Inadequate myocardial protection with cold cardioplegic arrest during repair of tetralogy of Fallot

Postoperative low cardiac output is the most common cause of death in patients undergoing elective repair of tetralogy of Fallot. The incidence is much higher than in elective adult bypass operations for coronary artery disease. To explain this difference, we investigated 16 children having elective repair of tetralogy (mean age 6.3 years). Myocardial biopsy specimens obtained during bypass before arrest, at the end of cold arrest by blood cardioplegia, and after 30 minutes of reperfusion were studied for adenosine triphosphate and lactate levels. Myocardium was submitted for microscopic study shortly after the onset of ischemia. The operation was successful in reducing right ventricular-pulmonary artery gradients from 82 +/- 28 to 9 +/- 1 mm Hg, yet seven patients required significant inotropic support (dopamine, greater than 5 micrograms/kg/min) for more than 24 hours and 12 patients needed prolonged use of digoxin and diuretics for right ventricular failure. Tissue levels of adenosine triphosphate and lactate in the tetralogy groups were compared with those in 20 adults with coronary artery disease having similar myocardial protection techniques. Adenosine triphosphate levels in the tetralogy group decreased during cross-clamping (41 +/- 8 minutes) from 24 +/- 3 to 16 +/- 2 mmol/kg dry weight (mean +/- 1 standard error), with a marked further drop after reperfusion to 9 +/- 2 mmol/kg (p less than 0.01). Adenosine triphosphate levels in the group with coronary disease also decreased from 20 +/- 1 to 16 +/- 1 mmol/kg after a longer cross-clamp time (70 +/- 17 minutes) but remained at 15 +/- 2 mmol/kg after reperfusion. Tissue lactate levels in the tetralogy group rose markedly during ischemia and remained elevated after reperfusion. In contrast, lactate levels in the group with coronary disease rose moderately during ischemia and returned to normal early on reperfusion. Microscopic study revealed focal myocyte necrosis in tetralogy of Fallot. Our findings, which demonstrate inadequate myocardial protection of patients with tetralogy during repair, with depression of adenosine triphosphate and increased lactate during ischemia and reperfusion, suggest a defect in oxidative metabolism. The drop in adenosine triphosphate after reperfusion in the patients with tetralogy implicates reperfusion injury as a mechanism of myocardial damage.     

Right ventricular sensitivity to metabolic injury during cardiopulmonary bypass

To determine intrinsic right ventricular susceptibility to metabolic injury, we examined the effect of ischemia and reperfusion during cardiopulmonary bypass on right and left ventricular myocardial adenine nucleotide metabolism in the absence of ventricular work load as a determinant of energy production and utilization. Dogs were subjected either to 30 minutes of normothermic or hypothermic myocardial ischemia and reperfusion or to 60 minutes of potassium-arrested normothermic ischemia; serial ventricular biopsy specimens were assayed for adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, nucleoside, and base content. In each group the depletion rates of right and left ventricular nucleotides with ischemia did not differ. Mitochondrial ability to rephosphorylate the nucleotide pool during and after ischemia also did not differ in the two ventricles, and there were no detectable differences in the catabolism of nucleotide precursors and loss of total purine content with reperfusion. These observations indicate that right ventricular myocardium is as equally sensitive to ischemic and reperfusion injury as left ventricular myocardium, and metabolic recovery from injury is equally prolonged.     

Effect of increasing volume of cardioplegic solution on postischemic myocardial recovery

Multidose cardioplegia has been reported to be superior to single-dose cardioplegia in protecting the heart during ischemia. However, large volumes of cardioplegic solution may be detrimental because of washout of adenine nucleotide degradation products that accumulate during ischemia, which limits recovery of adenosine triphosphate. We designed an experiment to test the effects of increasing the volume of cardioplegic solution on postischemic myocardial recovery. Four groups were studied: Group 1, initial 2 minute single dose of cardioplegic solution; Group 2, infusion of cardioplegic solution every 30 minutes for 1 minute; Group 3, infusion of cardioplegic solution every 20 minutes for 1 minute; and Group 4, infusion of cardioplegic solution every 20 minutes for 2 minutes. All groups were ischemic for 2 hours at 20 degrees C. Although washout of nucleotide degradation products during the ischemic interval increased with higher volumes of cardioplegic infusion, the total washout (infusion plus initial 5 minutes of reperfusion) was not different among all groups. The multidose groups recovered function better and had significantly higher levels of total tissue purines after 30 minutes of reperfusion. There was no difference in adenosine triphosphate levels among all groups after reperfusion. We conclude that increasing the volume of cardioplegic solution, within a clinically relevant range is not associated with increasing loss of adenine nucleotides from the cell or with impaired functional recovery of the heart.     

