aortic cross-clamp, and 2.51 ng/mL after cardiopulmonary bypass ( p = 0.014), leading to an increase in arterial cTn-I concentration from 0.18 to 0.98 and 3.01 ng/mL ( p = 0.0002). Thus, cTn-I release across the myocardium was absent at baseline, became detectable ( p = 0.012) after removal of the aortic cross-clamp, and correlated with cross-clamp and pump times. Similar changes occurred with creatine kinase-MB. Conclusions. Metabolic myocardial stress occurs during ischemic arrest with cardioplegia and is associated with inadequate suppression of metabolism and with a surge in cTn-I and creatine kinase-MB release, which is maximal after removal of the aortic cross-clamp. These changes are likely to represent structural myocardial cell injury.

Destruction of contrast microbubbles by ultrasound: effects on myocardial function, coronary perfusion pressure, and microvascular integrity.

Recent experimental data indicate that ultrasound-induced destruction of ultrasound contrast microbubbles can cause immediate rupture of the microvessels in which these microbubbles are located. To examine the functional and morphological significance of these findings in the heart, isolated rabbit hearts were perfused retrogradely with buffer containing ultrasound contrast agents and were insolated at increasing levels of acoustic energy with a broadband transducer emitting at 1.8 MHz and receiving at 3.6 MHz and operated in the triggered mode (1 Hz). At the end of each experiment, the hearts were fixed in glutaraldehyde and examined with light microscopy. Neither exposure to ultrasound alone or to contrast alone affected left ventricular developed pressure. By contrast, simultaneous exposure to contrast and ultrasound resulted in a reversible, transient mechanical index (MI)-dependent decrease in left ventricular developed pressure (to 83+/-5% of baseline at an MI of 1.6) and a transient MI-dependent increase in coronary perfusion pressure (to 120+/-6% of baseline at an MI of 1.6). Myocardial lactate release also showed significant increases with increasing MIs. Macroscopically, areas of intramural hemorrhage were identified over the beam elevation in hearts exposed to both contrast and high-MI ultrasound. Light microscopy revealed the presence of capillary ruptures, erythrocyte extravasation, and endothelial cell damage. The mean percentage of capillaries ruptured at an MI of 1.6 was 3.6+/-1.4%. Simultaneous exposure of isolated rabbit hearts to ultrasound and contrast agents results in an MI-dependent, transient depression of left ventricular contractile function, a rise in coronary perfusion pressure, an increase in lactate production, and limited capillary ruptures.

Lactate release during reperfusion predicts low cardiac output syndrome after coronary bypass surgery

Background. Cardioplegic arrest induces anaerobic myocardial metabolism with a net production of lactate from glycolysis. However, persistent lactate release during reperfusion suggests a delayed recovery of normal aerobic metabolism and may lead to depressed myocardial function necessitating inotropic or intraaortic balloon pump support (low output syndrome [LOS]). We examined the relation between perioperative myocardial metabolism and postoperative clinical outcomes in patients undergoing isolated coronary artery bypass surgery (CABG).Methods. We reviewed 623 patients who were enrolled in clinical studies evaluating perioperative myocardial metabolism between 1983 and 1996. Arterial and coronary sinus blood samples were obtained intraoperatively to assess myocardial metabolism. Clinical data regarding patient demographics and postoperative outcomes were prospectively collected and entered into our institutional database.Results. Low output syndrome developed in 36 patients (5.8%). Myocardial lactate release was higher in these patients compared with those who did not develop postoperative LOS. Advanced age and poor preoperative left ventricular function were independent predictors of lactate release during reperfusion. Persistent lactate release after 5 minutes of reperfusion was the only independent predictor of postoperative LOS in this low-risk population.Conclusions. Persistent lactate release during reperfusion occurs in a significant proportion of low-risk patients undergoing isolated CABG and is an independent predictor of postoperative low cardiac output syndrome. Persistent lactate release during reperfusion suggests a delayed recovery of aerobic myocardial metabolism and may be related to intraoperative misadventure or inadequate myocardial protection. Myocardial lactate release may be useful as an alternative end-point in clinical trials evaluating perioperative myocardial protection.

