The effectiveness of ischemic preconditioning on myocardial protection and comparison with K(+) cardioplegia

The purpose of this study is to investigate the effects of ischemic preconditioning on myocardial protection and to compare this method to K(+) crystalloid cardioplegia. Langendorff perfused isolated working rat hearts were used in the following groups. After 20 min of stabilisation, 30 hearts were divided into three groups. In group I (control, n=10), hearts were arrested with cold (+4 degrees C) Krebs-Henseleit (K-H) solution, in group II (cardioplegia, n=10) hearts were arrested with cold K(+) cardioplegia solution, and in group III (preconditioning, n=10) hearts were subjected to 5 min normothermic ischemia followed by 5 min reperfusion then arrested with cold K-H solution. All hearts were subjected to 30 min of global ischemia (24 degrees C) and 40 min of reperfusion. Hemodynamic measurements were performed with a left ventricular latex balloon using a data acquisition system. Creatine kinase (CK-MB) washout and Troponin I (cTnI) levels were determined from the coronary effluents. There was no significant difference among the three groups in any of the parameters (hemodynamic and biochemical) measured at the end of stabilisation period. During reperfusion, functional recovery and coronary flow were significantly improved in K(+) cardioplegia and preconditioned groups compared with control group. CK-MB washout and cTnI levels were significantly lower in groups II and III compared with group I at the reperfusion. However no significant difference was observed between K(+) cardioplegia and preconditioned groups among biochemical and hemodynamic parameters and coronary flow at the post-ischemic period. In conclusion, ischemic preconditioning is as effective as K(+) cardioplegia on myocardial protection and recovery of myocardial function during reperfusion.     

Orthotopic transplantation of pig hearts harvested after 30 min of normothermic ischemia: controlled reperfusion with blood cardioplegia containing the Na-H-exchange inhibitor HOE 642

Objectives: The aim of our study was to develop a surgical technique for a successful transplantation of hearts harvested after 30 min of normothermic ischemia without donor pretreatment. Successful transplantation of ischemic compromised hearts could help to expand the severely limited donor pool. We used the pig model because this species is very susceptible to myocardial ischemia. Na⁺-H⁺-exchange (NHE) inhibitors have shown excellent protective properties in several in vitro and in vivo models of myocardial ischemia and reperfusion. Methods: In group I (n=12) hearts were harvested after 30 min of normothermic ischemia following cardiac arrest induced by exsanguination. Hearts were perfused with warm blood cardioplegia and transplanted orthotopically. In group II (n=9) controlled reperfusion with cold leucocyte-depleted blood cardioplegia was performed after 30 min of normothermic ischemia. In group III (n=8) the same procedure was performed as in group II but blood cardioplegia contained 1 mmol/l HOE 642. Results: In group I massive myocardial oedema was observed and none of the animals could be weaned from cardiopulmonary bypass (CPB). In contrast, all animals in groups II and III could be weaned from CPB with low dose inotropic support. In groups II and III the contractility of the hearts, expressed as maximal left and right ventricular stroke work index was significantly impaired after transplantation as compared with the preoperative value. Supplementation of blood cardioplegia with HOE 642 resulted in a significantly better recovery of the LVSWImax (Group II vs. III). Conclusions: Successful transplantation of pig hearts is possible after 30 min of normothermic ischemia without donor pretreatment if a controlled reperfusion with cold leucocyte-depleted blood cardioplegia is performed. HOE 642 given during reperfusion only improves posttransplant left ventricular function.     

Effects of NHE-1 inhibition on cardioprotection and impact on protection by K/Mg cardioplegia

