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Background: Coronary artery disease (CAD) due to myocardial ischemia causes permanent loss of heart tissue., Objectives: We aimed to demonstrate the possible damage to the myocardium at the molecular level through the mechanisms of autophagy and apoptosis in coronary bypass surgery patients., Methods: One group was administered a Custodiol cardioplegia solution, and the other group was administered a Blood cardioplegia solution. Two myocardial samples were collected from each patient during the operation, just before cardiac arrest and after the aortic cross-clamp was released. The expressions of autophagy and apoptosis markers were evaluated. The level of statistical significance adopted was 5%., Results: The expression of the BECLIN gene was significant in the myocardial tissues in the BC group (p=0.0078). CASPASE 3, 8, and 9 gene expression levels were significantly lower in the CC group. Postoperative TnT levels were significantly different between the groups (p=0.0072). CASPASE 8 and CASPASE 9 gene expressions were similar before and after aortic cross-clamping (p=0.8552, p=0.8891). In the CC group, CASPASE 3, CASPASE 8, and CASPASE 9 gene expression levels were not found to be significantly different in tissue samples taken after aortic cross-clamping (p=0.7354, p=0.0758, p=0.4128, respectively)., Conclusions: With our findings, we believe that CC and BC solutions do not have a significant difference in terms of myocardial protection during bypass operations.

Background and Objectives : The cardioplegic arrest of the heart during cardiosurgical procedures is the crucial element of a cardioprotection strategy. Numerous clinical trials compare different cardioplegic solutions and cardioprotective protocols, but a relatively small number of papers apply to in vitro conditions using cultured cells. This work aimed to analyze whether it is possible to use the rat heart myocardium cells as an in vitro model to study the protective properties of St. Thomas cardioplegia (ST2C). Methods: The rat heart myocardium cells-H9C2 were incubated with cold cardioplegia for up to 24 h. After incubation, we determined: viability, confluency, and cell size, the thiol groups' level by modifying Ellman's method, Ki67, and Proliferating Cell Nuclear Antigen expression (PCNA). The impact on cells' morphology was visualized by the ultrastructural (TEM) study and holotomograpic 3D imaging. Results: The viability and confluency analysis demonstrated that the safest exposure to ST2C, should not exceed 4h. An increased expression of Ki67 antigen and PCNA was observed. TEM and 3D imaging studies revealed vacuolization after the longest period of exposure (24). Conclusions: According to obtained results, we conclude that STC can play a protective role in cardiac surgery during heart arrest.

In the case of serious cardiovascular diseases, such as refractory heart failure, heart transplantation is the only possible intervention. Currently, the modes of organ transport in hypothermic cardioplegic solution do not allow the implantation of the heart beyond 4-5 hours from the explant. The heart being an organ with a greater consumption of oxygen and high metabolism than the brain, its transport in hypothermic cardioplegic solutions presents critical issues in terms of time and conservation. An ambitious goal of many researchers and clinicians is to minimize the hypoxia of the explanted heart and extend the permanence time in cardioplegic solution without damage from hypoxia. Adequately oxygenating the explanted organs may extend the usability time of the explanted organ. This challenge has been pursued for years with approaches that are often expensive, risky, and/or difficult to use. We propose to consider oxygenated nanocarriers releasing oxygen for a long time. In this way, it will also be possible to use organs from distant countries with respect to the recipient, thus exceeding the canonical 4-5 hours tolerated up to now. In addition to the lack of oxygen, the transplanted organ can undergo the accumulation of catabolites due to the lack of perfusion during transport. Therefore, nanocarriers can also be perfused in adequate solution during organ transportation. A better oxygenation improving the postoperative recovery of the transplanted heart will improve the recipient's quality of life., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: This study investigated if the β-receptor blocking agent esmolol, added to standard oxygenated blood cardioplegia, improved myocardial function after weaning from bypass., Design: A block-randomized, blinded study., Setting: A university laboratory., Participants: Twenty anesthetized pigs, Norwegian Landrace., Interventions: After cardiopulmonary bypass, cardiac arrest was induced with cold (12°C), oxygenated blood cardioplegia, enriched with either esmolol or vehicle, repeated every 20 minutes. After 100 minutes the heart was reperfused and weaned., Measurements and Main Results: Left ventricular function was evaluated with pressure-volume loops, local myocardial function with multilayer strain and strain rate by epicardial short-axis tissue Doppler imaging. One hour after declamping, preload recruitable stroke work did not differ between groups, but increased to 72±3 mmHg in esmolol-treated animals v 57±4 mmHg (p<0.001) in controls after 3 hours. Radial peak ejection strain rate also was increased by esmolol; 6.0±1.0 s(-1)v 2.9±0.3 s(-1) (p<0.001) in subendocardium and 3.9±0.5 s(-1)v 2.3±0.2 s(-1) (p<0.005) in the midmyocardium. Cardiac index was increased, 4.0±0.2 L/min/m(2) by esmolol v 3.3±0.1 L/min/m(2) for controls (p<0.05). Isovolumetric relaxation time constant was reduced by esmolol, 23±1 ms v 26±1 ms (p<0.025). Troponin-T did not differ and was 339±48 ng/L for the esmolol group and 357±55 ng/L for the control group (p = 0.81)., Conclusions: Esmolol added to blood cardioplegia preserved systolic cardiac function during the first 3 hours after reperfusion in a porcine model with 100 minutes of cardioplegic arrest., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Oxidative stress markers and apoptosis were estimated during elective surgical heart revascularization. Eight patients with good ejection fraction underwent coronary artery bypass grafting (CABG) with the use of warm blood cardioplegia. Two right atrium auricle biopsy specimens were collected before and after the operation. Specimens underwent immunocytochemical analysis of mitochondrial manganese superoxide dismutase (MnSOD) expression and apoptosis estimation by the TUNEL method. Ultrastructure analysis under electron microscope was made. Satisfactory results of the operation were obtained. After CABG the MnSOD expression increase in sections of auricles was observed through the increase of stain intensity and the percentage of cells with positive stain (from 30 to 80%). The apoptotic cells percentage remained at approximately the same level. Under the electron microscope insignificant pathological changes were observed. On this basis one may assume that in the case of cardiosurgical procedures with short aorta cross-clamping time and low operation risk level the application of cardioplegia sufficiently prevents reactive oxygen forms (ROF) cytotoxic activity although it does not inhibit the expression of oxidative stress (OS) markers. In our opinion the method of examining right atrium sections is safe and provides results comparable with other publications. It may also be a voice in the discussion on new methods of heart protection during cardiac surgery procedures.

