Increased injury of hypertrophied myocardium with ischemic arrest: Preservation with hypothermia and cardioplegia

Many patients undergoing cardiac surgery have some degree of myocardial hypertrophy. To assess the response of hypertrophied myocardium to simulated cardiac surgery, left ventricular hypertrophy was induced in rats by aortic banding, and ventricular function was measured by means of the isolated, isovolumic heart perfusion technique. The hypertrophied hearts had a greater susceptibility to ischemic injury than nonhypertrophied control hearts, as manifested by a greater degree of diastolic contracture during the recovery period after 30 minutes of ischemic arrest at 37 degrees C. Hypothermia without cardioplegia during a 2-hour arrest did not completely preserve diastolic function in the hypertrophied hearts, but cardioplegia combined with hypothermia completely protected the hypertrophied hearts against 2 hours of ischemia. The results suggest a need for both hypothermic and cardioplegic preservation techniques in patients with myocardial hypertrophy who have cardiac surgical procedures requiring a significant period of myocardial ischemia.     

Amelioration of the effects of ischemic cardiac arrest by the intracoronary administration of cardioplegic solutions.

Interruption of coronary flow during cardiac surgical procedures provides a bloodless flaccid heart and allows precise and rapid correction of complex cardiac defects. However, myocardial damage occurs in direct proportion to the duration of the ischemia. As the induction of cardioplegia simulataneous with the initiation of cardiac ischemia helps to preserve cardiac energy reserves and thus myocardial integrity, the identification of a consistently reliable cardioplegic technique is desirable. Isolated perfused working rat hearts were made ischemic for one hour by aortic cross-clamping and were compared with hearts rendered cardioplegic at the onset of ischemia by the intracoronary administration of 5 ml of a hypothermic solution: 1) Krebs-Henseleit buffer, 2) Ringer's lactate, 3) tetrodotoxin, 4) potassium chloride, or 5) potassium citrate. Cardiac output, heart rate, aortic pressure and coronary flow were determined pre and post-ischemia. When compared to time-matched controls and hearts arrested with potassium or tetrodotoxin, the ischemia and ischemia-Ringer's lactate groups showed significant post cross-clamp depression of all measured parameters. Intracoronary Ringer's lactate, although often used as an adjunct to ischemic arrest, was not of significant value. In contrast, hearts arrested with tetrodotoxin, potassium chloride or potassium citrate showed no significant post-ischemic functional or histologic deficit. Perfusion with hypothermic Krebs-Henseleit buffer protected the myocardium better than did Ringer's lactate but less well than the tetrodotoxin or isotonic high potassium solutions. The induction of hypothermic metabolic arrest of the heart by briefly perfusing the coronary arteries via the aortic root with isotonic buffered solutions results in markedly improved myocardial tolerance to one hour of ischemia and avoids the problems of low cardiac output and ventricular irritability previously reported with hypertonic potassium citrate arrest.     

Captopril improves recovery of adenosine triphosphate during reperfusion of the ischemic isolated rat heart; a 31-phosphorusnuclear magnetic resonance study

Summary The effect of captopril on energy-rich phosphates and pH during normothermic ischemic arrest, hypothermic cardioplegic arrest and subsequent reperfusion was investigated in the isolated rat heart using 31P-nuclear magnetic resonance. The hearts remained in the probe during all perfusion procedures and captopril (80 ml·l^–1) treatment was started directly after cannulation.After normothermic ischemic arrest (15 min), the ATP content of captopril-treated hearts was not significantly different from that of untreated hearts (53±9% and 52±8%, respectively). Accumulation of inorganic phosphate at the end of ischemia was significantly less in treated hearts, suggesting a higher end-ischemic nucleotide content in treated hearts.Hypothermic cardioplegic arrest (St. Thomas' Hospital solution, 4°C) lasted for 3 h at 10°C. Adenosine triphosphate in treated hearts was significantly lower at the end of ischemia; 36±6% compared to 53±9% for untreated hearts.Adenosine triphosphate in untreated hearts recovered to 76±9% after normothermic ischemia and to 72±7% after hypothermic ischemia at the end of 30 min reperfusion. Captopril significantly improved adenosine triphosphate recovery in both treated groups; 89±4% after normothermic and 83±4% hypothermic ischemia.We conclude that captopril has a beneficial effect on recovery of adenosine triphosphate both after normothermic and after hypothermic ischemia.     