Optimal myocardial preservation with an acalcemic crystalloid cardioplegic solution

The effect of the calcium and oxygen contents of a hyperkalemic glucose-containing cardioplegic solution on myocardial preservation was examined in the isolated working rat heart. The cardioplegic solution was delivered at 4 degrees C every 15 minutes during 2 hours of arrest, maintaining a myocardial temperature of 8 degrees +/- 2 degrees C. Hearts were reperfused in the Langendorff mode for 15 minutes and then resumed the working mode for a further 30 minutes. Groups of hearts were given the oxygenated cardioplegic solution containing an ionized calcium concentration of 0, 0.25, 0.75, or 1.25 mmol/L or the same solution nitrogenated to reduce the oxygen content and containing 0 or 0.75 mmol ionized calcium per liter. The myocardial adenosine triphosphate concentrations at the end of arrest in these six groups of hearts were 15.6 +/- 1.2, 9.5 +/- 0.5, 8.2 +/- 1.1, 4.9 +/- 1.8, 10.1 +/- 2.0, and 1.6 +/- 0.4 nmol/mg dry weight, respectively. At 5 minutes of working reperfusion, the percentages of prearrest aortic flow were 80 +/- 2, 62 +/- 4, 33 +/- 6, 37 +/- 5, 48 +/- 7 and 46 +/- 8, respectively. The differences among the groups in adenosine triphosphate concentrations and in functional recovery diminished during reperfusion. In hearts given the hypoxic calcium-containing solution, there was a marked increase in coronary vascular resistance during the administration of successive doses of cardioplegic solution, which was rapidly reversible upon reperfusion. These data indicate that hearts given the acalcemic oxygenated solution had better adenosine triphosphate preservation during arrest and better functional recovery than hearts in any other group. Addition of calcium to the oxygenated cardioplegic solution decreased adenosine triphosphate preservation and functional recovery. Oxygenation of the acalcemic solution increased adenosine triphosphate preservation and functional recovery. The lowest adenosine triphosphate levels at end arrest were observed in hearts given the hypoxic calcium-containing solution. In the setting of hypothermia and multidose administration, the addition of calcium to a cardioplegic solution resulted in increased energy depletion during arrest and depressed recovery.     

The acute effects of AICAR on purine nucleotide metabolism and postischemic cardiac function

The purine precursor AICAR (5-amino-4-imidazolecarboxamide) has been advocated as a substrate for myocardial adenine nucleotide repletion during postischemic reperfusion. The purpose of this study was to investigate the acute effects of this agent on adenine nucleotides, inosine monophosphate, and postischemic ventricular function in an isolated rat heart preparation. The hearts were perfused at constant flow, either continuously for 90 minutes or for a 30 minute period followed by 10 minutes of global normothermic (37 degrees C) ischemia. The ischemic hearts were then reperfused for 15, 30, and 60 minutes. Both groups were treated with AICAR in a concentration of 100 mumol/L throughout the perfusion protocols. In the nonischemic time control group there was no effect on the levels of adenosine nucleotides or developed pressure over 90 minutes of perfusion. In contrast, AICAR treatment increased tissue inosine monophosphate content four-fold and sevenfold at 60 and 90 minutes, respectively (p less than 0.05), but had no effect on tissue adenosine monophosphate levels. During ischemia, there was a 50% decrease in adenosine triphosphate content in the AICAR-treated hearts and a thirteen-fold increase in adenosine monophosphate levels (p less than 0.05). After 60 minutes of reperfusion, adenosine triphosphate and monophosphate levels in the AICAR-treated hearts recovered to only 52% and 59% of preischemic values, respectively. These findings were similar to those observed in the untreated ischemic hearts. In contrast, tissue inosine monophosphate content in the AICAR-treated hearts during reperfusion remained significantly elevated and was fivefold greater than the reperfusion values in the untreated group. Concurrently, AICAR failed to enhance the recovery of postischemic left ventricular developed pressure. These results suggest that inhibition of the conversion of inosine monophosphate to adenosine monophosphate limits the usefulness of the agent in evaluating the temporal relationships between postischemic adenosine triphosphate repletion and recovery of myocardial function in the acute setting.     