Pyruvate-fortified cardioplegia protects myocardium and hastens postsurgical recovery of patients undergoing cardiopulmonary bypass (CPB). Pyruvate reportedly suppresses degradation of the alpha-subunit of hypoxia-inducible factor-1 (HIF-1), an activator of the gene encoding the cardioprotective cytokine erythropoietin (EPO). This study tested the hypothesis that pyruvate-enriched cardioplegia evoked EPO expression and mobilized EPO signaling mechanisms in myocardium. Hearts of pigs maintained on CPB were arrested for 60 min with 4:1 blood-crystalloid cardioplegia. The crystalloid component contained 188 mM glucose + or - 24 mM pyruvate. After 30-min cardiac reperfusion with cardioplegia-free blood, the pigs were weaned from CPB. Left ventricular myocardium was sampled 4 h after CPB for immunoblot assessment of HIF-1alpha, EPO and its receptor, the signaling kinases Akt and ERK, and endothelial nitric oxide synthase (eNOS), an effector of EPO signaling. Pyruvate-fortified cardioplegia stabilized arterial pressure post-CPB, induced myocardial EPO mRNA expression, and increased HIF-1alpha, EPO, and EPO-R protein contents by 60, 58, and 123%, respectively, vs. control cardioplegia (P < 0.05). Pyruvate cardioplegia also increased ERK phosphorylation by 61 and 118%, respectively, vs. control cardioplegia-treated and non-CPB sham myocardium (P < 0.01), but did not alter Akt phosphorylation. Nitric oxide synthase (NOS) activity and eNOS content fell 32% following control CPB vs. sham, but pyruvate cardioplegia prevented these declines, yielding 49 and 80% greater NOS activity and eNOS content vs. respective control values (P < 0.01). Pyruvate-fortified cardioplegia induced myocardial EPO expression and mobilized the EPO-ERK-eNOS mechanism. By stabilizing HIF-1alpha, pyruvate-fortified cardioplegia may evoke sustained activation of EPO's cardioprotective signaling cascade in myocardium.