BACKGROUND: Cardiac sodium hydrogen exchanger isoform-1 (NHE-1) activity during ischemia/reperfusion contributes to myocardial injury. The effects of NHE-1 inhibition during ischemia or reperfusion and on the protection afforded by K/Mg cardioplegia was unknown. METHODS: Rabbit hearts were used for Langendorff perfusion. Control hearts were perfused for 180 minutes. Global ischemia (GI) hearts received 30 minutes normothermic global ischemia and 120 minutes reperfusion. K/Mg hearts received cardioplegia 5 minutes before ischemia. Separate groups of GI and K/Mg hearts received the NHE-1 inhibitor, HOE-642, before ischemia (HOE-642-I), at the immediate start of reperfusion (HOE-642-R), or both before ischemia and at the immediate start of reperfusion (HOE-642-IR). RESULTS: Left ventricular peak developed pressure was significantly increased in HOE-I, HOE-R, and HOE-IR throughout reperfusion (p < 0.05 versus GI). Infarct size was significantly decreased (p < 0.05 versus GI) in all groups, but was significantly increased in HOE-R as compared with HOE-IR (p < 0.05). NHE-1 inhibition with K/Mg cardioplegia significantly decreased left ventricular peak developed pressure after 90 minutes of reperfusion (p < 0.05 versus K/Mg), with no significant effect on infarct size. CONCLUSIONS: NHE-1 inhibition used alone provides cardioprotection with optimal effects being observed with HOE-IR. NHE-1 inhibition with K/Mg cardioplegia decreases postischemic functional recovery during late reperfusion.     

Adverse effects of low-pressure reperfusion after hypothermic cardioplegia in normal and hypertrophic hearts.

The aim of this study was to determine the effect of low-pressure and high-pressure reperfusion, with and without ventricular fibrillation, on the recovery of hypertrophic and normal hearts after hypothermic cardioplegia. Fourteen hearts rendered hypertrophic by valvular aortic stenosis and 18 normal canine hearts were subjected to 1 hour of cardioplegic arrest at 28 degrees C during cardiopulmonary bypass. Each heart was then reperfused at a coronary pressure of either 40 mm Hg (low) or 80 mm Hg (high), initially in the empty beating state and then during ventricular fibrillation. Low-pressure reperfusion produced left ventricular subendocardial ischemia in hypertrophic and in normal hearts, shown by marked depression of subendocardial blood flow, myocardial pH, and myocardial oxygen consumption. In hypertrophic hearts the ischemia was more severe and resulted in a persistent depression of left ventricular function and myocardial oxygen consumption even when coronary pressure was returned to normal levels. High-pressure reperfusion was associated with rapid and complete recovery of myocardial metabolism and function in hypertrophic and in normal hearts. During low-pressure reperfusion, ventricular fibrillation exacerbated ischemia in hypertrophic and in normal hearts. During high-pressure reperfusion, a short period of ventricular fibrillation produced no adverse effects either in hypertrophic or in normal hearts. We conclude that low-pressure reperfusion produces subendocardial ischemia in normal and in hypertrophic hearts even in the empty beating state; in hypertrophic hearts it also impairs recovery of myocardial metabolism and function. The adverse effects of low-pressure reperfusion are exacerbated by ventricular fibrillation.     

Effects of supplemental L-arginine during warm blood cardioplegia.

OBJECTIVES: Effects of supplemental L-arginine, nitric oxide precursor, during warm blood cardioplegia were assessed in the blood perfused isolated rat heart. METHODS: The isolated hearts were perfused with blood at 37 degrees C from a support rat. After 20 minutes of aerobic perfusion, the hearts were arrested for 60 minutes with warm blood cardioplegia given at 20-minute intervals. This was followed by 60 minutes of reperfusion. The hearts were divided into the following three groups according to the supplemental drugs added to the cardioplegic solution. The control group (n = 10) received standard warm blood cardioplegia. The L-ARG group (n = 10) received warm blood cardioplegia supplemented with L-arginine (3 mmol/l). The L-NAME group (n = 10) received warm blood cardioplegia supplemented with L-arginine (3 mmol/l) and L-nitro-arginine methyl ester, a competitive inhibitor of nitric oxide synthase (1 mmol/l). After 60 minutes of cardioplegic arrest, cardiac function, myocardial metabolism and myocardial release of circulating adhesion molecules were measured during reperfusion. RESULTS: Left ventricular end-diastolic pressure was significantly lower (p<0.05) in the L-ARG group than in the control group and the L-NAME group during reperfusion. Isovolumic left ventricular developed pressure, dp/dt and coronary blood flow were significantly greater (p< 0.05) in the L-ARG group during reperfusion. The L-ARG group resulted in early recovery of lactate metabolism during reperfusion. Myocardial release of circulating intercellular adhesion molecule-1 (ICAM-1) and E-selectin were significantly less (p<0.05) in the L-ARG group at 15 minutes of reperfusion. CONCLUSIONS: The results suggest that augmented nitric oxide by adding L-arginine to warm blood cardioplegia can preserve left ventricular function and ameliorate endothelial inflammation. The technique can be a novel cardioprotective strategy in patients undergoing cardiac surgery.     

