Ischemic Cardiac Arrest Research Articles

Protective effects of amiodarone pretreatment on mitochondrial function and high energy phosphates in ischaemic rat heart

The effects of the antianginal and antiarrhythmic drug amiodarone on mitochondrial function and high-energy phosphate content were assessed during normothermic ischaemic cardiac arrest and reperfusion in Langendorff-perfused rat heart. Total ischaemia for 30 min at 37 degrees C produced highly significant changes in mitochondrial oxidative phosphorylation and high-energy phosphate content. Pretreatment of the rats with one single dose of amiodarone (20 mg/kg i.v., 30 min before killing) markedly attenuated the deleterious effect of ischaemia on mitochondrial function and slightly reduced ATP depletion. In normally perfused hearts, amiodarone pretreatment did not modify any parameter of mitochondrial respiratory function nor did it influence high-energy phosphate or glycogen content. After reperfusion for 15 min, amiodarone-treated hearts showed improved recovery of mitochondrial oxidative phosphorylation and tissue high-energy phosphate content as compared to control hearts. Pretreatment of hearts with amiodarone did not reduce ischaemia-induced leakage of total adenylic nucleotides but highly significantly reduced lactate dehydrogenase release during reperfusion. These results indicate that amiodarone could exert substantial protection on the infarcting myocardium.

Preliminary Evaluation of Cocarboxylase on Myocardial Protection of the Rat Heart

The presence of cocarboxylase (CC) is essential for the oxidation of pyruvate to acetylcoenzyme A (acetyl-CoA) and its subsequent degradation by means of the Krebs cycle. We compared the effects of various concentrations of CC in a cardioplegic solution on the survival and hemodynamic and metabolic recovery of 23 isolated, working rat hearts subjected to 60 minutes of hypothermic (23°C) ischemic arrest. Group 1 (N = 6) consisted of hearts infused with the basic cardioplegic solution (Tyers' solution with glucose), to which no CC was added. In group 2 (N = 6) CC was added at 0.1 ml/L to the cardioplegic solution. In group 3 (N = 5) CC was added at 1 ml/L, and in group 4 (N = 6) CC was added at 10 ml/L. The cardioplegic infusions were performed at a pressure of 40 mm Hg for 2 minutes just before arrest; 30 minutes later they were performed again for 1 minute. Only two hearts (33.3%) recovered in group 1 whereas five recovered in group 2, five (100%) in group 3, and five (83.3%) in group 4. The recovery of hemodynamic performance as a percentage of pre-ischemic control values showed marked improvement in the CC groups, especially group 3, when compared with group 1. The metabolic variables in the CC groups were also markedly improved, with significantly ( p < .05) decreased levels of tissue lactate and increased levels of creatine phosphate compared with those in group 1. Tissue glycogen content was also significantly increased in groups 2 and 3, whereas accumulation of glucose 6-phosphatase was unchanged. These results suggest that CC improves the hemodynamic and metabolic variables in rat hearts subjected to ischemic cardiac arrest and may be an effective additive to a cardioplegic solution.

Preservation of high energy phosphates during ischaemic cardiac arrest with glucose.

The possible myocardial protection by glucose-insulin-potassium infusion prior to cardioplegic ischaemic arrest was studied in rats. One group of animals was given intravenous infusions of high concentrations of glucose during 3 days. A control group received the same amount of saline. The isolated hearts were subjected to Langendorff perfusion followed by cardioplegic arrest at 15 degrees C for a period of 2 or 3.5 hours. The hearts were then subjected to reperfusion for a period of 45 min for those sustaining 2 hours of ischaemia and 60 min for those sustaining 3.5 hours of ischaemia. In the hearts that suffered 2 hours of ischaemia there were no differences in myocardial content of high energy phosphate compounds between the pretreated and controls, and there was no evidence of creatine kinase release. In the hearts exposed to 3.5 hours ischaemia, myocardial content of high energy phosphates was significantly higher in the pretreated than in the controls. The release of creatine kinase was also less, but this difference was not significant. The study indicates that preoperative treatment with glucose-insulin-potassium may improve myocardial tolerance to ischaemia.

