Lactate In Hearts Research Articles

Substrate selection in hearts subjected to ischemia/reperfusion: role of cardioplegic solutions and gender

In conditions of ischemia/reperfusion (I/R), the relative use of all available substrates by the heart has a significant effect on the recovery of the organ. This substrate preference in perfused hearts is influenced by ischemia. We followed the metabolic fate of [U-(13) C]glucose and [3-(13) C]lactate in hearts preserved in Celsior (Cs) and histidine buffer solution (HBS) for 4 or 6 h and subsequently perfused with a Krebs-Henseleit solution (KH) containing [U-(13) C]glucose and [3-(13) C]lactate. We also assessed gender-specific metabolic modulation in our I/R experimental conditions. Hearts from male and female Wistar rats (6-8 weeks) were subjected to moderate (0-240 min) or prolonged (240-360 min) cold ischemia whilst immersed in Cs and HBS, and perfused for 30 min with KH containing [U-(13) C]glucose and [3-(13) C]lactate. After perfusion, hearts were freeze-clamped and metabolites were extracted for (13) C NMR isotopomer analysis. In control conditions, there were no differences with regard to lactate origin in hearts from males and females. After 6 h of preservation in Cs, lactate origin was mostly from [U-(13) C]glucose in hearts from males and from [3-(13) C]lactate in hearts from females. During the 6 h of organ preservation in HBS, the lactate pool showed a strong contribution from unenriched sources in male hearts and from [U-(13) C]glucose in female hearts. The glutamate C2/C4 ratio was stable or increased in hearts from females after I/R, and the alanine index increased in hearts from both males and females. Octanoate was, as predicted, the preferential substrate during perfusion. Glucose and lactate suffer a distinct metabolic fate in our I/R conditions, which is related to the cardioplegic solution used during organ storage, and the gender. Hearts from females appear to be less sensitive to I/R injury, and heart preservation in HBS proved to be effective in enhancing anaplerosis during perfusion, especially in hearts from females.

Perfusion Preservation versus Static Preservation for Cardiac Transplantation: Effects on Myocardial Function and Metabolism

Continuous perfusion of donor hearts for transplantation has received increasing interest, but the effects on cellular metabolism, myocyte necrosis, and myocardial edema are not well defined. Pig hearts were instrumented with sonomicrometry crystals and left ventricular catheters. Left ventricular function was quantified by the pre-load-recruitable stroke work (PRSW) relationship. Hearts were arrested with Celsior solution with 5.5 mM 13C-glucose added, and removed and stored in cold solution (n = 4) or placed in a device providing continuous perfusion of this solution at 10 ml/100 g/min (n = 4). After 4 hours of storage, left atrial samples were frozen, extracted, and analyzed by magnetic resonance spectroscopy. Hearts were then transplanted into recipient pigs and reperfused for 6 hours, with function measured hourly. At the end of the experiment, left ventricular water content and serum creatine kinase-MB isoenzyme levels were measured. Baseline left ventricular function was similar in both groups. During reperfusion, the volume-axis intercept of the PRSW relationship was significantly lower in hearts stored with continuous perfusion (p < 0.05), suggesting reduced contractile impairment. Magnetic resonance spectroscopy revealed a decrease in tissue lactate in hearts that received continuous perfusion. Serum creatine kinase-MB isoenzyme levels were higher hearts that had static storage (30.8 +/- 9.0 vs 13.2 +/- 2.7 ng/ml; p < 0.05). Left ventricular water content was similar in both groups (0.797 +/- 0.012 vs 0.796 +/- 0.014; p = 0.45). Donor hearts sustain less functional impairment after storage with continuous perfusion. This technique reduces tissue lactate accumulation and myocardial necrosis without increasing myocardial edema and appears promising as a method to improve results of cardiac transplantation.

Benefits of Perfusion Preservation in Canine Hearts Stored for Short Intervals

Continuous perfusion of donor hearts for transplantation has been proposed to improve graft function or extend preservation intervals, but the effects on cellular metabolism, myocyte loss, and myocardial edema are not well-defined. Hearts from mongrel dogs were instrumented with sonomicrometry crystals and left ventricular (LV) catheters. LV function was quantified by the preload-recruitable stroke work (PRSW) relationship. Hearts were arrested with a modified Celsior solution, and stored in cold solution (n=6) or placed in a device providing continuous perfusion of this solution at 10 mL/100 g/min (n=6). After 4 h of storage, left atrial samples were frozen, extracted, and analyzed by magnetic resonance spectroscopy (MRS). Hearts were then transplanted into recipient dogs and reperfused for 6 h with function measured hourly. At end-experiment, LV specimens were assayed for water content and apoptosis. Serum CK-MB levels were measured. LV functional recovery was excellent in both groups over 6 h of reperfusion. MRS revealed a dramatic decrease in tissue lactate in hearts protected with continuous perfusion (P<0.01). Apoptotic cell counts were significantly lower in post-reperfusion heart tissue in animals undergoing a continuous perfusion strategy (P<0.01). CK-MB levels and LV water content were similar in both groups. Although both methods of preservation lead to good early graft function after 4 h of protected ischemia, continuous preservation dramatically reduces tissue lactate accumulation without increasing myocardial edema and may reduce tissue damage during storage and reperfusion. It appears promising as a method to improve results of cardiac transplantation.