温血停搏液术终灌注对缺血再灌注心肌的保护作用

利用猫体外循环模型观察含甘露醇的温血停搏液术终灌注对缺血再灌注心肌的保护作用。心肌缺血恢复正常血液灌注前，从主动脉根部以５～６ｋＰａ的压力注入３７℃含甘露醇的低钾温血停搏液５０ｍｌ。结果显示用含甘露醇的温血停搏液术终灌注可保护缺血后再灌注心肌的功能，提高心肌能量储备，降低线粒体丙二醛含量。结论：含甘露醇的温血停搏液术终灌注，可提高心肌对氧自由基的清除能力，减轻线粒体膜脂质过氧化，提高心肌能量储备，有利于再灌注后心肌功能的恢复     

Metabolic changes induced by ischemia and cardioplegia: a study employing cardiac microdialysis in pigs.

OBJECTIVE: The present study investigates dynamic changes of myocardial metabolism in response to ischemia, cardioplegia, and extracorporeal circulation (ECC) in order to differentiate between the contributing effects of each of these interventions. Furthermore, warm blood cardioplegia versus empty beating of the heart were compared as methods to resuscitate the ischemic myocardial metabolism. METHODS: Swedish Landrace pigs on ECC (ECC) were compared with pigs on ECC with warm ischemic cardiac arrest (ischemia) or on ECC with warm ischemic arrest followed by warm blood cardioplegia (ischemia-cardioplegia), using sham-operated pigs as controls (n=7 in each group). Microdialysis probes were placed on the surface of the left ventricle and in the femoral artery for serial evaluation of metabolites in the intracardiac extracellular fluid and arterial blood. When hearts started in ventricular fibrillation (VF), it was electroconverted after 10 min of normal blood reperfusion. If VF started after 10 min of reperfusion electroconversion was immediately performed. RESULTS: There were no differences between groups in arterial contents of serine, citrulline, arginine, inosine, hypoxanthine, guanosine, aspartate, glutamate, pyruvate, or asparagine throughout the observation period. Systemic lactate increased in pigs subjected to ischemia (P<0.001) or ischemia and cardioplegia (P=0.002), highest in the ischemia only group (P=0.002). In left ventricular microdialysates, lactate increased in pigs subjected to ischemia alone (P<0.001 vs. ECC) and ischemia and cardioplegia (P=0.004 vs. ECC). Guanosine increased in ischemia versus ECC (P=0.002), while hypoxanthine was increased in microdialysates of both ischemic (P=0.002) and ischemic-cardioplegic (P=0.001) pig hearts. Inosine was increased in pigs subjected to ischemia and cardioplegia (P<0.001 vs. ECC). All ischemic hearts started with VF, but while in the warm ischemia group VF started within 10 min of reperfusion, the ischemia-cardioplegia group had a longer asystolia with VF starting 11-22 min of blood reperfusion. CONCLUSION: The heart should be allowed to start empty beating rather than by the use of warm continuous blood cardioplegia. Microdialysis and sampling of interstitial metabolites may be advantageous when an increased sensitivity is needed or when repeated blood sampling is difficult or contraindicated in monitoring of the myocardium.     

Protectant activity of defibrotide in cardioplegia followed by ischemia/reperfusion injury in the isolated rat heart