Glucose-insulin interactions during cardiopulmonary bypass: Hypothermia versus normothermia

Since hypothermia is commonly used to lower local and general metabolism during cardiopulmonary bypass, we attempted to identify its specific effects on glucose-insulin interactions. A group of nondiabetic patients undergoing hypothermic (28 degrees C) cardiopulmonary bypass with ischemic (cold) cardiac arrest was compared to a similar group operated on under normothermic conditions with potassium cardioplegia. In the absence of exogenous dextrose administration, hypothermia blocked insulin secretion for the duration of the operation. It also inhibited insulin secretion in response to an exogenous dextrose load (e.g., the priming fluid of the cardiopulmonary bypass circuit) or a glucagon injection, but this inhibition was lifted by rewarming. Blood glucose levels, which during normothermia were mildly elevated even in the absence of dextrose administration, remained normal during the hypothermic phase of cardiopulmonary bypass. By the end of the rewarming period, however, blood glucose levels had reached the same level as observed under normothermic bypass, a fact suggesting that the cold inhibition of hepatic glucose production had been only temporary. Cold inhibition of hepatic glucose production also explains why glucose clearance after a sudden dextrose load was initially faster at low body temperature than at normal temperature. Glucose-clamp studies indicated that insulin resistance was initiated by anesthesia and surgical trauma, and further accentuated by cardiopulmonary bypass, in association with elevated levels of hormones indicative of surgical stress. Regardless of body temperature changes, the assimilation of glucose by nondiabetic subjects during and immediately after bypass called for the infusion of large doses of insulin. A comparison with diabetic subjects showed that insulin-dependent patients (type I diabetes) required no more insulin during cardiopulmonary bypass than normal subjects, whereas patients with type II diabetes exhibited a marked insulin resistance during the operation and in the immediate postoperative period.

Normothermic ischemic cardiac arrest and reperfusion of the isolated working rat heart: Effect of carbocromene pretreatment on functional and metabolic recovery

Normothermic Ischemic Cardiac Arrest and Reperfusion of the Isolated Working Rat Heart: Effect of Carbocromene Pretreatment on Functional and Metabolic Recovery. This paper describes the effect of carbocromene pretreatment on the functional recovery of the isolated rat heart submitted to ischemic cardiac arrest and reperfused. In a previous study we showed that hearts isolated from rats which had been pretreated for 8 days with a daily oral administration of carbocromene at 15 mg/kg body weight, exhibit higher mechanical performances (aortic output, coronary flow, cardiac work) than hearts isolated from untreated animals. This was associated with a greater tissue content of high energy phosphates and glycogen. In the present work, carbocromene-pretreated hearts are submitted to 30 minutes of normothermic no-flow ischemia after being arrested by a 2 min high potassium, substrate-free perfusion, containing 2 mg/l carbocromene (cardioplegic solution). After reperfusion, post-ischemic recovery of function is significantly better in treated hearts as compared to control untreated preparations submitted to a similar protocol. Although no significant difference can be demonstrated in the metabolic status of either groups of preparations after 30 min of reperfusion, lactate dehydrogenase release, taken as an index of myocardial cell damage, is significantly reduced in the carbocromene-treated group. In view of these results it is suggested that carbocromene pretreatment and/or the addition of carbocromene to cardioplegic solutions could be beneficial in improving functional recovery after temporary ischemic cardiac arrest.