European versus North American cardioplegia: comparison of Bretschneider's and Roe's cardioplegic solutions in a canine model of cardiopulmonary bypass

Roe's and Bretschneider's crystalloid cardioplegic solutions were compared in a canine model of total cardiopulmonary bypass with 4.5 hours of hypothermic (27 degrees C) ischemic arrest and 60 minutes of reperfusion. Bretschneider's solution (Group I, six dogs) preserved tissue adenosine triphosphate (ATP) near control levels and maintained coronary effluent pH near 7.0 throughout the ischemic interval, while Roe's solution (Group II, six dogs) allowed progressive acidosis and depletion of ATP (P less than 0.005 versus control). Group I had supranormal left ventricular function during reperfusion (greater than 100% of pre-arrest function) but Group II regained only 40-75% of pre-arrest function. Group I had 2.82% +/- 3.61% necrosis of heart mass and Group II 9.33% +/- 8.26 (P less than 0.10). We conclude that Bretschneider's solution provided better myocardial protection than Roe's solution. The development of acidosis in the Roe group suggests that the more effective buffering of Bretschneider's solution with histidine is the probable basis for its superiority.     

Continuous tepid blood cardioplegia can preserve coronary endothelium and ameliorate the occurrence of cardiomyocyte apoptosis

OBJECTIVE: In modern cardiac surgery, crystalloid or blood cardioplegic solutions have been used widely for myocardial protection; however, ischemia does occur during protection with intermittent infusion of cold crystalloid or blood cardioplegic solutions. The present study was designed to evaluate the effect of different cardioplegic methods on myocardial apoptosis and coronary endothelial injury after global ischemia, cardiopulmonary bypass (CPB), and reperfusion in anesthetized open-chest dogs. METHODS: The dogs were classified into five groups to identify the injury of myocardium and coronary endothelium: group 1, normothermic CPB without cardiac arrest; group 2, hypothermic CPB with continuous tepid blood cardioplegia, and with cardiac arrest; group 3, hypothermic CPB with intermittent cold blood cardioplegia, and with cardiac arrest; group 4, hypothermic CPB with intermittent cold crystalloid cardioplegia, and with cardiac arrest; and group 5, sham-operated control group. During CPB, cardiac arrest was achieved with different cardioplegia solutions for 60 min, followed by reperfusion for 4 h before the myocardium and coronary arteries were harvested. Coronary arteries were harvested immediately and analyzed by scanning electron microscopy. Cardiomyocytic apoptosis was detected using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling, Western blot, and DNA ladder methods. RESULTS: Regardless of the detection method used, significantly higher percentages of apoptotic cardiomyocytes were found in group 3 and group 4 than in other groups. Expression of caspase-3 correlated with increased apoptosis. Scanning electron microscopy revealed severe endothelial injury of coronary arteries in group 3 and group 4. CONCLUSION: These results point to an important explanation for the difference in cardiac recovery after hypothermic ischemia and arrest with various cardioplegic solutions.     

Histopathological study on myocardial hypertrophy associated with ischemic heart disease

The mode and causes of myocardial hypertrophy occurring in association with ischemic heart disease were studied. The investigation involved autopsied hearts (15 cases of subendocardial infarction, 27 of transmural infarction, 20 of non-infarcted three vessel disease and 17 controls) and biopsied materials obtained during coronary-aorta bypass graft surgery (23 patients with angina pectoris and 46 with myocardial infarction). The subendocardial infarction group showed most marked myocardial hypertrophy that reflected extensive infarction and fibrosis, dilatation of the left ventricular cavity and the loss of myocytes. Despite a marked decrease in the number of myocyte layers, the residual myocardium of the left ventricle was uniformly hypertrophic, accompanied by an increase in the heart weight. The larger the area of fibrosis, the more marked was myocardial hypertrophy irrespective of the luminal diameter of the responsible coronary artery. These findings indicate that myocardial hypertrophy associated with ischemic heart disease is enhanced by the compensatory mechanisms for a decrease in the contractile myocardium due to fibrosis.     