BACKGROUND: Previous studies have shown that defibrotide, a polydeoxyribonucleotide obtained by depolymerization of DNA from porcine tissues, has important protective effects on myocardial ischemia, which may be associated with a prostacyclin-related mechanism. The purpose of this study was to investigate the direct effects of defibrotide (given in cardioplegia or after ischemia) on a model of rat heart recovery after cardioplegia followed by ischemia/reperfusion injury. METHODS: Isolated rat hearts, undergoing 5 minutes of warm cardioplegic arrest followed by 20 minutes of global ischemia and 30 minutes of reperfusion, were studied using the modified Langendorff model. The cardioplegia consisted of St. Thomas' Hospital solution augmented with defibrotide (50, 100, and 200 microg/mL) or without defibrotide (controls). Left ventricular mechanical function and the levels of creatine kinase, lactate dehydrogenase, and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha; the stable metabolite of prostacyclin) were measured during preischemic and reperfusion periods. RESULTS: After global ischemia, hearts receiving defibrotide in the cardioplegic solution (n = 8) manifested in a concentration-dependent fashion lower left ventricular end-diastolic pressure (p < 0.001), higher left ventricular developed pressure (p < 0.01), and lower coronary perfusion pressure (p < 0.001) compared to the control group. After reperfusion, hearts receiving defibrotide in the cardioplegic solution also had, in a dose-dependent way, lower levels of creatine-kinase (p < 0.01), lactate dehydrogenase (p < 0.001), and higher levels of 6-keto-PGF1alpha (p < 0.001) compared to the control group. Furthermore, when defibrotide was given alone to the hearts at the beginning of reperfusion (n = 7), the recovery of postischemic left ventricular function was inferior (p < 0.05) to that obtained when defibrotide was given in cardioplegia. CONCLUSIONS: Defibrotide confers to conventional crystalloid cardioplegia a potent concentration-dependent protective effect on the recovery of isolated rat heart undergoing ischemia/reperfusion injury. The low cost and the absence of contraindications (cardiac toxicity and hemodynamic effects) make defibrotide a promising augmentation to cardioplegia.     

Experimental evaluation of myocardial protective effect of prostacyclin analog (OP-41483) as an adjunct to cardioplegic solution

A stable prostacyclin analog (OP-41483) was evaluated for myocardial protective effect against global ischemia with the use of cardioplegia. Isolated canine hearts (n = 25) were exposed to 60 minutes of warm (37 degrees C) global ischemia after the arrest by crystalloid cardioplegia. Prostaglandin analog was given in three different ways: preadministration (700 ng/kg body weight per minute) before ischemia for 30 minutes (group I, n = 5), given as a component of cardioplegic solution (600 ng/ml, group II, n, = 6), and post-administration (25 ng/kg body weight per minute) during reperfusion for 30 minutes (group III, n = 7). During reperfusion, coronary sinus blood flow, 6-keto-prostaglandin F1 alpha in coronary sinus blood, and myocardial oxygen consumption were measured during reperfusion. As a result, groups II and III showed significantly better global left ventricular function (developed pressure, maximum dP/dt, and diastolic compliance) than the control group (without prostaglandin analog, n = 7) and group I. Myocardial oxygen consumption at reperfusion (1 minute) was significantly larger in group II than in the control group. 6-keto-prostaglandin F1 alpha flux was significantly larger in group II than in the other three groups during reperfusion. The results indicated that prostaglandin analog has a beneficial effect on myocardial protection under global ischemia with cardioplegia, particularly when used as a component of cardioplegic solution and also during reperfusion. The mechanism may relate to the cytoprotective effect (including protection of endothelium with enhanced endogenous prostacyclin production at reperfusion and also to the modulation of reperfusion per se.     

Effect of oxygenated crystalloid cardioplegia on the functional and metabolic recovery of the isolated perfused rat heart

The use of an oxygenated crystalloid cardioplegic solution to improve myocardial preservation during elective cardiac arrest was evaluated with the isolated perfused rat heart used as a model. Experiments were conducted at 4 degrees C and 20 degrees C. The oxygen tension of the nonoxygenated and oxygenated cardioplegic solutions averaged 117 and 440 mm Hg, respectively. At 4 degrees C, the adenosine triphosphate content of hearts subjected to 120 minutes of oxygenated cardioplegia was significantly higher than that of the nonoxygenated cardioplegia group. However, functional recovery during reperfusion was similar for both groups. At 20 degrees C, the myocardial adenosine triphosphate concentration decreased at a significantly faster rate during ischemia in the group receiving nonoxygenated cardioplegia compared with the oxygenated cardioplegia group. Hearts subjected to 180 minutes of ischemia with oxygenated cardioplegia had a normal ultrastructural appearance whereas hearts subjected to 120 minutes of nonoxygenated cardioplegia showed severe ischemic damage. Myocardial functional recovery in the group receiving oxygenated cardioplegia exceeded that of the group receiving nonoxygenated cardioplegia. The use of myocardial adenosine triphosphate concentration at the end of the ischemic period to predict subsequent cardiac output, peak systolic pressure, and total myocardial work showed significant positive correlations.     