Na(+)/K(+) pump activation induced by normothermic reperfusion with high potassium cardioplegia may exert a protective effect on reperfusion-induced myocardial damage. We investigated (1) temperature dependency and extracellular potassium dependency of the Na(+)/K(+) pump current (Ip), (2) effects of high potassium or ouabain during reperfusion on the post-ischemic left ventricular (LV) function. Ip-voltage relation was constructed at 5.0 and 20 mM of KCl (37 degrees C) using a whole-cell clamp technique in guinea pig myocytes. Ip at -40 mV was measured at 37, 27 and 18 degrees C (KCl: 5.0 mM). Isolated rat hearts were Langendorff-perfused and subjected to 20 min of global ischemia (37 degrees C) followed by 35 min of reperfusion (37 degrees C). The post-ischemic recovery of LV developed pressure (%LVDP) was assessed in the four reperfusate groups (4.8 mM KCl, 10 mM KCl, 20 mM KCl, or 4.8 mM KCl plus 50 microM ouabain during the first 10 min of reperfusion). The 4.8 mM KCl and 10.0 mM KCl groups were compared under metabolic inhibition (glucose-free, NaCN, or hypoxia) during reperfusion. The Ip-voltage relation shifted upward when extracellular KCl was increased from 5.0 to 20 mM. Ip was significantly greater at 37 degrees C than at 18 degrees C (114.3+/-17.2 vs. 22.7+/-1.2 pA, respectively). %LVDP was significantly greater at the 10.0 mM KCl group than at the 4.8 mM KCl group (54.9+/-5.5% vs. 34.2+/-5.9%, respectively). Metabolic inhibition abolished the difference between the two groups. Ouabain significantly decreased %LVDP (15.9+/-1.6%). Potassium-induced cardiac arrest during normothermic reperfusion may exert a cardioprotective effect by inducing Na(+)/K(+) pump activation, which may be supported by aerobic metabolism during reoxygenation rather than by energy saving during cardiac arrest.

In experiments on rats we studied the effects of cardioplegic solutions with L-aspartic acid or L-arginine on functional recovery and metabolism of isolated working heart after 40-min normothermal global ischemia and 30-min reperfusion. After reperfusion of the hearts preventively protected with cardioplegic solution containing L-aspartic acid or L-arginine, coronary flow decreased in comparison with the initial values. As a component of cardioplegic solution, L-arginine was less efficient in recovery of contractility and cardiac output of the hearts in comparison with L-aspartic acid. In hearts protected with L-aspartic acid, the postischemic levels of ATP and phosphocreatine were significantly higher, and the level of lactate was significantly lower than in hearts protected with L-arginine. In comparison with L-arginine, L-aspartic acid is a more efficient component of cardioplegic solution in protection of the heart from metabolic and functional damages caused by global ischemia and reperfusion.

Inflammation and oxidative damage are believed to play an important role in the postoperative complications after cardiopulmonary bypass (CPB) in neonates. During the preparation of the prime, red blood cells (RBCs) release non-protein-bound iron (NPBI) and free haemoglobin/haem (Hb/haem). The presence of these prooxidants in the prime solution may increase oxidative stress in neonates undergoing CPB. The solution used as the basis of the prime solution may influence the degree of this oxidative stress. We investigated the NPBI and the Hb/haem binding capacities of two different prime solutions: a prime based on pasteurized human albumin and a prime based on fresh frozen plasma. The presence of NPBI and free Hb/haem were measured during and after the preparation of the prime solution. Only in the albumin prime was NPBI detectable. However, in both primes, the concentrations of free Hb/haem increased. Thus, to reduce the prooxidative effects of NPBI and free Hb/haem, RBCs should be added to the prime at the last possible moment. Adding fresh frozen plasma should be considered, as this would result in no detectable NPBI in the prime solution.

The introduction of blood cardioplegia has been proven to limit ischaemia and reperfusion injury in cardiac surgery. But the presence of activated neutrophils in the capillary bed may cause further damage. Leukocyte filters have been shown to be very effective in reducing the leukocytes in blood cardioplegia to less than 10%. Leukocyte depletion of blood cardioplegia provides an excellent approach to minimizing myocardial injury, predominantly in high-risk cardiac surgery.

Filtration of cardiopulmonary bypass (CPB) priming fluid before connection of the circuit to the patient was first accomplished by arterial line filtration. When dedicated prebypass filters (PBFs) with smaller pore sizes became available, a large number of particles could be found on the filter surface. In recent years, modern manufacturing methods for CPB circuit components were believed to be associated with a reduced number of particles found in components of extracorporeal circuits, making separate filtration of CPB priming solution unnecessary. Microemboli generated during the preparation and priming procedure of the CPB circuit may consist of either solid particles or gaseous emboli and may contribute to patient morbidity. Endotoxins found in infusion solutions and CPB priming solutions may trigger inflammatory responses when administered into the circulatory system. Filtration of crystalloid CPB priming solutions with a PBF consisting of a filter membrane with a pore size of 0.2 microm was found to effectively reduce the number of microemboli. Infusion filters with a filter pore size of 0.2 microm were found to reduce the endotoxin contamination in infusion solutions. Prebypass filtration with filters containing pores of 0.2 pm should be a necessity for contemporary perfusion practice.

