Intramyocardial electrical and metabolic activity during hypothermia and potassium cardioplegia

Hypothermic potassium cardioplegia is widely used to reduce myocardial metabolism as a means of myocardial protection. To investigate the efficacy of intramyocardial electrical activity as an indicator of myocardial metabolism, 12 dogs were placed on cardiopulmonary bypass and myocardial oxygen consumption, partial pressure of carbon dioxide (PCO2) in the coronary sinus, myocardial temperature, and intramyocardial and surface electrocardiograms were measured. The hearts were fibrillated and cooled to 15 degrees C. In Group 1 (6 dogs), potassium cardioplegia was given at 15 degrees C. In Group 2 (6 dogs), it was given at 25 degrees C. Maximum coronary sinus PCO2 and oxygen consumption occurred at 36 degrees C and gradually decreased, but there was still evidence of metabolic activity and intramyocardial electrical activity at 15 degrees C. When cardioplegia was given at 15 degrees C, all electrical activity ceased and there was a further significant reduction in metabolic activity (coronary sinus PCO2 and oxygen consumption). In Group 2 similar findings were found at 25 degrees C, and there was no further reduction in metabolic activity at 15 degrees C. These data indicate that: (1) myocardial metabolic activity is lowest when there is electrical quiescence as measured with an intramyocardial electrode; (2) potassium arrest and hypothermia are both necessary to achieve electrical quiescence; and (3) in the potassium-arrested heart, lowering temperature from 25 degrees to 15 degrees C does not result in a further reduction of metabolic activity.     

Advantages of potassium cardioplegia and perfusion hypothermia in left ventricular hypertrophy.

An attempt was made to determine the effect of hypothermic potassium cardioplegia (35 mEq of potassium chloride) on the hypertrophic ventricle. Puppies with induced left ventricular hypertrophy were divided into four groups and studied after one hour on global ischemia. Myocardial adenosine triphosphate (ATP) was best preserved in the hypothermically perfused groups and correlated well with measurements of coronary sinus creatine phosphokinase (CPK). In Groups 1 and 2 (anoxic arrest at 37 degrees C and KC1 perfusion at 37 degrees C), CPK at 30 minutes of reperfusion was 1,031 and 198 IU, respectively, compared to 35 IU in Group 3 (KC1 perfusion at 4 degrees C) and 44 IU in Group 4 (Ringer's lactate at 4 degrees C). Myocardial injury was milder in Groups 3 and 4 regardless of whether potassium chloride was added. It is apparent that hypothermic perfusion of a hypertrophic ventricle was the major factor in myocardial preservation, as determined by myocardial ATP and coronary sinus CPK.     

Cold-blood potassium cardioplegia: evaluation of glutathione and postischemic cardioplegia

Potassium (34 mEq/L) cardioplegia was induced with cold blood (CBK) in three groups of six dogs undergoing 60 minutes of myocardial ischemia at a systemic temperature of 27 degrees +/- 2 degrees and a myocardial temperature of 7 degrees +/- 2 degrees C (crushed ice). Group 1 (CBK) animals were reperfused initially with 400 ml cold blood over 8 to 10 minutes at increasing pressures of up to 75 mm Hg. Group II (CBK-K) dogs were reperfused in the same manner as Group I with the addition of potassium chloride, 30 mEq/L. In Group III (CBKG-KG) glutathione, 30 mg/100 ml, was added to both the pre- and postischemic perfusions with CBK. After 30 minutes of reperfusion control studies were repeated. Heart rate, peak systolic pressure, rate of rise of left ventricular pressure, maximum velocity of contractile element, pressure-volume curves, coronary flow distribution, muscle stiffness, and heart water were not significantly different from control values. Total coronary flow and myocardial uptake of oxygen, lactate, and pyruvate did not serve to separate the three groups; the same was true for right ventricular creatine phosphate, adenosine triphosphate, and adenosine diphosphate during ischemia and recovery. Ultrastructural myofibrillar lesions were noted in all groups. thus, postischemic cardioplegia and use of a physiological reducing agent do not enhance CBK cardioplegia with topical and systemic hypothermia.     