K(ATP) channel opener protects neonatal rabbit heart better than St. Thomas' solution

OBJECTIVES: Myocardial protection with ATP-sensitive potassium channel (K(ATP) channel) openers is as effective as St. Thomas' cardioplegia (StTCP) in adult rabbit hearts. This study compares the effectiveness of the K(ATP) channel opener pinacidil to StTCP in protecting neonatal rabbit hearts exposed to global ischemia. METHODS: Seventeen neonatal rabbit hearts (7-9 days old) perfused with Krebs-Henseleit buffer (KHB) on a Langendorff apparatus underwent 90 min of normothermic ischemia. Six (ischemia control) received no pretreatment before or during ischemia. Six others (pinacidil) received a 3-min infusion of 50 microM pinacidil in KHB without StTCP at the onset of ischemia. Five others (StTCP) received a 3-min infusion of StTCP at the onset of ischemia. After 60 min of KHB reperfusion, recovery of left ventricular (LV) performance and coronary flow (CF) were measured and compared to preischemia. A paired t test was used for comparison between drug-treated and untreated groups. RESULTS: Pinacidil-treated hearts had significantly better recovery of left ventricular developed pressure (47 +/- 3.8 mmHg vs 32 +/- 2.5 mmHg, P < 0.05), contractility (+dP/dt(max); 885.4 +/- 74 mmHg vs 643.7 +/- 65 mmHg, P < 0.05), left ventricular end diastolic pressure (10.5 +/- 0.9 mmHg vs 17.4 +/- 1.2 mmHg P < 0.05), compliance (-dP/dt(max); 994.2 +/- 86 mmHg vs 673.6 +/- 69 mmHg, P < 0.05), and CF (5.9 +/- 0.4 ml/min vs 4.2 +/- 0.2 ml/min, P < 0.05) compared to ischemic control. StTCP only improved the recovery of -dP/dt(max) (877.4 +/- 73 mmHg/s vs 673.6 +/- 69 mmHg/s, P < 0.05) and CF (5.7 +/- 0.3 ml/min vs 4.2 +/- 0.2 ml/min, P < 0.05) compared to control. CONCLUSIONS: Pinacidil pretreatment provided superior recovery of systolic performance compared to St. Thomas' cardioplegia solution in neonatal hearts. Myocardial protection by pretreatment with the K(ATP) channel opener pinacidil may be a new strategy for myocardial protection during pediatric cardiac surgery.     

Amino acid substrate preloading and postischemic myocardial recovery.

During induced myocardial ischemia for cardiac surgery, myocardial stunning occurs and aerobic metabolism of glucose, fatty acids, and lactate is inhibited as anaerobic pathways predominate. Even following reperfusion, stunned myocardium uses oxygen and substrate inefficiently leading to poor functional recovery as less mechanical work is developed per oxygen utilized. Amino acids potentially can act as cardiac metabolic substrates during and after ischemia, utilizing the transamination of amino acids by the malate-aspartate shuttle to form high energy phosphates via the tricarboxylic acid cycle. We investigated if "preloading" hearts with a physiologic spectrum of amino acids could increase postischemic myocardial recovery. Isolated perfused rabbit hearts were subjected to 120 min of 34 degrees C cardioplegic ischemia. Hearts received cardioplegia alone as controls or were "preloaded" with a 0.05% amino acid perfusion for 30 min prior to cardioplegic ischemia. Following reperfusion, analysis of functional recovery revealed that contractility and cardiac efficiency were improved with amino acids substrate preloading. The mechanism of this may be due to uptake of amino acids prior to ischemia, which are later utilized for internal reparative work during ischemia and external contractile work after ischemia.     