Nifedipine and cardioplegia: rat heart studies with the St Thomas' cardioplegic solution

The ability of nifedipine to enhance myocardial protection was assessed using an isolated rat heart model of cardiopulmonary bypass and ischaemic cardiac arrest. With normothermic ischaemic arrest (35 min, 37 degrees C), nifedipine addition improved the protective properties of the St Thomas' cardioplegic solution. Optimal protection was observed with 0.075 mumol nifedipine X litre-1, where post-ischaemic recovery of aortic flow was improved from 47.9 +/- 5.2% to 76.7 +/- 2.9% (P less than 0.001) and creatine kinase leakage was reduced by approximately 50%. Despite the marked additional protection under normothermic conditions the drug was unable to improve contractile recovery after a period of hypothermic ischaemic arrest (150 min, 20 degrees C) although it did allow a significant reduction (22%) in creatine kinase leakage. In other studies, the ability of nifedipine to replace the cardioplegic solution was examined. Under normothermic conditions, it showed a good ability to protect against ischaemia, but this protection did not match that afforded by the St Thomas' cardioplegic solution. Under hypothermic conditions the drug failed to substitute for the cardioplegic solution, suggesting that a common modality between hypothermia and nifedipine-induced protection.     

Beta-adrenoceptor density in chronic infarcted myocardium: a subtype specific decrease of beta1-adrenoceptor density

Beta-adrenoceptor density is altered in different cardiac diseases. In heart failure beta-adrenoceptor density is down regulated but in acute myocardial ischemia beta-adrenoceptor density is up regulated. In hearts with myocardial infarction total beta-adrenoceptor density is decreased shortly after myocardial infarction. AIMS AND METHODS: To investigate whether total beta-adrenoceptor number is altered in the chronic phase after myocardial infarction, and to identify the specificity of alteration, we studied male Wistar rats (n = 18) which underwent a ligation of the left coronary artery or a sham operation. Twelve weeks after coronary ligation, rats were sacrificed and hearts were excised, perfused to obtain blood-free myocardium and frozen in liquid nitrogen. Infarcted myocardium was identified visually and separated from non-infarcted myocardium. Total beta-adrenoceptor number was calculated in fmol (-)-[125I]iodocyanopindolol specifically bound/mg protein and the relative amount of beta1- and beta2-adrenoceptor density was measured by inhibition of (-)-[125I]iodocyanopindolol binding with CGP 20712 A. RESULTS: Total beta-adrenoceptor number in infarcted myocardium was significantly decreased (25.7+/-1.4 vs. 24.9+/-2.2 vs. 20.1+/-3.2 fmol/mg protein (P=0.03) resp. Sham vs. Non-infarcted vs. Infarcted myocardium), due to a decrease of only beta1-adrenoceptor density (14.7+/-0.61 vs. 12.7+/-1.09 vs. 4.84+/-0.96 fmol/mg protein (P=0.004) resp.), whereas the beta2-adrenoceptor density and the dissociation constant (Kd) were not significantly decreased. CONCLUSION: In the infarcted myocardium total beta-adrenoceptor density is decreased due to a decreased beta1-adrenoceptor density at 12 weeks after myocardial infarction.     

Clinical advantages of papaverine cardioplegia

To determine the efficacy of papaverine in improving myocardial protection by causing a uniform distribution of the cardioplegic solution, a prospective study was carried out in 200 consecutive patients undergoing various open heart procedures. Several parameters (creatine kinase MB, electron microscopy of myocardium, perioperative myocardial infarction rate, frequency of postoperative arrhythmias) were monitored and compared with those of a control group which consisted of the previous 200 consecutive patients in whom the same cardioplegic solution was used, but without papaverine. In the papaverine group the operative mortality due to low cardiac output was 0.5% compared to 3%, and the spontaneous recovery of the heart after release of the aortic cross-clamp was 89% compared to 47% in the control group (P less than 0.01). The perioperative myocardial infarction rate was 5% and the incidence of postoperative temporary arrhythmias was also 5% in the papaverine group, while in the control group the perioperative myocardial infarction rate was 10% and the postoperative arrhythmia incidence was 13% (P less than 0.01).     