Background: Gene therapy in cardiovascular disease promises to be of great impact. The ideal vector for the therapeutic gene transfection remains to be determined. The aim of the present study was to investigate the efficacy of gene transfer using adeno-associated virus vectors carrying the lacZ-reporter gene (AAV-lacZ) in a previously described coronary recirculation model., Methods: Beating Lewis rat hearts perfused with oxygenated Krebs-Henseleit solution were harvested, after which an atrial septal defect (ASD) was created. All vessels were tied, and AAV-lacZ was injected into the aortic root. The solution was recirculated through the ASD to the left side of the heart and pumped back to the coronary arteries by the left ventricle. Incubation was allowed for 20 min at 15 degrees C, and the hearts were subsequently transplanted heterotopically in syngeneic rats. Three increasing doses (109, 1,010, 1,011 e. u.) of AAV-lacZ virus vectors were used to study the rate of gene transfer. All hearts were harvested after 7-60 days and evaluated histologically for expression of the lacZ-gene., Results: Dose-dependent gene transfer was observed. Even after 60 days, there was no obvious decline in gene expression., Conclusion: Adeno-associated virus vectors offer effective and uniform gene transfer in the myocardium after transcoronary injection and recirculation. Due to the lack of immune response previously described, no decrease in gene expression can be observed up to 60 days after injection.

Objectives: 1. Identify clinical, biochemical and inflammatory predictors of allograft ischemic injury in clinical heart transplantation. 2. Evaluate the impact of high dose insulin (GIK) on allograft metabolism during blood cardioplegia and post-ischemic injury., Design: A clinical, prospective, randomized open trial comprising 25 consecutive heart transplantations at a university hospital. Ischemic injury was evaluated from plasma levels of creatine kinase isoenzyme MB (CK-MB). Blood cardioplegic arterial and coronary sinus concentrations of C3a, IL-6, substrates, amino acids and blood gases were measured at the end of the implantation period, prior to reperfusion. Twelve patients received high dose insulin with glucose, potassium and amino acids., Results: CK-MB increased from 1.9 +/- 0.2 to 161 +/- 13 microg/l (range 47-293 microg/l). The peak level of CK-MB correlated with donor age (r = 0.48, p = 0.02) and implantation time (r = 0.53, p = 0.02); and with recipient plasma IL-6 (r = 0.56, p = 0.02), allograft oxygen extraction (r = 0.56, p = 0.02), lactate release (r = 0.47, p = 0.02) and allograft arterial-coronary sinus (cs) pH (r = 0.47, p = 0.02) all during final cardioplegia before reperfusion. Seventy-two percent of the variance of CK-MB was explained by a model which included donor age, art-cs pH difference and arterial IL-6. In contrast, CK-MB was unrelated to total ischemic time (r = -0.17, p = 0.38). Insulin infusion had no effect on myocardial substrates during cardioplegia, or on post-ischemic CK-MB., Conclusion: Donor age, duration and quality of the implantation period are significant predictors of allograft ischemic injury in heart transplantation. High dose insulin had no detectable effects on allograft metabolism during cardioplegia, or on subsequent ischemic injury.

Compared to murine and human hemoglobin, bovine hemoglobin has a less exothermic oxygen binding and delivers oxygen even at low temperatures. This property could improve oxygen availability for myocytes during hypothermic arrest of hearts. The aim of this study was to evaluate the advantage of using cardioplegic solutions enriched with bovine hemoglobin when storing rat hearts. Hearts excised from rats after perfusion with different cardioplegic solutions (Celsior, Celsior plus 4% human hemoglobin, Celsior plus 4% and 8% bovine hemoglobin) were compared. Biopsies were obtained from the beating hearts before cardioplegic infusion and during a 48 h period of cold storage. Adenosine triphosphate, its catabolites and markers of oxidative stress were measured as indices of preservation. The results show that bovine hemoglobin-enriched solutions highly improve adenosine triphosphate content, decreasing its catabolites; no significant changes in antioxidant status were evident. The statistically significant difference was evident up to 6 h of storage. Doubling the concentration of bovine hemoglobin produces only slight improvement. Alternative hemoglobins with different properties may improve and prolong heart storage. As bovine hemoglobin delivers oxygen even at low temperatures, it improves energy content and anabolic reactions, without decreasing oxidative stress.