The effects of cardioplegia washout on myocardial preservation

Preservation of the myocardium in vitro is more effective than preservation in vitro when preservation conditions are apparently the same. The washout of cardioplegia from the myocardium by noncoronary blood flow has been implicated as a probable cause of the poorer myocardial preservation seen in vivo. Isolated dog hearts were used to study the effects of cardioplegia washout by low flow perfusion (0.05 ml/min/g LV weight) during a 2-hr preservation period. Six experimental groups of five hearts each underwent 2 hr of myocardial preservation at temperatures of 20 degrees C (three groups) or 30 degrees C (three groups). The three groups for each temperature consisted of retrograde coronary sinus perfusion (to simulate cardioplegia washout by collateral flow) with blood cardioplegia (BC), normal blood (NB), or no perfusion at all (No CSP). The quality of preservation in each group was assessed by measuring recovery of left ventricular function, tissue water and electrolyte content, and myocardial high-energy phosphate and adenylate content prior to, during, and following preservation. In hearts maintained at 20 degrees C, cardioplegia washout did not significantly affect left ventricular function or myocardial levels of H2O, Na, K, ATP, or total adenylates. When myocardial temperature was allowed to increase to 30 degrees C, preservation was better with low flow perfusion during the preservation period. Hearts warmed to 30 degrees C with no cardioplegia washout experienced a 50% loss of tissue ATP levels and recovered less than 30% of normal left ventricular function during a 150-min reperfusion period. In contrast, hearts slowly perfused during the preservation period maintained nearly normal levels of ATP and returned to normal function by 150 min of reperfusion. Although myocardial warming by noncoronary perfusion has a detrimental effect on myocardial preservation, the slow washout of cardioplegia per se has no apparent detrimental effect on preservation.     

ATP precursor depletion and postischemic myocardial recovery

Although cardioplegia reduces myocardial metabolism during ischemia, adenosine triphosphate (ATP) depletion occurs, which may contribute to poor functional recovery after reperfusion. Augmenting myocardial adenosine during ischemia is successful in improving ATP repletion and myocardial recovery following ischemia. If adenosine is an important determinant of ischemic tolerance, then depletion or elimination of myocardial adenosine should lead to poor functional and metabolic recovery after ischemia. To test this hypothesis, isolated, perfused rabbit hearts were subjected to 120 min of 34 degrees C ischemia. Hearts received St. Thomas cardioplegia alone or cardioplegia containing 200 microM adenosine, or cardioplegia containing 15, 5, 2.5, or 0.025 micrograms/ml adenosine deaminase (ADA), which catalyzes the breakdown of adenosine to inosine, making adenosine unavailable as an ATP precursor. Functional recovery was determined and myocardial nucleotide levels were measured before, during, and after ischemia. Following ischemia and reperfusion, control hearts recovered to 51 +/- 3% of preischemic developed pressure (DP). There was significantly better recovery in adenosine-augmented hearts (68 +/- 7%), while ADA hearts had significantly worse recovery. Hearts treated with 0.025 microgram/ml ADA recovered to only 29 +/- 5% of DP and higher dose ADA hearts failed to demonstrate any recovery of systolic function. Furthermore, adenosine enhanced metabolic recovery, whereas ADA resulted in greatly depleted ATP and precursor reserves. Postischemic developed pressure closely paralleled the availability of myocardial adenosine, consistent with the hypothesis that myocardial adenosine levels at end ischemia and early reperfusion are important determinants of functional recovery after global ischemia.     

Adding bupivacaine to high-potassium cardioplegia improves function and reduces cellular damage of rat isolated hearts after prolonged, cold storage

BACKGROUND: Bupivacaine retards myocardial acidosis during ischemia. The authors measured function of rat isolated hearts after prolonged storage to determine whether bupivacaine improves cardiac protection compared with standard cardioplegia alone. METHODS: After measuring cardiac function on a Langendorff apparatus, hearts were perfused with cardioplegia alone (controls), cardioplegia containing 500 microm bupivacaine, or cardioplegia containing 2 mm lidocaine; were stored at 4 degrees C for 12 h; and were then reperfused. Heart rate and left ventricular developed pressures were measured for 60 min. Maximum positive rate of change in ventricular pressure, oxygen consumption, and lactate dehydrogenase release were also measured. RESULTS: All bupivacaine-treated, four of five lidocaine-treated, and no control hearts beat throughout the 60-min recovery period. Mean values of heart rate, left ventricular developed pressure, maximum positive rate of change in ventricular pressure, rate-pressure product, and efficiency in bupivacaine-treated hearts exceeded those of the control group (P < 0.001 at 60 min for all). Mean values of the lidocaine group were intermediate. Oxygen consumption of the control group exceeded the other groups early in recovery, but not at later times. Lactate dehydrogenase release from the bupivacaine group was less than that from the control group (P < 0.001) but did not differ from baseline. CONCLUSIONS: Adding bupivacaine to a depolarizing cardioplegia solution reduces cell damage and improves cardiac function after prolonged storage. Metabolic inhibition may contribute to this phenomenon, which is not entirely explained by sodium channel blockade.     