High cardiac angiotensin-II-forming activity in infarcted and non-infarcted human myocardium

The aims of this study were to compare human cardiac angiotensin-II-forming activity (AIIFA) between the intact area of control autopsy hearts without cardiac disease (n = 10) and the infarcted or non-infarcted area of autopsy hearts with myocardial infarction (MI, n = 7) and to determine responsible angiotensin-II-forming enzymes. Cardiac total and chymase-dependent AIIFAs were significantly higher in the infarcted and non-infarcted myocardium than those in non-MI heart, while angiotensin-converting enzyme-dependent AIIFA increased only in the infarcted myocardium. The density of chymase antibody-positive mast cells in the non-infarcted area of MI heart correlated positively with total or chymase-dependent AIIFA. Augmented AIIFA was also detected in the left atrium of post-MI hearts. Our results indicated that cardiac angiotensin II formation could be activated in the infarcted as well as in non-infarcted myocardium of the post-MI human heart.     

Re-excitation of the cardioplegic heart. A possible hazard in clinical cardioplegic arrest

Clinical cardioplegic arrest may coincide with a washout of cardioplegic agents by varying amounts of extracoronary collateral blood flow. This may shorten the duration of electromechanical arrest. Furthermore, even in the absence of electromechanical cardiac activity, washout may influence the cardioprotective properties of cardioplegic methods. The present study was designed to quantify the effects of cardioplegic washout. In a standardized isolated paracorporeal dog heart model, the St. Thomas's Hospital solution (ST-CP) and the Bretschneider histidine buffered solution (B-CP) were compared under the condition of washout by arterial blood. An inverse relationship was found between the amount of blood flowing through the coronary system and the duration of electromechanical arrest. Flow rates compatible with a 100 min period of complete electromechanical arrest were less than 0.41 ml/100 gr heart weight . min in ST-CP arrest and less than 0.21 ml/100 gr . min in B-CP arrest. This would indicate a greater safety against washout-induced re-excitation in ST-CP arrest. Postarrest myocardial function after 2 hours of complete electromechanical arrest at 20 degrees C was distinctly influenced by washout with arterial blood (20 degrees C) even in the absence of cardiac activity. A 100-min period of 0.2 ml/100 gr . min blood flow during arrest improved postarrest recovery of left ventricular developed pressure by 10% (76% versus 66%) after ST-CP arrest. By contrast, after B-CP arrest at equal rates of washout, recovery was diminished by 20% (79% versus 99%). It is concluded, that ST-CP, as compared to B-CP, provides longer periods of electromechanical arrest under the same washout conditions. Whereas postarrest recovery in the B-CP group is clearly superior to ST-CP in totally ischemic hearts, i.e. in hearts without collateral blood supply (99% versus 66%), this advantage may vanish in the presence of cardioplegic washout.     

Expression of heme oxygenase-1 in response to myocardial infarction in rats

Heme oxygenase-1 (HO-1) is a heat shock protein catalysing the degradation of heme to yield biliverdin, carbon monoxide and iron. Several recent studies have proposed the stress-inducible HO-1 to participate in cellular protection also in the heart. We, therefore, examined the expression and localization of HO-1 in a rat experimental myocardial infarction model. Male Wistar rats were subjected to left anterior coronary artery ligation or sham-operation and sacrificed at 1 day, 1 week and 4 weeks after ligation. The expression of HO-1 mRNA was assessed by real-time quantitative RT-PCR and the localization of HO-1 protein by immunoconfocal microscopy. At day 1, HO-1 mRNA was increased 3.9-fold in the peri-infarct border area vs sham-operated hearts (P<0.001) and 2.9-fold vs remote areas of the same hearts (P<0.001). At 1 week, HO-1 mRNA levels remained significantly higher (5-fold) in the peri-infarct border area than in sham-operated hearts (P<0.001). In addition, HO-1 mRNA transiently increased 1.6-fold in the remote non-infarcted myocardium vs sham operated hearts (P<0.05). HO-1 mRNA returned to basal levels by 4 weeks. The increase in HO-1 mRNA was accompanied by increased immunoreactivity of HO-1 protein in the vascular walls throughout the myocardium, and in the cardiomyocytes and fibroblast-like cells of the peri-infarct border areas. Cardiomyocytes showed immunoreactivity at the intercalated disc area, and in the sarcoplasmic reticulum as indicated by the striated pattern of staining. The results suggest that the induction of HO-1 may have an important role in the heart during the first days after myocardial infarction.     