Right and left ventricular metabolites

Current methods of cardioplegic delivery may delay the recovery of right ventricular metabolism and function. To evaluate right and left ventricular metabolism, we performed biopsies in 37 patients undergoing elective coronary bypass operation with aortic root blood cardioplegia. Right ventricular temperatures were warmer than left ventricular temperatures during cardioplegic arrest (right ventricle: 16.8 degrees +/- 3.8 degrees C, left ventricle: 14.3 degrees +/- 3.7 degrees C, p = 0.02). Adenosine triphosphate concentrations were lower in the right ventricle than in the left ventricle before cardioplegic arrest (right ventricle: 13.8 +/- 7.8 mmol/kg, left ventricle: 21.5 +/- 8.7 mmol/kg, p = 0.02). After reperfusion, right ventricular adenosine triphosphate concentrations fell to low levels (10 +/- 6 mmol/kg). Postoperative left and right ventricular high energy phosphate concentrations (the sum of adenosine triphosphate and creatine phosphate levels) correlated inversely with myocardial temperatures during cardioplegia (r = -0.29, p = 0.048). Aortic root cardioplegia did not cool the right ventricle as well as it did the left ventricle. The lower preoperative high energy phosphate concentrations may have increased the susceptibility of the right ventricle to ischemic injury. Alternative methods of myocardial preservation may improve right ventricular cooling and protection.     

Effect of aprotinin to improve myocardial viability in myocardial preservation followed by reperfusion.

Isolated canine hearts were preserved at 4 degrees C with multi-dose cardioplegic solution every hour for 6 hours. Reperfusion was observed for 2 hours under cross-circulation without cardiotonic drugs. The aprotinin group (n = 8), which received cardioplegic solution with added aprotinin (150 KIU/mL), was compared with the control group (n = 6). The increase in tissue adenosine triphosphate and total adenine nucleotide content during reperfusion was significant in the aprotinin group; there was no change in the control group, and the levels at the end of reperfusion tended to be higher in the aprotinin group than in the control group. Tissue adenosine diphosphate levels remained unchanged in both groups. Tissue adenosine monophosphate levels declined during reperfusion in both groups and were slightly lower in the control group. Tissue levels of cyclic adenosine monophosphate remained unchanged in the aprotinin group whereas they increased during ischemia and declined significantly during reperfusion in the control group. Tissue levels of cyclic guanosine monophosphate declined during reperfusion in both groups without difference. Creatine phosphate levels recovered in both groups without difference. Serum cyclic guanosine monophosphate concentration tended to be lower in the aprotinin group than in the control group. Serum creatine kinase-MB level increased slightly during reperfusion in both groups without difference. N-acetyl-beta-D-glucosaminidase levels were significantly suppressed during reperfusion in the aprotinin group as compared with the control group. These results suggest that aprotinin is effective in preserving adenine nucleotide and adenosine triphosphate levels and in stabilizing tissue cyclic adenosine monophosphate levels in prolonged hypothermic cardioplegic preservation followed by reperfusion.     

Metabolic intervention to affect myocardial recovery following ischemia.

Myocardial recovery during reperfusion following ischemia is critical to patient survival in a broad spectrum of clinical settings. Myocardial functional recovery following ischemia correlates well with recovery of myocardial adenosine triphosphate (ATP). Adenosine triphosphate recovery is uniformly incomplete during reperfusion following moderate ischemic injury and is therefore subject to manipulation by metabolic intervention. By definition ATP recovery is limited either by (1) energy availability and application in the phosphorylation of adenosine monophosphate (AMP) to ATP or (2) availability of AMP for this conversion. Experimental data suggest that substrate energy and the mechanisms required for its application in the creation of high energy phosphate bonds (AMP conversion to ATP) are more than adequate during reperfusion following moderate ischemic injury. Adenosine monophosphate availability, however, is inadequate following ischemia due to loss of diffusable adenine nucleotide purine metabolites. These purine precursors are necessary to fuel adenine nucleotide salvage pathways. Metabolic interventions that enhance AMP recovery rather than those that improve substrate energy availability during reperfusion are therefore recommended. The mechanisms of various metabolic interventions are discussed in this framework along with the rationale for or against their clinical application.     

Degradation of myocardial high-energy phosphates during twenty-four hours of cold storage. Effects of cardioplegic versus noncardioplegic arrest.