Effect of ATP synthesis promoters on postischemic myocardial recovery

The use of cardioplegia during surgically induced ischemia greatly reduces myocardial metabolic requirements. However, adenosine triphosphate (ATP) depletion may occur, resulting in poor functional recovery after ischemia. This study investigated if augmentation of intracellular ATP could be achieved by delivering known ATP synthesis promoters (adenosine and/or phosphate) during cardioplegic arrest, and whether this could enhance myocardial functional and metabolic recovery following ischemia. Isolated, perfused rabbit hearts were subjected to 120 min of hypothermic (34 degrees C) cardioplegia-induced ischemia. Controls received St. Thomas cardioplegia (CTL); remaining hearts received cardioplegia containing 200 microM adenosine (ADO), or 25 microM phosphate (PO4), or both ADO and PO4. Following ischemia and reperfusion, recovery of developed pressure (%DP) and postischemic diastolic stiffness was significantly better in adenosine hearts when compared with control or PO4 hearts. To determine if ADO or PO4 minimized depletion of ATP during ischemia or accelerated synthesis of ATP in the postischemic period, nucleotide levels were obtained before, during, and after ischemia. During ischemia, ATP fell equally in all groups, indicating that ADO and PO4 did not alter ischemia-induced depletion of ATP. However, intracellular adenosine was augmented during ischemia in adenosine-treated hearts. Consequently, during reperfusion, ADO and ADO/PO4 hearts had significantly enhanced ATP levels, suggesting that augmenting myocardial adenosine accelerated synthesis of ATP postischemia. The addition of phosphate, a stimulus for ATP synthesis, did not augment postischemic ATP. In fact, the beneficial effect of adenosine may have been decreased when phosphate was added to adenosine. In conclusion, adenosine but not PO4 augments intracellular ATP by allowing better metabolic repletion following ischemia, thereby improving postischemic myocardial functional recovery.     

Adding Bupivacaine to High-potassium Cardioplegia Improves Function and Reduces Cellular Damage of Rat Isolated Hearts after Prolonged, Cold Storage

Background: Bupivacaine retards myocardial acidosis during ischemia. The authors measured function of rat isolated hearts after prolonged storage to determine whether bupivacaine improves cardiac protection compared with standard cardioplegia alone.

Methods: After measuring cardiac function on a Langendorff apparatus, hearts were perfused with cardioplegia alone (controls), cardioplegia containing 500 [mu]m bupivacaine, or cardioplegia containing 2 mm lidocaine; were stored at 4[degrees]C for 12 h; and were then reperfused. Heart rate and left ventricular developed pressures were measured for 60 min. Maximum positive rate of change in ventricular pressure, oxygen consumption, and lactate dehydrogenase release were also measured.

Results: All bupivacaine-treated, four of five lidocaine-treated, and no control hearts beat throughout the 60-min recovery period. Mean values of heart rate, left ventricular developed pressure, maximum positive rate of change in ventricular pressure, rate-pressure product, and efficiency in bupivacaine-treated hearts exceeded those of the control group (P < 0.001 at 60 min for all). Mean values of the lidocaine group were intermediate. Oxygen consumption of the control group exceeded the other groups early in recovery, but not at later times. Lactate dehydrogenase release from the bupivacaine group was less than that from the control group (P < 0.001) but did not differ from baseline.     