Effects of verapamil on cardiac function, Ca ++ binding and uptake, and Ca ++ ATPase during ischemic cardiac arrest using cardiopulmonary bypass

Effects of verapamil on cardiac function, Ca ++ binding and uptake, and Ca ++ ATPase during ischemic cardiac arrest using cardiopulmonary bypass

Diltiazem on cardiac function, Ca ++-binding and uptake and Ca ++atpase during ischemiccardiac arrest using cardiopulmonary bypass

Diltiazem on cardiac function, Ca ++-binding and uptake and Ca ++atpase during ischemiccardiac arrest using cardiopulmonary bypass

Does Perioperative Myocardial Ischemia Lead to Postoperative Myocardial Infarction?

To determine if a relationship exists between perioperative myocardial ischemia (ST segment depression greater than or equal to 0.1 mV) and postoperative myocardial infarction (PMI), nonparticipating observers recorded all ECG, hemodynamic, and other events between arrival of patients in the operating room and onset of cardiopulmonary bypass during 1,023 elective coronary artery bypass operations (CABG). The roles of preoperative patient characteristics, quality of the operation limited by disease as rated by the surgeon and duration of ischemic cardiac arrest as risk factors for PMI also were quantified. ECG ischemia occurred in 36.9% of all patients, with almost half the episodes occurring before induction of anesthesia. PMI was almost three times as frequent in patients with ischemia (6.9% vs. 2.5%) and was independent of when ischemia occurred. Ischemia was related significantly to tachycardia but not hypertension nor hypotension and was frequent in the absence of any hemodynamic abnormalities. The anesthesiologist whose patients had the highest rate of tachycardia and ischemia had the highest rate of PMI. Although neither single nor multiple preoperative patient characteristics related to PMI, suboptimal quality of operation and prolonged ischemic cardiac arrest increased the likelihood of PMI independent of the occurrence of myocardial ischemia. The authors conclude that perioperative myocardial ischemia is common in patients undergoing CABG, occurs randomly as well as in response to hemodynamic abnormalities, and is one of three independent risk factors the authors identified as related to PMI. PMI is unrelated to preoperative patient characteristics such as ejection fraction and left main coronary artery disease, and its frequency will relate primarily to perioperative management rather than patient selection.

Normothermic ischaemic cardiac arrest of the isolated perfused rat heart: effects of trifluoperazine and lysolecithin on mechanical and metabolic recovery.

To evaluate the hypothesis that maintenance of the integrity of myocardial membrane systems and prevention of Ca2+ influx into the cell are significant in the survival of ischaemic tissue, the effect of trifluoperazine and lysolecithin, were tested on the recovery of globally ischaemic rat hearts. Trifluoperazine increases membrane stabilization, inhibits calmodulin and binds to other Ca2+-dependent proteins. Lysolecithin, on the other hand, has a detergent action on myocardial cell membranes and facilitates Ca2+ ingress in ischaemic tissue. With trifluoperazine (2.45 microM), added before induction of ischaemia or during reperfusion only, hearts subjected to 40 min normothermic ischaemic cardiac arrest recovered mechanically. Untreated hearts failed after 20 min of ischaemia. The drug had no effect on tissue high energy phosphate levels or mitochondrial oxidative phosphorylation. Conversely, lysolecithin (2.5-10 microM) caused all hearts to fail after being subjected to 15 min ischaemia. Mechanical failure during reperfusion of such hearts was associated with a significant reduction in tissue ATP and CrP levels. Trifluoperazine counteracted the harmful effects of lysolecithin to a limited extent.

Solutions for preservation of the heart at 0° C

Solutions developed for cardioplegia and myocardial protection during elective ischemic cardiac arrest have also been used for the storage of heart grafts at 0° C. In this study we show that a solution based upon the principles established in renal preservation experiments gives superior preservation of rabbit hearts at 0° C. The solution contained K+ 25 mmol/L, Mg++ 10 mmol/L, sufficient glucose to prevent fluid uptake during storage (30 mmol/L), and a low concentration of calcium (0.1 mmol/L). The complete omission of calcium was detrimental to function after prolonged storage.

Does perioperative myocardial ischemia lead to postoperative myocardial infarction?