The objective of this study was to investigate whether the addition of magnesium to a hyperkalemic cardioplegic solution containing 1.2-1.5 mmol/L ionized calcium improves myocardial protection. Twenty-seven coronary artery disease (CAD) patients underwent coronary artery bypass grafting (CABG) received hyperkalemic (20-22 mmol/L potassium) cardioplegic solutions containing 1.2-1.5 mmol/L ionized calcium and were randomized to one of the following groups: Group A (n = 9) received 3-4 mmol/L magnesium cool blood cardioplegia (4 degrees C), Group B (n = 9) received 8-10 mmol/L magnesium cold blood cardioplegia (4 degrees C). Group C (n = 9) received 16-18 mmol/L magnesium cold blood cardioplegia (4 degrees C). The effect of myocardium protection of the three kinds of cardioplegic solutions were evaluated by clinical outcome, cTnI and CK-MB mass. Serial venous blood samples were obtained before induction, after cardiopulmonary bypass (CPB), postoperative 6 h, 24 h, 72 h, and 6th day, respectively. The percentage of myocardial autoresusciation in group B (100%) was significantly higher than that in groups A (77.8%) and C (66.7%). One patient in group A and two patients in group C needed an interim pacemaker, but none in group B. The period of postoperative mechanical ventilation and ICU stay in group B was shorter than in the other two groups. The level of cTnI and CK-Mb mass increased from postoperative 6 h (p < .05), reached peak in 24 h-72 h, and recovered postoperative 6th day. As compared with groups A and C, the plasma concentrations of cTnI and CK-MB mass in group B were significantly lower at 6 h, 24 h, and 72 h (p < .01). 8 approximately 10 mmol/L magnesium cold blood cardioplegia provides better myocardium protection than higher or lower concentrations.

Background: Ca(2+) overload plays an important role in the pathogenesis of cardioplegic ischemia-reperfusion injury. The standard technique to control Ca(2+) overload has been to reduce Ca(2+) in the cardioplegic solution (CP). Recent reports suggest that Na(+)/H(+) exchange inhibitors can also prevent Ca(2+) overload. We compared 4 crystalloid CPs that might minimize Ca(2+) overload in comparison with standard Mg(2+)-containing CP: (1) low Ca(2+) CP (0.25 mmol/L), (2) citrate CP/normal Mg(2+) (1 mmol/L Mg(2+)), (3) citrate CP/high Mg(2+) (9 mmol/L Mg(2+)), and (4) the addition of the Na(+)/H(+) exchange inhibitor HOE-642 (Cariporide). We also tested the effect of citrate titration in vitro on the level of free Ca(2+) and Mg(2+) in CPs., Methods and Results: Isolated working rat heart preparations were perfused with oxygenated Krebs-Henseleit buffer and subjected to 60 minutes of 37 degrees C arrest and reperfusion with CPs with different Ca(2+) concentrations. Cardiac performance, including aortic flow (AF), was measured before and after ischemia. Myocardial high-energy phosphates were measured after reperfusion. The in vitro addition of citrate to CP (2%, 21 mmol/L) produced parallel reductions in Mg(2+) and Ca(2+). Because only Ca(2+) was required to be low, the further addition of Mg(2+) increased free Mg(2+), but the highest level achieved was 9 mmol/L. Citrate CP significantly impaired postischemic function (AF 58.3+/-2. 5% without citrate versus 41.6+/-3% for citrate with normal Mg(2+), P:<0.05, versus 22.4+/-6.2% for citrate with high Mg(2+), P:<0.05). Low-Ca(2+) CP (0.25 mmol/L Ca(2+)) significantly improved the recovery of postischemic function in comparison with standard CP (1.0 mmol/L Ca(2+)) (AF 47.6+/-1.7% versus 58.3+/-2.5%, P:<0.05). The addition of HOE-642 (1 micromol/L) to CP significantly improved postischemia function (47.6+/-1.7% without HOE-642 versus 62.4+/-1. 7% with HOE-642, P:<0.05). Postischemia cardiac high-energy phosphate levels were unaffected by Ca(2+) manipulation., Conclusions: (1) A lowered Ca(2+) concentration in CP is beneficial in Mg(2+)-containing cardioplegia. (2) The use of citrate to chelate Ca(2+) is detrimental in the crystalloid-perfused isolated working rat heart, especially with high Mg(2+). (3) The mechanism of citrate action is complex, and its use limits precise simultaneous control of Ca(2+) and Mg(2+). (4) HOE-642 in CP is as efficacious in preservation of the ischemic myocardium as is the direct reduction in Ca(2+).