Interactions between pharmacological cardioplegia and hypothermia for intraoperative myocardial protection

Cold cardioplegia is currently the method of choice for providing myocardial protection during open-heart surgical procedures. Two components of protection, perfusion cooling and pharmacological cardiac arrest, were investigated in the guinea pig heart-lung model. The effects of two cardioplegic solutions, the University of Alabama Hospital solution and the St. Thomas' Hospital solution, and a control perfusate were compared. The results confirmed the efficacy of hypothermia as a protective agent and the additional protection afforded by pharmacological cardioplegia. Infusion temperature critically influenced the cardioprotective action of the Alabama solution: Striking protection was afforded only under hypothermic conditions, whereas myocardial damage was exacerbated by the infusion at 37 degrees C. The St. Thomas' Hospital solution provided substantial protection independent of infusion temperature. Thus, the safety margin of the Alabama solution was narrower than that of the St. Thomas' solution. It is suggested that the difference between the two cardioplegic solutions partially depends on their coronary vasoactivity, since the administration of the Alabama solution at 37 degrees C increased coronary perfusion pressure. It would seem worthwhile to use a temperature-independent cardioplegic solution devoid of coronary vasoconstricting action.     

Improved myocardial protection with nifedipine and potassium-based cardioplegia

Thirty dogs were studied acutely on cardiopulmonary bypass in four groups. Hearts in Groups 1C (standard cardioplegia, n = 5) and 2c (n = 10) were subjected to periods of global ischemia of 1 and 2 hours, respectively. Both groups received 300 cc boluses of hypothermic (4 degrees C), potassium-based cardioplegic solution infused via an 18 gauge needle proximal to the aortic cross-clamp, at every 30 minute interval of ischemia. Groups 1CN (standard cardioplegia plus nifedipine, n = 5) and 2CN (n = 10) were treated similarly, except that nifedipine (5 microgram/kg) was added to each 300 cc bolus of cardioplegic solution. The addition of nifedipine in Groups 1CN and 2CN resulted in statistically significant reduction in myocardial water content (p less than 0.005), mean left atrial pressure (MLAP) (p less than 0.05), and myocardial compliance (p less than 0.005) as compared to the control groups (1C and 2C). Recovery of left ventricular dp/dt in Experimental Group 2CN was also statistically better (p less than 0.025) than in Control Group 2C. Examination of myocardial biopsy tissue by electron microscopy was not conclusive. Nifedipine used in combination with hypothermic, potassium-based cardioplegia provided significant additional myocardial protection over cardioplegia alone.     

Metabolic effect of glucose, insulin and potassium cardioplegia

Glucose-insulin-potassium (GIK) solution is widely used as a cardioplegic infusate for myocardial protection during aortic cross-clamping, to obtain rapid diastolic arrest and preservation of energy stores. Nine male patients with aorto-coronary bypass grafting procedure were studied with regard to the metabolic influence of GIK cardioplegia. Hyperglycemia was induced by the infusion of GIK solution for one week after surgery. The serum level of non-esterified fatty acid was high for one week while the triglyceride level was maintained at a high level only in the early post-operative period. Insulin, glucagon and growth hormone which influence carbohydrate and lipid metabolism were also elevated for one week after infusion of GIK solution. We conclude that the derangement of carbohydrate and lipid metabolism which is provoked by the use of GIK cardioplegia normalizes within two weeks after operation.     

Verapamil potassium cardioplegia and cardiac conduction

This clinical study analyzes the effect of potassium cardioplegic solution containing verapamil hydrochloride (1 mg/L) on cardiac conduction after release of the aortic cross-clamp and throughout recovery. Fifty consecutive patients undergoing open-heart operation were studied as a unit for postoperative conduction abnormalities. They were also analyzed in groups based on spontaneous ventricular conversion to regular rhythm (54%) and the need for single DC cardioversion (32%), or multiple DC cardioversions (14%). Results showed that spontaneous ventricular conversion had no relationship to aortic cross-clamp time and that DC cardioversion using 10 Ws had no detrimental effects on the myocardium or incidence of conduction abnormalities. The need for transient intraoperative pacing was lowest with spontaneous ventricular conversion, but not statistically different from single or multiple DC cardioversions. Only 3 patients (6%) required pacing in the intensive care unit. The incidence of postoperative atrial and ventricular arrhythmias was similar in all groups, and no deaths or episodes of malignant ventricular arrhythmias occurred. This study concludes that verapamil potassium cardioplegia is associated with excellent myocardial protection and a high incidence of transient intraoperative dysfunction of the atrioventricular node (70%) but a low incidence of postoperative pacing. Benign postoperative arrhythmias occur, but at hospital discharge, few conduction abnormalities (10%) persist.     