To determine if a relationship exists between perioperative myocardial ischemia (ST segment depression greater than or equal to 0.1 mV) and postoperative myocardial infarction (PMI), nonparticipating observers recorded all ECG, hemodynamic, and other events between arrival of patients in the operating room and onset of cardiopulmonary bypass during 1,023 elective coronary artery bypass operations (CABG). The roles of preoperative patient characteristics, quality of the operation limited by disease as rated by the surgeon and duration of ischemic cardiac arrest as risk factors for PMI also were quantified. ECG ischemia occurred in 36.9% of all patients, with almost half the episodes occurring before induction of anesthesia. PMI was almost three times as frequent in patients with ischemia (6.9% vs. 2.5%) and was independent of when ischemia occurred. Ischemia was related significantly to tachycardia but not hypertension nor hypotension and was frequent in the absence of any hemodynamic abnormalities. The anesthesiologist whose patients had the highest rate of tachycardia and ischemia had the highest rate of PMI. Although neither single nor multiple preoperative patient characteristics related to PMI, suboptimal quality of operation and prolonged ischemic cardiac arrest increased the likelihood of PMI independent of the occurrence of myocardial ischemia. The authors conclude that perioperative myocardial ischemia is common in patients undergoing CABG, occurs randomly as well as in response to hemodynamic abnormalities, and is one of three independent risk factors the authors identified as related to PMI. PMI is unrelated to preoperative patient characteristics such as ejection fraction and left main coronary artery disease, and its frequency will relate primarily to perioperative management rather than patient selection.

Superoxide radical formation by nuclear membranes of human brain tumors

The protective effects of cardioplegic solutions (CS) containing creatine phosphate (CP) were studied in a rat heart model of cardiopulmonary bypass and ischemic cardiac arrest. Isolated rat hearts were subjected to a 3-minute coronary infusion with CS containing CP in normothermic (37 degrees C) and hypothermic (4-6 degrees C) regimes. In the normothermia group, the postischemic functional recovery was 70-75% of the preischemic control value, while the cellular ATP and CP content was reduced but insignificantly. By contrast, in the hypothermia group, the postischemic functional recovery was markedly depressed, with the tissue high-energy phosphate content being appreciably lowered. The data obtained confirm high efficacy of CP-containing cardioplegic solutions administered under normothermia conditions.

Effects of Coenzyme Q 10 Added to a Potassium Cardioplegic Solution for Myocardial Protection during Ischemic Cardiac Arrest

To evaluate effects of coenzyme Q 10 added to a potassium cardioplegic solution for myocardial protection, 17 mongrel dogs underwent 60 minutes of ischemic cardiac arrest under cardiopulmonary bypass. Cardiac arrest was induced by infusing the cardioplegic solution into the aortic root every 20 minutes. Experimental animals were divided into three groups according to the cardioplegic solution used. In Group 1, we used our clinical potassium cardioplegic solution (K +, 22.31 mEq/L); in Group 2, potassium cardioplegic solution with coenzyme Q 10 added (coenzyme Q 10, 30 mg/500 ml of solution); and in Group 3, cardioplegic solution with coenzyme Q 10 solvent. Exogenous coenzyme Q 10 in the cardioplegic solution provided significantly high myocardial stores of adenosine triphosphate and creatine phosphate and a low level of lactate during induced ischemia and reperfusion. Furthermore, percent recovery of the aortic flow in Group 2 was significantly higher than that in the other two groups. Ultrastructures of the ischemic myocardium in Group 2 were better preserved than those in Group 1. Addition of coenzyme Q 10 to potassium cardioplegia resulted in improved myocardial oxygen utilization and accelerated recovery of myocardial energy metabolism after reestablishment of circulation.