Background: Alteration of endothelial permeability by perfusion solutions used may influence the outcome of bypass grafts., Method: Carotid arteries of New Zealand rabbits were locally perfused in situ for 20 or 60 min with various solutions used in bypass surgery. After restoring normal circulation, horseradish peroxidase was injected in the ear vein. Endothelial permeability was measured by electronmicroscopy as the peroxidase accumulation in the subendothelial space during 6min circulation., Results: The density indices (mean standard deviation) as a parameter for permeability in comparison to the control vessels were significantly greater than 100% for all solutions: for physiological saline 254+/-22% and 358+/-15%, for Ringer's lactate 206+/-26% and 302+/-17%, for St. Thomas' Hospital solution 163+/-15 % and 252+/-29%, and for Bretschneider's HTK solution 130+/-15% (p=0.003) and 169+/-26%, after 20 and 60 min perfusion. Addition of heparin (50IU/ml) caused a significant increase in endothelial permeability (p<0.05)., Conclusions: Bretschneider's is the most suitable of the solutions studied as a graft storage medium in bypass and cardiothoracic surgery, but a solution causing even less damage is desireable.

There is increasing evidence that the availability of different metabolic substrates can influence post-ischemic functional recovery of the heart and the damage incurred during episodes of myocardial ischemia. Here we present the rationale for metabolic interventions, describe their mechanisms of action and suggest potential clinical applications. In cardiac surgery, basic research, studies of human myocardial metabolism after cardiac operations, and available experience with metabolic interventions provide a rationale for metabolic support with glutamate and/or high-dose glucose-insulin-potassium (GIK) in postoperative cardiac failure. In the treatment of acute myocardial infarction GIK deserves serious evaluation as recent randomized studies in diabetics with myocardial infarction and in patients undergoing reperfusion strategies demonstrate significant reductions in mortality. However, before large scale prospective randomized studies are undertaken, further studies of myocardial metabolism in acute myocardial infarction and the impact of different GIK regimes may be advisable in order to determine appropriate doses. A brief overview of metabolic modulation with pharmacological measures is given as it eventually may prove that we have to await the introduction of pharmacological agents which enhance full glucose oxidation at the expense of free fatty acids to create the commercial interest necessary to achieve widespread use of metabolic therapies.

Glucose-insulin-potassium therapy has shown its efficacy in diminishing the myocardial damage under ischemia-reperfusion conditions in experimental models. This effect appears to be mainly due to the increase of anaerobic glycolysis in ischemic cells with a consequent reduction in the use of fatty acids. On the other hand, clinical studies in the acute phase of myocardial infarction are out-dated and almost non-existent in the thrombolytic era. The absence of current consistent data makes it difficult to draw conclusions concerning the real utility of this therapy in the clinical practice.

Several therapeutic approaches have been proposed for the management of acute myocardial infarction (AMI). In 1961, Sodi-Pallarés presented the Glucose-Insulin-Potassium (GIK) infusion as a valid adjunctive therapy for the treatment of the acute phase. He observed a decrease in mortality which could be explained by some mechanisms such as: arrhythmia prevention, hypoxic cell nutrition, diminution of infarct size and others. Due to the lack of Coronary Care Units at that time, acute myocardial ischemia was considered a high mortality disease. Therefore, the first studies concerning the efficacy of this treatment showed a significant decrease in mortality. After the development of better care and medical attention of AMI patients, and above all after the introduction of fibrinolysis, mortality dramatically diminished. Thus, GIK was considered to give no additional benefit, and its use became restricted to a small number of centers. In this review the physiopathological bases of GIK solution use are given, as well as the results of the main experimental studies and a critical analysis of the scarce clinical studies available. It is concluded that there are enough data to support the use of GIK solution in non-thrombolized AMIs. It could probably also benefit thrombolised ones, although there is no available evidence in this context.

Background: Tepid blood (TB) cardioplegia combines the improved rheologic characteristics and the augmented oxygen and substrate delivery of blood cardioplegia with the advantages of moderate hypothermia. In addition, the intramyocardial distribution of continuous TB cardioplegia may also be better than intermittent cold crystalloid (CC) cardioplegia. We sought to compare the distribution of TB and CC cardioplegia at varying infusion pressures., Methods: In situ, isolated canine hearts were randomized to antegrade, continuous TB (28 degrees C, n = 8) or intermittent CC (n = 8) cardioplegia infused at 50, 75, and 100 mm Hg. The regional distribution of cardioplegia at each pressure was measured by 15-microm colored microspheres. Cardioplegia distribution was measured from three areas each of the right ventricle (inflow, outflow, and apex) and the left ventricle (anterior, lateral, and posterior). Left ventricular samples were subdivided into subepicardial, midmyocardial, and subendocardial., Results: Delivery of cardioplegia to all areas of the right and left ventricles showed a linear pressure-flow relationship over the range of pressures tested. Right ventricular distribution was two-thirds of that to the left ventricle, and left ventricular subepicardial distribution was approximately one half of subendocardial flow in both groups at all delivery pressures. However, the subendocardial to subepicardial ratio was significantly greater with TB cardioplegia than with CC cardioplegia. Transmural right ventricular cardioplegia flow was comparable in both groups. In contrast, left ventricular distribution of CC cardioplegia was greater than TB cardioplegia at all three pressures tested., Conclusions: The pressure-flow relationship in both CC and TB cardioplegia is linear in both the right and left ventricular myocardium over clinically applicable delivery pressures. The distribution of cardioplegia to the right ventricle is not altered by increased pressure.