Effects of metabolic stimulation on cardiac allograft recovery

Background. We previously demonstrated that continuous perfusion of cardiac allografts during hypothermic storage with donor blood harvested at the time of organ retrieval improves myocardial recovery after transplantation. However, myocardial metabolism and function remain depressed compared to base line values. This study evaluated the use of a continuous infusion of donor blood enhanced with insulin to augment aerobic myocardial metabolism during and after hypothermic storage. Methods. Yorkshire pigs (45 to 50 kg) were used to perform 14 orthotopic cardiac transplants using either continuous perfusion with donor blood (blood group, n = 7) or perfusion with donor blood enhanced with 10 IU/L insulin (insulin group, n = 7). After heparinization, hypothermic (4°C) cardioplegic arrest, and donor heart extraction, donor blood (2844 ± 210 mL) was harvested in both groups and perfused at room temperature (20°C) at a pressure of 60 mm Hg for 3 hours. Blood cardioplegia was delivered after each anastomosis in both groups and arterial and coronary sinus blood samples were obtained to examine myocardial metabolism. A Millar micromanometer was used to measure left ventricular developed pressure and the rate–pressure product at varying preloads. Results. There were no differences in either myocardial lactate or acid release between the two groups. Hearts in the insulin group displayed higher myocardial oxygen extraction than those in the blood group. The recovery of developed pressure was higher in the insulin group compared to the blood group (91% ± 19% vs 73% ± 2%, p = 0.04). Conclusions. In this model, continuous perfusion of cardiac allografts with donor blood and insulin preserves myocardial metabolism during hypothermic storage and improves metabolic and functional recovery after orthotopic cardiac transplantation.

Effect of perhexiline and oxfenicine on myocardial function and metabolism during low-flow ischemia/reperfusion in the isolated rat heart.

Perhexiline is a potent prophylactic anti-anginal agent that has been shown to inhibit myocardial utilization of long-chain fatty acids and to inhibit the mitochondrial enzyme carnitine palmitoyltransferase (CPT)-1. We compared the hemodynamic and biochemical effects of perhexiline (0.5 and 2.0 microM) and of another CPT-1 inhibitor, oxfenicine (0.5 mM), in Langendorff-perfused rat hearts subjected to 60 min of low-flow ischemia (95% flow reduction) followed by 30 min of reperfusion. Both perhexiline (2 microM only) and oxfenicine attenuated (p < 0.003, p < 0.0002, respectively) increases in diastolic tension during ischemia, without significant effects on developed tension, or on cardiac function during reperfusion. Myocardial concentrations of long-chain acylcarnitines (LCAC), products of CPT-1 action, were decreased (p < 0.05) by oxfenicine, unaffected by 2 microM perhexiline, and increased slightly by 0.5 microM perhexiline. Perhexiline, but not the active metabolite of oxfenicine, also inhibited cardiac CPT-2 with similar IC50 and Emax, although lower Hill slope, compared with CPT-1. Oxfenicine, but not perhexiline, reduced concentrations of the endogenous CPT-1 inhibitor, malonyl-CoA. Perhexiline, but not oxfenicine, inhibited myocardial release of lactate during normal flow. We conclude that (a) perhexiline protects against diastolic dysfunction during ischemia in this model, independent of major changes in LCAC accumulation and (b) this may result from simultaneous effects of perhexiline on myocardial CPT-1 and CPT-2.

Glucose-insulin-potassium preserves systolic and diastolic function in ischemia and reperfusion in pigs.