Intravenous mesenchymal stem cell therapy early after reperfused acute myocardial infarction improves left ventricular function and alters electrophysiologic properties

Direct intramyocardial injection of mesenchymal stem cells (MSCs) improves left ventricular ejection fraction (LVEF) and may increase ventricular arrhythmia in hearts with myocardial infarction (MI). We hypothesized that intravenous MSCs given early after acute MI would engraft in injured myocardium, improve LV function, and result in pro-arrhythmic electrical remodeling. We created an apical infarction in swine by balloon occlusion/reperfusion, administered diI-labeled allogeneic bone marrow derived MSCs intravenously 30 min post-reperfusion and measured LVEF and wall thickness at baseline, 1 month, and 3 months. Epicardial effective refractory periods (ERPs) were determined before sacrifice. At 3 months, treated pigs [n=7] had significantly higher LVEF than controls [n=8] (49+/-2% vs. 44+/-3%, P=0.015) and significantly less wall thickening of non-infarcted myocardium. ERPs were significantly shorter than controls at all pacing cycle lengths (P相似文献   

Effect of a Calcium-Sensitizing Agent, Levosimendan, on the Postcardioplegic Inotropic Response of the Myocardium

Myocardial contractile function after coronary artery bypass graft surgery is often depressed and may require inotropic support, particularly in patients on treatment with beta-adrenergic and Ca²⁺ blockers. In view of the increase in cytosolic Ca²⁺ during early reperfusion, use of Ca²⁺ sensitizing agents may be preferable to adrenergic agonists for enhancement of contractile function after cardioplegic arrest. The aim of this study was to assess the efficacy of the Ca²⁺ sensitizer, levosimendan, as an inotrope on the mechanical recovery of hearts after normothermic and hypothermic cardioplegic arrest in the absence and presence of Ca²⁺ and beta-blockers. Isolated perfused working guinea pig hearts were perfused in the absence or presence of propranolol (10^–6 M) and/or nifedipine (10^–8 M), subjected to 45 minutes of normothermic or 180 minutes of hypothermic cardioplegic arrest, reperfused, and exposed to increasing concentrations of levosimendan (10^–9 to 10^–6 M). Levosimendan (10^–7 to 10^–6 M) has positive inotropic, chronotropic, and vasodilatory effects on normoxic perfused control hearts, as well as during reperfusion after 45 minutes of normothermic cardioplegic arrest. Similar effects were elicited in the presence of the blockers. Levosimendan had no stimulatory effect during reperfusion of hearts subjected to prior hypothermic arrest. Except for the increase in heart rate, the effects of levosimendan on functional performance during reperfusion were comparable with those of adrenaline. Levosimendan elicits a positive inotropic and chronotropic response during reperfusion of hearts after normothermic cardioplegic arrest, both in the absence and presence of Ca²⁺ and beta-adrenergic blockers.     

Altered expression of proteins of metabolic regulation during remodeling of the left ventricle after myocardial infarction