Background: The development of myocardial protective strategies depends on a complete understanding of the pathophysiology of myocardial ischemia and reperfusion. This article reviews the rationale for inclusion of metabolic substrates in cardioplegic solutions on the basis of our current understanding of the underlying pathophysiologic pathways and speculates on the inclusion of future additives that await further investigation., Methods: The pathophysiology of myocardial ischemia and reperfusion was evaluated from an extensive review of the pertinent literature. Experimental and clinical studies supporting the inclusion of metabolic substrates in clinical cardioplegic solutions were reviewed and summarized. Speculation on possible future additives to these formulas was made on the basis of encouraging, albeit preliminary, experimental data., Results: Sound experimental and clinical evidence supports the inclusion of glucose, amino acids, calcium chelators, and oxygen as fundamental substrate additives to current cardioplegic solutions. Antioxidants, calcium-channel blockers, and tricarboxylic acid cycle intermediates may be of value. Adenosine, potassium-adenosine triphosphate channel modulators, and nitric oxide may join these lists after further research., Conclusions: Substrate enhancement of clinical cardioplegic solutions is based on physiologic principles that have been confirmed in the clinical setting. Further definition of the intricacies of myocardial ischemia and reperfusion promises to expand the current list of additives.

Aspartate and glutamate each have been shown to improve cardiac recovery after hypoxia or ischemia under normothermic conditions, but whether their effects are additive and to what extent they are modified by hypothermia has not been studied systematically. We set out to compare the individual and combined protective effects of aspartate and glutamate during cardioplegic arrest under normothermic and hypothermic conditions in the rat. Using isolated working rat hearts, functional and metabolic recovery was assessed after 0.5 hours of potassium arrest at 37 degrees C or 5 hours at 2 degrees C in control hearts (C) and in hearts in which 20 mmol/L glutamate (G), 20 mmol/L aspartate (A), or both (A + G) was added to the cardioplegic solution. Under normothermic conditions, percentage recovery of prearrest work (mean +/- standard error of the mean) was as follows: C = 31.7 +/- 2.8, G = 34.8 +/- 0.2, A = 49.6 +/- 2.8*, A + G = 53.7 +/- 2.3*. Under hypothermic conditions, the values were as follows: C = 40.4 +/- 4.0, G = 45.2 +/- 2.3, A = 59.4 +/- 1.8*, A + G = 54.1 +/- 1.2* (*p < 0.01 versus C and G). Recovery of postischemic high-energy phosphate content followed the same pattern: A = A + G > G or C. Measurement of postischemic myocardial content of amino acids showed that recovery of function and energy status correlated with maintenance of myocardial levels of aspartate (r = 0.9; p < 0.01) but not glutamate.(ABSTRACT TRUNCATED AT 250 WORDS)

Unlabelled: This study documents the gross flow characteristics and capillary distribution of cardioplegic solution delivered retrogradely with the coronary sinus open versus closed., Methods: Five explanted human hearts from transplant recipients were used as experimental models. Hearts served as their own controls and received two doses of warm blood cardioplegic solution, each containing colored microspheres. The first dose was delivered through a retroperfusion catheter with the coronary sinus open and the second dose was delivered with the sinus occluded. Capillary flow was measured at twelve ventricular sites and gross flow was measured by examining coronary sinus regurgitation, thebesian vein drainage, and aortic effluent (nutrient flow)., Results: Coronary sinus ostial occlusion allowed for a significant decrease in total cardioplegic flow (1.74 +/- 0.40 ml/gm versus 1.06 +/- 0.32 ml/gm; p < 0.05) to occur while maintaining an identical intracoronary sinus pressure. Ostial occlusion also resulted in an increase in the ratio of nutrient flow/total cardioplegic flow from 32.3% +/- 15.1% to 61.3% +/- 7.9% (p < 0.05). A statistically significant improvement in capillary flow was found at the midventricular level in the posterior intraventricular septum and posterolateral right ventricular free wall. This improvement was also documented for the intraventricular septum and right ventricle at the level of the apex., Conclusion: Coronary sinus occlusion during retrograde cardioplegia significantly improves cardioplegic delivery to the right ventricle and posterior intraventricular septum. Furthermore, the technique affords a significant improvement in nutrient cardioplegic flow while reducing the overall volume of cardioplegic solution administered.