Clinical and experimental studies have suggested benefit of treatment with intravenous glucose-insulin-potassium (GIK) in acute myocardial infarction. However, patients hospitalized with acute coronary syndromes often experience recurrent myocardial ischemia without infarction that may cause progressive left ventricular (LV) dysfunction. This study tested the hypothesis that anticipatory treatment with GIK attenuates both systolic and diastolic LV dysfunction resulting from ischemia and reperfusion without infarction in vivo. Open-chest, anesthetized pigs underwent 90 min of moderate regional ischemia (mean subendocardial blood flow 0.3 ml x g(-1) x min(-1)) and 90 min reperfusion. Eight pigs were treated with GIK (300 g/l glucose, 50 U/l insulin, and 80 meq/l KCl; infused at 2 ml x kg(-1) x h(-1)) beginning 30 min before ischemia and continuing through reperfusion. Eight untreated pigs comprised the control group. Regional LV wall area was measured with orthogonal pairs of sonomicrometry crystals. GIK significantly increased myocardial glucose uptake and lactate release during ischemia. After reperfusion, indexes of regional systolic function (external work and fractional systolic wall area reduction), regional diastolic function (maximum rate of diastolic wall area expansion), and global LV function (LV positive and negative maximum rate of change in pressure with respect to time) recovered to a significantly greater extent in GIK-treated pigs than in control pigs (all P < 0.05). The findings suggest that the clinical utility of GIK may extend beyond treatment of acute myocardial infarction to anticipatory metabolic protection of myocardium in patients at risk for recurrent episodes of ischemia.

Myocardial lactate metabolism in fetal and newborn lambs.

Around birth, myocardial substrate supply changes from carbohydrates before birth to primarily fatty acids after birth. Parallel to these changes, the myocardium is expected to switch from the use of primarily lactate before birth to fatty acids thereafter. However, myocardial lactate uptake and oxidation around birth has not been measured in vivo. We measured myocardial lactate uptake, oxidation, and release with infusion of [1-13C]lactate and myocardial flux of fatty acids and glucose in chronically instrumented fetal and newborn (1 to 15 days) lambs. Myocardial lactate oxidation was the same in newborn (81.7+/-14.7 micromol. min-1. 100 g-1, n=11) as in fetal lambs (60.7+/-26.7 micromol. min-1. 100 g-1, n=7). Lactate uptake was also the same in newborn as in fetal lambs. Lactate uptake was higher than lactate flux, indicating lactate release simultaneously with uptake. In the newborn lambs, lactate uptake declined with age. Lactate uptake was strongly related to lactate supply, whereas lactate oxidation was not. The supply of fatty acids or glucose did not interfere with lactate uptake, but the flux of fatty acids was inversely related to lactate oxidation. We show that lactate is an important energy source for the myocardium before birth as well as in the first 2 weeks after birth in lambs. We also show that there is release of lactate by the myocardium simultaneously with uptake of lactate. Furthermore, we show that lactate oxidation may be attenuated by fatty acids but not by glucose, probably at the level of pyruvate dehydrogenase.

Increased myocardial lactate oxidation in lambs with aortopulmonary shunts at rest and during exercise.

Free fatty acids are the major fuels for the myocardium, but during a higher load carbohydrates are preferred. Previously, we demonstrated that myocardial net lactate uptake was higher in lambs with aortopulmonary shunts than in control lambs. To determine whether this was caused by an increased lactate uptake and oxidation or by a decreased lactate release, we studied myocardial lactate and glucose metabolism with 13C-labeled substrates in 36 lambs in a fasting, conscious state. The lambs were assigned to two groups: a resting group consisting of 8 shunt and 9 control lambs, and an exercise group (50% of peak O2 consumption) consisting of 9 shunt and 10 control lambs. Myocardial lactate oxidation was higher in shunt than in control lambs (mean +/- SE, rest: 10.33 +/- 2.61 vs. 0. 17 +/- 0.82, exercise: 38.05 +/- 8.87 vs. 16.89 +/- 4.78 micromol. min-1. 100 g-1; P < 0.05). There was no difference in myocardial lactate release between shunt and control lambs. Oxidation of exogenous glucose, which was approximately zero at rest, increased during exercise in shunt and control lambs. The contribution of glucose and lactate to myocardial oxidative metabolism increased during exercise compared with at rest in both shunt and control lambs. We conclude that myocardial lactate oxidation is higher in shunt than in control lambs, both at rest and during exercise, and that the contribution of carbohydrates in myocardial oxidative metabolism in shunt lambs is higher than in control lambs. Thus it appears that this higher contribution of carbohydrates occurs not only in the case of pressure-overloaded hearts but also in myocardial hypertrophy due to volume overloading.