Coronary artery bypass graft surgery: clinical comparison of cold blood potassium cardioplegia, warm cardioplegic induction, and secondary cardioplegia

An analysis of myocardial protection was performed in 45 low-risk patients undergoing coronary bypass procedures who were divided into three equal groups with similar preoperative ejection fractions and coronary artery obstructions. Group 1 (N = 15) received cold blood cardioplegia, Group 2 received cold blood cardioplegia and secondary cardioplegia, and Group 3 received cold blood cardioplegia plus warm cardioplegic induction. The aortic cross-clamp time and the number of bypass grafts were similar among the groups. The following variables were measured serially: electrocardiographic changes, serum myocardial-specific isoenzyme of creatine kinase, cardiac output, left ventricular filling pressure, ejection fraction, and left ventricular wall motion. The three methods evaluated were all effective in protecting the myocardium during global myocardial ischemia. Patients who received secondary cardioplegia (Group 2) were more likely to exhibit spontaneous defibrillation (12/15) than those in Group 1 (5/15) or Group 3 (6/15) (p less than 0.05). However, measurements of left ventricular performance and evidence of perioperative myocardial infarction were similar among all three groups. These data suggest that a standard technique of cold potassium cardioplegia alone should be the method of choice in elective, low-risk coronary bypass operations rather than this technique in combination with either of the other two more costly and complex methods evaluated in this study.     

Cold potassium cardioplegia versus topical hypothermia and intermittent aortic occlusion for myocardial protection during coronary artery surgery: a randomized clinical study

The effect of two different myocardial preservation techniques on perioperative myocardial necrosis during coronary artery bypass surgery was assessed by serial myocardial creatine kinase determinations in 100 consecutive patients operated on by the same surgeon. Topical hypothermia with cold potassium cardioplegia was used randomly in 50 patients (group 1), and topical hypothermia with local interruption of the coronary circulation was used in the other 50 patients (group 2). Myocardial creatine kinase was measured by column chromatography every 6 hours for 36 hours after surgery. There was no significant difference between the two groups in terms of age, sex, functional class, extent of coronary artery disease, number of bypassed arteries, ejection fraction, or cardiopulmonary bypass time. Myocardial creatine kinase release (mean +/- standard error of the mean) was 193 +/- 33 IU/L X hours in group 1 patients operated on with cardioplegia and 210 +/- 31 IU/L X hours in group 2 patients operated on with topical hypothermia (p greater than 0.5). Myocardial creatine kinase peaks were 9.2 +/- 1.9 IU/L and 10.0 +/- 1.6 IU/L, respectively (p greater than 0.5). Perioperative myocardial infarction, as defined by serum enzyme activity and electrocardiographic criteria, occurred in 4 patients in group 1 and 3 patients in group 2. Thus, the addition of cardioplegia to topical hypothermia, although perhaps offering technical advantages, does not appear to improve myocardial protection over topical hypothermia with local interruption of the coronary circulation during coronary artery bypass surgery.     

Calcium channel blockers and prostate cancer

The relationship between calcium channel blockers and prostate cancer has been an area of increased interest to investigators. Calcium channel blockers have been shown to influence cell proliferation, differentiation, and apoptosis. Clinically, the association between calcium channel blockers and the development of prostate cancer has been controversial. However, on a basic science level, there is evidence that calcium channel blockers induce cytotoxicity in androgen receptor positive cell lines and may offer an innovative strategy for the treatment of castration-resistant prostate cancer.     