Warm retrograde blood cardioplegia is frequently used for myocardial protection, despite experimental studies questioning the adequacy of capillary flow to the right ventricle and septum. The capillary distribution of retrograde blood cardioplegia in the human heart is unknown. Hearts from eight transplant recipients with the diagnosis of idiopathic or dilated cardiomyopathy were arrested in situ with cold blood cardioplegia and excised with the coronary sinus intact. Within 20 minutes of explanation, colored microspheres mixed in 37 degrees C blood cardioplegia were administered through the coronary sinus at a pressure of 30 to 40 mm Hg for 2 minutes. Twelve transmural myocardial samples were taken horizontally at the level of midventricle and apex to determine regional capillary flow rates. When retrograde warm blood cardioplegia was administered at a rate of 0.42 +/- 0.06 ml/gm/min, the left ventricle, the septum, the posterior wall of the right ventricle, and the apex consistently received capillary flow rates in excess of their metabolic requirements. The capillary perfusion of anterior and lateral walls of the right ventricle was marginally adequate to sustain aerobic metabolism. In explanted human hearts, retrograde blood cardioplegia provides adequate capillary flow to the left ventricle, the septum, the posterior wall of the right ventricle, and the apex; however, capillary flow to the anterior and lateral walls of the right ventricle is marginal. This study delineates the tenuous balance between supply and demand for right ventricular protection with warm continuous retrograde blood cardioplegia.

The merits of oxygenated crystalloid cardioplegic solutions have been well established in experimental animals. The positive effects of oxygenation of Plasmalyte B (Sabax Ltd) and St. Thomas Hospital solution (Plegisol) were achieved by gassing with 95% O2/5% CO2 and 100% O2, respectively. In view of the marked pH differences induced by these gas mixtures, we evaluated the effect of mode of oxygenation on myocardial recovery during reperfusion after hypothermic cardioplegic arrest. Oxygenation with 100% O2 of Plasmalyte B containing high K+ levels caused marked deterioration in myocardial recovery, whereas the mode of oxygenation did not affect recovery after arrest with St. Thomas Hospital solution. Because the major differences between these solutions reside in their respective K+, Mg2+, and HCO3- contents, the effects of variations in the levels of these ions were investigated. The results showed that oxygenation with 100% O2 was deleterious only in the presence of high K+ (29 mmol/L), low Mg2+ (3 mmol/L), and high NaHCO3 (28 mmol/L) levels. The marked decline in mechanical recovery during reperfusion was associated with significant changes in myocardial adenosine triphosphate and intracellular Ca2+ levels. Although an explanation for these findings is not readily available, it is suggested that complex ionic interactions and possibly oxygen free radical generation may lead to intracellular Ca2+ overload, depression in mitochondrial adenosine triphosphate generation, and, hence, deterioration in mechanical recovery.

Hydroxyl is one of the most cytotoxic of all oxygen-derived free radicals produced during the myocardial ischaemia-reperfusion sequence. The purpose of the present study was to determine the effects of various interventions aimed at diminishing the production of hydroxyl radicals by reducing either one of their precursors (hydrogen peroxide) or the metal (ferric iron) which catalyzes the reaction generating these radicals. Sixty isolated and perfused rat hearts with isovolaemic contraction were studied. Except for non-ischaemic controls, these hearts were subjected to a 3-hour cardioplegic arrest in hypothermia (15-18 degrees C) followed by a 45-min reperfusion. The following interventions were performed: pretreatment with peroxidase, a hydrogen peroxide scavenger; pretreatment with peroxidase combined with deferoxamine, an ironchelating agent; pretreatment with peroxidase followed by addition of deferoxamine to the cardioplegic solution; addition of deferoxamine to the cardioplegic solution without pretreatment with the enzyme. Judging from the post-ischaemic values of developed pressure (maximum systolic pressure--diastolic pressure), left ventricular dP/dt and diastolic pressure and coronary flow rate, it appeared that the best myocardial protection was provided by deferoxamine-enriched cardioplegia. This study confirms that hydroxyl radicals most probably play a role in the genesis of the myocardial lesions associated with global ischaemia followed by reperfusion. Moreover, our results highlight the potential value of deferoxamine added to cardioplegic protection in heart surgery performed under extracorporeal circulation.