Preservation of myocardial metabolism in acute coronary artery occlusions with retrograde coronary sinus perfusion and iloprost

A total of 12 healthy mongrel dogs were subjected to the study. The left anterior descending artery was occluded. The occlusion was done for 15 min. At the end of this period, without removing the occlusion, the heart was retroperfused for 3 h. Then, occlusion was removed and reperfusion was supplied. Animals were divided into two equal groups. Six animals received iloprost and the other six control did not receive any additional treatment. In the iloprost group, the drug was administered into the coronary sinus. After 15 min following occlusion, iloprost was infused at a rate of 50 μg/min continuously. Cardiac output (CO), mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), heart rate (HR), pulmonary capillary wedge pressure (PCWP), right atrium pressure (RAP), myocardial oxygen extraction (MOE) and myocardial lactate extraction (MLE) parameters were examined in the two groups, before and during retroperfusion and during the reperfusion (1–4 h). Iloprost retroperfusion (50 μg/min) was started at the fifteenth minute of occlusion and continued till the end of the observation period (3 h). The measured hemodynamic data showed that the hearts treated with iloprost had satisfactory preservation of cardiac function. At the end of the reperfusion period cardiac output was 1.5 ± 0.06 L/min in the control and 1.7 ± 0.04 L/min in the iloprost group ( P < 0.05). At the end of the reperfusion period, tumor necrosis factor level was raised significantly in the control group ( P < 0.05). Myocardial lactate release was also high in the control group ( P < 0.05). CPK-MB release was low in the iloprost group ( P < 0.05). We conclude that retrogradely administered iloprost reduced the risk of myocardial injury and it is probable that this drug effectively distributes to the area of myocardium at risk.

Addition of α-Ketoglutarate to Blood Cardioplegia Improves Cardioprotection

Background. We hypothesized that myocardial content of α-ketoglutarate (α-KG), an intermediate of the Krebs cycle, can be critically low during heart operations, and that provision of α-KG could reduce metabolic abnormalities and lead to improved myocardial protection.Methods. Twenty-four men aged 46 to 78 years who were undergoing heart operations participated in a prospective, controlled, randomized study. In 13 patients, an average of 28 g of α-KG was added to blood cardioplegia. Plasma creatine kinase isoenzyme MB and troponin T, and myocardial extraction of oxygen, substrates, and amino acids were measured.Results. α-Ketoglutarate treatment was associated with lower creatine kinase isoenzyme MB (F = 39.6, df = 1.172, p < 0.001) and lower troponin (F = 12.9, df = 1.172, p < 0.001). The values at 4 hours were 31 ± 2.4 μg/L versus 49 ± 4.9 μg/L (creatine kinase isoenzyme MB) and 1.1 ± 0.05 μg/L versus 2.0 ± 0.34 μg/L (troponin T). Myocardial oxygen extraction was higher during α-KG cardioplegia (p < 0.01), but there were no significant differences in myocardial uptake or release of substrates or amino acids. Lactate release was observed in both groups during cardioplegia. Myocardial lactate release had ceased after 30 minutes of reperfusion in nearly half the α-KG–treated patients (6 of 13) but remained in all the control patients (11 of 11, p = 0.016). There were no other differences after 30 minutes of reperfusion.Conclusion. Provision of α-KG during blood cardioplegia improves myocardial protection in patients undergoing coronary operations. This may be linked to enhanced oxidation.(Ann Thorac Surg 1997;63:1625–34)