The role of paramedics in resuscitation of patients with prehospital cardiac arrest from coronary artery disease

Columbus, Ohio added prehospital coronary care to its Emergency Medical Services System (EMS) in 1969. The EMS System, which is citizen activated and tax supported ($5 per citizen per year), currently sees 32,000 patients a year in a city with a population of 650,000. Ninety-six per cent of the population is aware of the system. Over two thirds of patients with ischemic sudden death or myocardial infarction are seen by advanced life support paramedic (EMT-P) units. The EMT-Ps operate by protocol without telemetry and carry all standard resuscitative drugs and devices. Serial evaluations have shown that within the limits of the protocol, the EMT-Ps perform as effectively as physicians in diagnosis and care of acute cardiovascular emergencies, including endotracheal intubation. One third of ischemic cardiac arrest patients in whom resuscitation is possible (60% of such patients seen) are discharged from the hospital alive ( 14.2 100,000 lives saved per year). Lives are also saved by treatment of other life-threatening prehospital complications. In Columbus, the estimated annual mortality from ischemic heart disease is only 19%. The EMS System contributes significantly to this low figure.

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.

Normothermic ischemic cardiac arrest of the isolated working rat heart. Effects of time and reperfusion on myocardial ultrastructure, mitochondrial oxidative function, and mechanical recovery.

The ischemic state of the myocardium of the isolated working rat heart after induction of normothermic ischemic cardiac arrest was assessed by the interrelationship among changes in myocardial ultrastructure, mitochondrial oxidative phosphorylation, and tissue high energy phosphate contents. At all time intervals (10-40 minutes) studied, the ultrastructural changes were more severe in the subendocardium than in the subepicardium. After 25-40 minutes of normothermic ischemic cardiac arrest, the mitochondrial oxygen uptake (state 3) became increasingly depressed, particularly in mitochondria isolated from the subendocardium. Mitochondrial oxidative function, as measured in vitro, did not correlate well with mitochondrial ultrastructural damage. In addition, the effects of coronary reperfusion on the ability of the ischemic heart to recover in terms of ultrastructure, mechanical, and metabolic function were evaluated. Hearts subjected to 10-40 minutes of normothermic ischemic cardiac arrest showed almost complete ultrastructural recovery of the subepicardium upon reperfusion; regression of ultrastructural changes occurred to a lesser extent in the subendocardium. Reperfusion for 30 minutes did not alleviate the depression in mitochondrial oxidative function, while tissue ATP levels did not return to control, preischemic levels. After 20 minutes of normothermic ischemic cardiac arrest, the mechanical performance of the working heart during reperfusion was significantly depressed, compared with pre-ischemic control values. Normal ultrastructure of the subendocardium always accompanied mechanical recovery, while improvement of mitochondrial oxidative function was not essential.

Normothermic ischaemic cardiac arrest and reperfusion of the isolated working heart: effect of chlorpromazine on functional, metabolic and morphological recovery.

The effects of chlorpromazine, an inhibitor of both Ca2+ flux and phospholipase activity, on myocardial ultrastructure, function and metabolism were assessed during normothermic ischaemic cardiac arrest and reperfusion of the isolated working rat heart. Normothermic ischaemic cardiac arrest produced significant changes in myocardial ultrastructure, high energy phosphate contents and mitochondrial oxidative phosphorylation within 20 min. Reperfusion of untreated hearts subjected to 20 and 25 min ischaemia failed to restore mitochondrial function, mechanical activity and ATP content to control, pre-ischaemic levels. Morphological signs of ischaemic injury regressed, especially in the subendocardial layer. Pretreatment of hearts with chlorpromazine did not prevent the ischaemia-induced changes in myocardial ultrastructure and mitochondrial function. However, during reperfusion the chlorpromazine-treated, totally ischaemic heats (20 to 25 min) exhibited improved coronary flow rates, and ultrastructural and mechanical recovery. The mitochondrial oxidative phosphorylation process and tissue high energy phosphate contents were not affected by the drug.