Adenosine as adjunct to potassium cardioplegia: effect on function, energy metabolism, and electrophysiology

Adenosine is known to induce rapid cardioplegic arrest and to improve postischemic recovery in the isolated rat heart. Long exposures to high doses of adenosine impair postischemic recovery, however. In this paper we tested the combination of low-dose adenosine (1 mmol/L) with potassium (26 mmol/L), with the aim of achieving rapid arrest (as with high-dose adenosine) but eliminating the need for postarrest washout of adenosine. Cardioplegic solutions studied were (1) Krebs-Henseleit potassium (26 mmol/L) (K); (2) K plus adenosine (1 mmol/L) (KA); (3) K plus an adenosine deaminase inhibitor [erythro-9-(2-hydroxy-3-nonyl)adenine] (0.1 mmol/L) (KE); and as control (4) Krebs-Henseleit potassium (6 mmol/L) (C). We induced cardiac arrest in Langendorff-perfused rat hearts by infusing the cardioplegic solution for 3 minutes at 3 ml/min. Total ischemia lasted 20 minutes at 37 degrees C, followed by reperfusion for 30 minutes. High potassium decreased the arrest time from 260 +/- 16 seconds (group C, mean values +/- standard error of the mean) to 22 +/- 4 seconds (group K). A further decrease to 10 +/- 2 seconds was observed with KA (p = 0.016 versus K). KE, which increased endogenous adenosine, gave intermediate effects. All hearts recovered during reperfusion; the product of developed tension and heart rate (grams per minute) was superior in KA hearts (6250 +/- 740 versus K hearts 4380 +/- 390; p = 0.050). KE gave an intermediate result (5290 +/- 900), while C showed the worst recovery (3180 +/- 830). Our electrophysiologic studies with sinus node and atrial tissue suggest that adenosine induced hyperpolarization and an increase in potassium permeability, thereby arresting the sinus node before depolarization of the membrane by potassium (26 mmol/L). We conclude that low-dose adenosine as an adjunct to potassium shortens the arrest time in this model and improves postischemic recovery.     

The interaction of the calcium channel blockers verapamil and nifedipine with cyclosporin A in pediatric renal transplant patients

The elimination of cyclosporin A was assessed in eight pediatric renal transplant patients who received calcium channel blockers concomitantly with their immunosuppressive therapy. In three children, verapamil decreased the rate of elimination of cyclosporin A. In five children who received nifedipine, cyclosporin A elimination was also impaired, which contrasts with the reports in adult patients indicating that this calcium channel blocker has no effect on cyclosporin A elimination. When both calcium channel blockers were used on separate occasions in the same patient, nifedipine was less potent than verapamil in depressing cyclosporin A elimination. Although the number of subjects studied is small, these results likely indicate that nifedipine, as well as other calcium channel blocking drugs, must be used with caution in pediatric renal transplant patients.     

Influences of cardiopulmonary bypass, temperature, cardioplegia, and topical hypothermia on cardiac innervation.

The effects of normothermic and hypothermic cardiopulmonary bypass, crossclamping of the aortic root, cold cardioplegia, as well as epicardial application of iced slush, on the efficacy of the efferent sympathetic nervous system to augment the heart and the efferent parasympathetic nervous system to depress the heart were studied in anesthetized dogs. Cardiac rate and force are augmented by stimulation of the intrathoracic efferent sympathetic nervous system and reduced by stimulation of the intrathoracic efferent parasympathetic nervous system. After cardiopulmonary bypass, which included systemic and topical hypothermia, aortic crossclamping, and crystalloid cardioplegia, the augmentor effects of the efferent sympathetic nervous system were obtunded whereas the depressor effects exerted by the efferent parasympathetic nervous system were not. Direct cardiac myocyte augmentor responses induced by isoproterenol were unaffected by these interventions. Normothermic cardiopulmonary bypass, hypothermic cardiopulmonary bypass, crossclamping of the aorta, or cold cardioplegia did not result in blunting of the efferent sympathetic cardiac nervous system. Significant blunting of cardiac augmentation induced by the efferent sympathetic nervous system occurred after topical application of iced slush alone. These data demonstrate that blunting of the efferent sympathetic, but not parasympathetic, innervation of the heart occurs after cardiopulmonary bypass, which presumably is primarily due to altering the function of subepicardial efferent sympathetic axons by topical hypothermia and not due to altered cardiac myocyte function. These data imply that after cardiopulmonary bypass involving the procedures described, the ability of the efferent sympathetic nervous system to support cardiac rate and force is transiently impaired.