Non-infarcted myocardium after coronary occlusion undergoes progressive morphological and functional changes. The purpose of this study was to determine whether non-infarcted myocardium exhibits (1) alteration of the substrate pattern of myocardial metabolism and (2) concomitant changes in the expression of regulatory proteins of glucose and fatty acid metabolism. Myocardial infarction was induced in rats by ligation of the left coronary artery. One day and eight weeks after coronary occlusion, glucose and palmitate oxidation were measured. Expression of selected proteins of metabolism were determined one day to 12 weeks after infarction. One day after coronary occlusion no difference of glucose and palmitate oxidation was detectable, whereas after eight weeks, glucose oxidation was increased (+84%, P<0.05) and palmitate oxidation did not change significantly (-19%, P=0.07) in infarct-containing hearts, compared with hearts from sham-operated rats. One day after coronary occlusion, myocardial mRNA expression of the glucose transporter GLUT-1 was increased (+86%, P<0.05) and the expression of GLUT-4 was decreased (-28%, P<0.05) in surviving myocardium of infarct-containing hearts. Protein level of GLUT-1 was increased (+81%, P<0.05) and that of GLUT-4 slightly, but not significantly, decreased (-16%, P=NS). mRNA expressions of heart fatty acid binding protein (H-FABP), and of medium chain acyl-CoA dehydrogenase (MCAD), were decreased by 36% (P<0.05) and 35% (P=0. 07), respectively. Eight weeks after acute infarction, the left ventricle was hypertrophied and, at this time-point, there was no difference in the expression of GLUT-1 and GLUT-4 between infarcted and sham-operated hearts. However, myocardial mRNA and protein content of MCAD were decreased by 30% (P<0.01) and 27% (P<0.05), respectively. In summary, in surviving myocardium, glucose oxidation was increased eight weeks after coronary occlusion. Concomitantly, mRNA and protein expression of MCAD were decreased, compatible with a role of altered expression of regulatory proteins of metabolism in post-infarction modification of myocardial metabolism.     

Decreased expression of Na+/H+ exchanger isoform 1 (NHE1) in non-infarcted myocardium after acute myocardial infarction

Although cardiac NHE1 is activated during myocardial ischemia and reperfusion injury, little is known about changes in expression in non-infarcted myocardium after acute myocardial infarction (AMI). The purpose of this study was to examine left ventricular function and region dependent NHE1 expression after myocardial infarction. Therefore, we produced two AMI models in rats, a small infarction model which was continuously ligated at the branches of the left coronary artery, and an extensive infarction model continuously ligated at the root of the artery. We examined NHE1 mRNA expression using RNase protection assay and protein levels using Western blot analysis in non-infarcted myocardium during the 24 hour period after AMI. The level of NHE1 mRNA and protein expression in the whole heart including the infarcted myocardium did not change after a small infarction. On the other hand, in the case of an extensive infarction, the levels of NHE1 mRNA and protein expression decreased significantly by 21.5% (P<0.05) and by 22.0% (P<0.05), respectively, in non-infarcted myocardium. Left ventricular systolic pressure (LVSP) decreased significantly by 13% and 38% with the branch and root ligation, respectively. However, left ventricular end-diastolic pressure (LVEDP) only increased with the root ligation. These results indicate that NHE1 expression decreased in response to extensive myocardial infarction only in non-infarcted myocardium. The present study may be important in furthering the understanding of NHE1 in myocardial infarction and suggests that decreased expression of NHE1 in non-infarcted myocardium may decrease the extent of cardiac cell injury.     

Potentiation of the anti-ischemic effect of cardioplegic solutions by phosphorylated metabolites

An experimental study in 307 isolated rat hearts was concerned with variations in myocardial resting tension, resting membrane potential, ATP levels and myocardial heat production in conditions of cardioplegic heart arrest by an ion-balanced cardioplegic solution with and without phosphorylated metabolites (ATP, phosphocreatine, inosine-F, glucose-6-phosphate) and dephosphorylated metabolites (glucose, inosine, and inorganic phosphates). Phosphorylated metabolites, incorporated in the solution, had a marked protective effect due to the activation of substrate regulation mechanisms at different stages of ATP synthesis and facilitation of cardiomyocyte adaptation to ischemic, hypothermic and cardioplegic exposure.     

Myocardial protection during ischemia in the isolated perfused rabbit heart

Although many studies of the protective effects of cardioplegic solutions using hypothermia have been conducted, it is also necessary to examine their protective effects under normothermia as regional increases in myocardial temperature during hypothermic arrest are often reported. For this purpose myocardial protection was investigated in the isolated perfused rabbit heart exposed to 60 minutes of normothermic global ischemia during which Krebs-Henseleit, blood with heparin, Tyers', and St. Thomas' Hospital solutions were infused at 0.2 mL/min. Percent functional recovery dP/dtmax (mm hg/sec) at 5 minutes relative to pre-ischemic values using Tyers' (12 +/- 5)% was significantly less (p less than 0.05) than recovery using Krebs-Henseleit (57 +/- 13)% and St. Thomas' Hospital solution (47 +/- 5)%. Recovery using blood (79 +/- 7)% was significantly better than all other solutions. Following 25 minutes reperfusion, 4/6 hearts perfused with Tyers' experienced left ventricular fibrillation, while recovery of developed pressure with Krebs-Henseleit (74 +/- 5.8)%, St. Thomas' Hospital (66 +/- 3.4)% and blood (98 +/- 2.9)% was again significantly improved relative to Tyers', (p less than 0.05). Time to develop 5 mm contracture during the ischemic period was significantly shorter using Tyers' than with the other solutions. Using these indices of function, whereas Tyers' solution provided poor protection, blood provided excellent protection in rabbit hearts under normothermic conditions.     