Cardioplegia and slow calcium-channel blockers: Studies with verapamil

The ability of dl-verapamil to enhance myocardial protection when given before, during, or after myocardial ischemia was assessed with the use of an isolated working rat heart model of cardiopulmonary bypass and ischemic cardiac arrest. Under conditions of normothermic ischemic arrest (30 minutes at 37 degrees C), the addition of verapamil enhanced the protective properties of the St. Thomas' Hospital cardioplegic solution. Optimal protection was observed with verapamil concentrations of 0.5 mg/L (1.09 mumol/L) of cardioplegic solution. Under these conditions, postischemic enzyme leakage was reduced by 32.2% and the postischemic recovery of aortic flow was improved by 18.7%. Despite the additional protection at normothermia, the drug at several concentrations appeared unable to improve functional recovery after an extended period of hypothermic arrest (150 minutes at 20 degrees C), although under these conditions its inclusion in the cardioplegic solution could substantially reduce enzyme leakage. In other studies, the ability of various doses of verapamil alone as a substitute for the cardioplegic solution was examined. At the optimal dose (again 0.5 mg/L), and under normothermic conditions, verapamil alone was a good protection against ischemic injury, although this protection did not match that afforded by the St. Thomas' Hospital cardioplegic solution. In similar studies under hypothermic conditions, the drug failed to afford tissue protection, perhaps indicating some common modality between hypothermia and verapamil-induced protection. Pretreatment with verapamil (0.1 mg/L) prior to ischemia offered moderate additional protection, but its use during reperfusion failed to enhance overall recovery.

Bioelectrical Tissue Resistance during Various Methods of Myocardial Preservation

Twenty-one mongrel dogs underwent cardiopulmonary bypass (CPB) and ischemic cardiac arrest for 60 minutes. The bioelectrical tissue impedance, water content, and ultrastructure of the myocardium were studied and correlated with various types of myocardial protection applied. The animals were divided into three groups according to the myocardial protection applied: Group 1, moderate general hypothermia; Group 2, moderate general and local hypothermia; Group 3, moderate general hypothermia and crystalloid cardioplegia. The hearts from 3 normal dogs served as controls. After 35 minutes of ischemic arrest, the difference in bioelectrical impedance of the myocardium of the left ventricle between Groups 1 and 2 was highly significant ( p < 0.001); in Groups 2 and 3, a significant difference was observed after 50 minutes. The heart water content in all three groups increased over that found in the hearts of the control animals, but there was no significant difference between Groups 2 and 3. There was evidence by ultramicroscopic study of ischemic damage to the myocardium in all of the experimental groups. Damage was less evident in Groups 2 and 3. We conclude that measurement of myocardial bioelectrical tissue resistance is a sensitive indicator of myocardial damage due to ischemia and may be useful clinically in determining the need for and type of cardiac resuscitation, particularly following CPB.

Correlation among water content, left ventricular function, coronary blood flow, and myocardial metabolism after hypothermic ischemic cardiac arrest.

Subendocardial ischemia is a common cause of death following ischemic cardiac arrest. We studied relationships among myocardial water content (WC), left ventricular function, coronary blood flow, and myocardial metabolism following ischemic cardiac arrest. Under cardiopulmonary bypass with hypothermia, 120 min of aortic occlusion was employed, and myocardial temperature was kept around 20 degrees C in 10 mongrel dogs. Left ventricular function (peak LVP, max dp/dt, LVEDP, LVSWI), coronary blood flow, myocardial enzymes (m-GOT, total CPK, MB-CPK), myocardial ATP and creatine phosphate (CP), and WC of the subendocardium of the left ventricle were measured. Data were obtained in the control state and immediately and 30 and 60 min after aortic unclamping. Significant negative correlations were obtained between WC and max dp/dt (r = -0.8384), coronary blood flow (r = -0.9928), ATP (r = -0.7038), and CP (r = -0.7835). Significant positive correlations were obtained between WC and LVEDP (r = 0.7525), m-GOT (r = 0.7638), and total CPK (r = 0.7079). These data suggest that myocardial edema results in depression of left ventricular function and metabolism.