Celsior versus custodiol: early postischemic recovery after cardioplegia and ischemia at 5 degrees C

BACKGROUND: The aim of this experimental study was to compare the protective efficacy of the cardioplegic solutions Celsior and Custodiol. Canine hearts were examined with regard to energy metabolism and early postischemic recovery after 8 or 12 hours of ischemia at 5 degrees C. METHODS: Canine hearts were preserved with Celsior or Custodiol (each n = 19). Five hearts of each group were used to determine myocardial content of energy-rich phosphates immediately after preservation and after 8 and 12 hours of ischemia at 5 degrees C; the remainder were reperfused after 8 and 12 hours of ischemia. Control variables during reperfusion were myocardial content of energy-rich phosphates, myocardial K+ uptake, left ventricular dP/dtmax and dP/dtmin, and incidence of arrhythmias in percentage of heart rate. RESULTS: Custodiol-preserved hearts contained more ATP than Celsior-preserved hearts after 8 and 12 hours of ischemia (8 hours p = ns, 12 hours, p < 0.05). During reperfusion after 8 hours of ischemia, dP/dtmax and dP/dtmin showed the same values for both solutions, after 12 hours values were significantly higher in Custodiol-preserved hearts (p < 0.005). The incidence of reperfusion arrhythmias was higher in hearts of the Celsior group (8 hours p < 0.01, 12 hours p = ns). Myocardial K+ uptake during reperfusion after 8 and 12 hours of ischemia was about twice as high in Celsior-preserved compared to Custodiol-preserved hearts (p < 0.005). CONCLUSIONS: In the Langendorff model of the canine heart, cardioplegia with Celsior showed no advantage over cardioplegia with Custodiol. Differences were observed, however, which may be clinically important, especially in the case of long cold-storage times.     

Effect of high-volume cardioplegia on small-amplitude electrical activity during cardioplegia arrest

The effects of high-volume cardioplegia on the presence of small-amplitude electrical activity during cardioplegia arrest were investigated in 19 mongrel dogs. The animals were randomly assigned to receive either high-volume crystalloid cardioplegia (HV-plege) or crystalloid cardioplegia guided by continuous electrical monitoring (V-plege). Cardiac index, left ventricular stroke work index dp/dt, and myocardial oxygen consumption were measured before bypass and following 90 min ischemia and 45 min reperfusion. Biopsies were taken for measurement of adenosine triphosphate (ATP) and examination of myocardial ultrastructure. Nine animals received HV-plege, while the remaining 10 animals received cardioplegia guided by voltage criteria. Small-amplitude electrical potentials were recorded within 10-15 min after the infusion of cardioplegia in all animals receiving cardioplegia guided by voltage criteria. Electrical activity, however, was immediately abolished by reinfusion of cardioplegia. HV-plege reduced the incidence of small-amplitude electrical activity during cardioplegia arrest but did not prevent electrical activity. Left ventricular function and myocardial ultrastructure were better preserved when cardioplegia was guided by electrical monitoring. ATP decreased similarly in both groups following cardioplegic arrest, but myocardial oxygen consumption was significantly higher following the arrest in the V-plege group. Conclusions: HV-plege does not prevent small-amplitude electrical activity and may have adverse effects on myocardial metabolic and functional recovery.     

Effects of initial reperfusion temperature and pressure after prolonged cardioplegic ischemic arrest. A metabolic and functional study in rat hearts

The effects of temperature and pressure during early cardiac reperfusion after 3.5 hours of hypothermic, cardioplegic ischemia were investigated in isolated Langendorff-perfused rat hearts. The hearts were randomized in two groups and subjected to different techniques of reperfusion. The group I hearts were exposed to rapidly rising perfusion pressure and temperature, and in group II slowly rising pressure and temperature were employed. After 60 min of reperfusion, left ventricular developed pressure, coronary flow and tissue content of high-energy phosphates were evaluated. Left ventricular pressure and coronary flow were significantly better preserved in group II. Recovery of adenosine triphosphate and creatine phosphate was significantly lower in group I (5.27 +/- 0.38 and 8.72 +/- 0.62 mumol x g dry weight-1) than in group II (9.31 +/- 0.41 and 14.97 +/- 0.62). The study thus demonstrated that functional recovery, restoration of coronary flow and normalization of high-energy phosphate stores after long periods of hypothermic cardioplegic ischemia can be considerably influenced by the employed reperfusion technique.