Acute diabetes modulates response to ischemia in isolated rat heart.

Diabetic hearts are suggested to exhibit either increased or lower sensitivity to ischemia. Detrimental effects of prolonged ischemia can be attenuated by preconditioning, however, relatively little is known about its effects in the diseased myocardium. This study was designed to test the susceptibility to ischemia-induced arrhythmias and the effect of preconditioning in the diabetic heart. Rats were made diabetic with streptozotocin (45 mg/kg, i.v.). After 1 week, isolated Langendorff-perfused hearts were subjected to 30 min occlusion of LAD coronary artery without or with preceding preconditioning induced by one cycle of 5 min ischemia and 10 min reperfusion. Glycogen and lactate contents were estimated in the preconditioned and non-preconditioned hearts before and after ischemia. Diabetic hearts were more resistant to ischemia-induced arrhythmias: incidence of ventricular tachycardia (VT) decreased to 42% and only transient ventricular fibrillation (VF) occurred in 17% of the hearts as compared to the non-diabetic controls (VT 100% and VF 70% including sustained VF 36%; p < 0.05). Preconditioning effectively suppressed the incidence and severity of arrhythmias (VT 33%, VF 0%) in the normal hearts. However, this intervention did not confer any additional protection in the diabetic hearts. Despite higher glycogen content in the diabetic myocardium and greater glycogenolysis during ischemia, production of lactate in these hearts was significantly lower than in the controls. Preconditioning caused a substantial decrease in the accumulation of lactate in the normal hearts, whereby in the diabetic hearts, this intervention did not cause any further reduction in the level of lactate. In conclusion, diabetic rat hearts exhibit lower susceptibility to ischemic injury and show no additional response to preconditioning. Reduced production of glycolytic metabolites during ischemia can account for the enhanced resistance of diabetic hearts to ischemia as well as for the lack of further protection by preconditioning.

Cardiac magnetic resonance spectroscopy

The article reviews cardiac magnetic resonance spectroscopy (MRS) in Canada. 31P MRS has been used to study cardiac energetics and intracellular pH in hearts subjected to ischemia-reperfusion and to evaluate the effects of pharmacological interventions. 23Na, 87Rb, and 7Li MRS have provided unique probes to study ion balance and fluxes in intact tissue under normal and stressful physiological conditions. 1H MRS has been used to monitor the accumulation of lactate and lipids in hearts subjected to ischemia-reperfusion and follow the effects of diet on cardiac lipid levels and function. The isolated rat heart has been used most commonly to study the effects of pharmacological agents on energy balance, pH, ion fluxes, and contractile function of the heart subjected to ischemia-reperfusion. The pig heart has been developed as an alternative to the rodent heart because its metabolism is more similar to that of the human heart. Human atrial appendages have been useful in evaluating the effects of preservation strategies (temperature, composition of preservation solutions) on energy levels. The pig heart model has been useful in evaluating the effects of preservation solutions on cardiac function of hearts destined for transplantation. An isolated blood-perfused pig heart model has been developed to assess the effects of cardioplegic strategies on the preservation of contractile function of hearts following surgery on the heart. An in vivo canine model has been used to study myocardial infarction and the effects of therapies to reduce the infarct zones and areas of the heart at risk of infarction. Studies of human hearts in vivo have provided insight into the metabolic adaptations that occur in individuals living at high altitudes.Key words: ion transport, metabolism, heart disease, organ preservation, drug effects.

Cardiac magnetic resonance spectroscopy.

The article reviews cardiac magnetic resonance spectroscopy (MRS) in Canada. 31P MRS has been used to study cardiac energetics and intracellular pH in hearts subjected to ischemia-reperfusion and to evaluate the effects of pharmacological interventions. 23Na, 87Rb, and 7Li MRS have provided unique probes to study ion balance and fluxes in intact tissue under normal and stressful physiological conditions. 1H MRS has been used to monitor the accumulation of lactate and lipids in hearts subjected to ischemia-reperfusion and follow the effects of diet on cardiac lipid levels and function. The isolated rat heart has been used most commonly to study the effects of pharmacological agents on energy balance, pH, ion fluxes, and contractile function of the heart subjected to ischemia-reperfusion. The pig heart has been developed as an alternative to the rodent heart because its metabolism is more similar to that of the human heart. Human atrial appendages have been useful in evaluating the effects of preservation strategies (temperature, composition of preservation solutions) on energy levels. The pig heart model has been useful in evaluating the effects of preservation solutions on cardiac function of hearts destined for transplantation. An isolated blood-perfused pig heart model has been developed to assess the effects of cardioplegic strategies on the preservation of contractile function of hearts following surgery on the heart. An in vivo canine model has been used to study myocardial infarction and the effects of therapies to reduce the infarct zones and areas of the heart at risk of infarction. Studies of human hearts in vivo have provided insight into the metabolic adaptations that occur in individuals living at high altitudes.