Effects of beta-blockers and Ca2+ -antagonists on the response of the isolated working rat heart to adrenergic stimulants after cardioplegic arrest

Summary During coronary artery bypass graft (CABG) surgery, patients pretreated with the combination of beta-blocking drugs and Ca²⁺ antagonists for control of myocardial ischemia often respond inadequately to adrenergic stimulants administered after cardioplegic arrest. In this study, the effects of the combination of a beta-blocker (propranolol) and a Ca²⁺ antagonist (nifedipine) on the spontaneous recovery, as well as the adrenergic response of the isolated, perfused, working rat heart after a period of cardioplegic arrest were evaluated. After pretreatment of the animals with propranolol and/or nifedipine, hearts were removed, perfused in the presence of pretreatment drugs, subjected to 45 minutes of normothermic cardioplegic arrest, reperfused, and finally stimulated with exponentially increasing concentrations of a sympathomimetic drug. Propranolol, and to a lesser extent nifedipine, protected the hearts during cardioplegic arrest, as indicated by the improved recovery and maximum response to adrenergic stimulation after cardioplegia. Isoprenaline, a beta-stimulant, (at a 100 × higher than conventional concentration), elicited an adequate inotropic and chronotropic response. Stimulation by the alpha, beta-stimulant adrenaline or dobutamine improved only the inotropic response of propranolol and combination treated hearts. Cautious extrapolation of the results to human may suggest continuation of drug therapy of patients before CABG surgery.     

Protection of hearts from reperfusion injury by propofol is associated with inhibition of the mitochondrial permeability transition

OBJECTIVE: Diminishing oxidative stress may protect the heart against ischaemia-reperfusion injury by preventing opening of the mitochondrial permeability transition (MPT) pore. The general anaesthetic agent propofol, a free radical scavenger, has been investigated for its effect on the MPT and its cardioprotective action following global and cardioplegic ischaemic arrest. METHOD: Isolated perfused Wistar rat hearts were subjected to either warm global ischaemia (Langendorff) or cold St. Thomas' cardioplegia (working heart mode) in the presence or absence of propofol. MPT pore opening was determined using [3H]-2-deoxyglucose-6-phosphate ([3H]-DOG-6P) entrapment. The respiratory function of isolated mitochondria was also determined for evidence of oxidative stress. RESULTS: Propofol (2 micrograms/ml) significantly improved the functional recovery of Langendorff hearts on reperfusion (left ventricular developed pressure from 28.4 +/- 6.2 to 53.3 +/- 7.3 mmHg and left ventricular end diastolic pressure from 52.9 +/- 4.3 to 37.5 +/- 3.9 mmHg). Recovery was also improved in propofol (4 micrograms/ml) treated working hearts following cold cardioplegic arrest. External cardiac work on reperfusion improved from 0.42 +/- 0.05 to 0.60 +/- 0.03 J/s, representing 45-64% of baseline values, when compared to controls (P < 0.05). Propofol inhibited MPT pore opening during reperfusion, [3H]-DOG-6P entrapment being 16.7 vs. 22.5 ratio units in controls (P < 0.05). Mitochondria isolated from non-ischaemic, propofol-treated hearts exhibited increased respiratory chain activity and were less sensitive to calcium-induced MPT pore opening. CONCLUSION: Propofol confers significant protection against global normothermic ischaemia and during cold cardioplegic arrest. This effect is associated with less opening of mitochondrial MPT pores, probably as a result of diminished oxidative stress. Propofol may be a useful adjunct to cardioplegic solutions in heart surgery.