Purine nucleotide catabolism was examined during 24 hours of cold (0.5 degree C) storage of human transplant recipient hearts, baboon hearts, and dog hearts. The hearts were excised either after cold hyperkalemic cardioplegic arrest or after simple hypothermic arrest (25 degrees C). In human myocardium, hypothermia alone preserved the adenosine triphosphate pool markedly. Even after 24 hours of cold storage, adenosine triphosphate was still 9.5 +/- 2.5 mumol/gm dry weight (58% of the preischemic value). The major fraction of catabolites remained nucleotides: adenosine triphosphate plus adenosine diphosphate plus adenosine monophosphate decreased only from 99% +/- 1% (preischemic value) to 80% +/- 13% of the total purine content. The remaining catabolites were mainly nucleosides (adenosine 0.2% +/- 0.1% and inosine 19% +/- 13% of the total purine content). Cardioplegic arrest before cold storage did not change the pattern of purine nucleotide catabolism in any respect (p greater than 0.05). In baboon myocardium, hypothermia alone preserved the adenosine triphosphate content somewhat less than in human myocardium. Adenosine triphosphate content after 24 hours was 5.2 +/- 1.6 mumol/gm dry weight (40% of the preischemic value). The catabolism of adenosine triphosphate, however, did not proceed far beyond the level of adenosine monophosphate, so that the sum of nucleotides remained the same as in human hearts. Adenosine was 0.2% +/- 0.3% and inosine 17% +/- 4% of the total sum of purines. Also in the baboon heart, cardioplegia did not influence the pattern of catabolism significantly (p greater than 0.05). In the dog myocardium, hypothermia alone did not protect against severe catabolism of adenosine triphosphate. The adenosine triphosphate content at 24 hours of storage was 3.5 +/- 2.5 mumol/g dry weight (25% of the preischemic value). Catabolism of adenosine triphosphate proceeded far beyond the level of the nucleotides (63% +/- 17% of the total sum of purines), resulting in an accumulation of adenosine and inosine (5% +/- 4% and 30% +/- 13% of the total sum of purines) and even of hypoxanthine (1% +/- 1% of the total sum of purines). In the dog heart cardioplegic arrest inhibited adenosine triphosphate catabolism considerably. Adenosine triphosphate content at 24 hours was 8.1 +/- 1.8 mumol/gm dry weight (56% of the preischemic value); 83% +/- 5% of the total purine content remained present as nucleotides, and the nucleoside content was reduced to 2% +/- 3% for adenosine and 11% +/- 6% for inosine.(ABSTRACT TRUNCATED AT 400 WORDS)     

Mechanisms of myocardial protection by adenosine-supplemented cardioplegic solution: myofilament and metabolic responses

OBJECTIVE: Adenosine supplementation of cardioplegic solutions in cardiac operations improves postarrest myocardial recovery after cardioplegic arrest and reperfusion; however, the mechanism of the action of adenosine remains unknown. We tested the hypotheses that adenosine-supplemented cardioplegic solution improves myofibrillar protein cooperative interaction and increases myocardial anaerobic glycolysis. METHODS: The hearts of male Sprague-Dawley rats were randomized to undergo 120 minutes of cardioplegic arrest with 1 of 3 cardioplegic solutions: (1) St Thomas' Hospital No. 2 cardioplegic solution (St Thomas group), (2) St Thomas' Hospital No. 2 cardioplegic solution plus adenosine (100 micromol/L) (adenosine group), and (3) St Thomas' Hospital No. 2 cardioplegic solution plus adenosine (100 micromol/L) plus the nonspecific adenosine receptor antagonist 8-p -sulfophenyltheophylline (50 micromol/L) (sulfophenyltheophylline group). A fourth group of hearts underwent no cardioplegic arrest. RESULTS: Systolic and diastolic functional recovery was improved in the adenosine group compared with that in the other two groups, independent of coronary flow. Adenosine supplementation of cardioplegic solution prevented the decrease in myofibrillar protein cooperative interaction seen after cardioplegic arrest and reperfusion (St Thomas and sulfophenyltheophylline groups). Adenosine-supplemented cardioplegic solution also caused significantly increased anaerobic glycolysis during cardioplegic arrest. These responses were blocked in the sulfophenyltheophylline group. CONCLUSIONS: The changes in myocardial glycolytic activity and myofilament cooperativity coincided with functional recovery in the three cardioplegia groups and may represent mechanisms underlying protection with adenosine-supplemented cardioplegic solution.     

Enhanced myocardial protection during global ischemia with 5'-nucleotidase inhibitors.

Depletion of adenosine triphosphate precursors, such as myocardial adenosine, during global ischemia results in poor postischemic adenosine triphosphate repletion and functional recovery. Neonatal hearts may be more resistant to this deleterious effect of ischemia, because they are characterized by low 5'-nucleotidase activity, which may result in higher sustained endogenous myocardial adenosine triphosphate precursor levels during ischemia. Adult hearts, however, have high levels of 5'-nucleotidase activity leading to depleted precursors during ischemia and poor postischemic functional recovery. Augmenting myocardial adenosine exogenously during ischemia in adult hearts has a beneficial effect on recovery. The present study tested if preservation of nucleotide precursors, better adenosine triphosphate repletion, and enhanced postischemic myocardial recovery in adult hearts could be achieved with a "neonatal" strategy. Therefore 5'-nucleotidase inhibitors were administered to isolated, perfused adult rabbit hearts subjected to 120 minutes of ischemia (at 34 degrees C) to determine if this improved functional recovery. Hearts received St. Thomas' Hospital cardioplegic solution (control hearts) or cardioplegic solution containing 5'-nucleotidase inhibitors: pentoxifylline, thioinosine, [s-(p-nitrophenyl)-4-thioinosine], or thioinosine's dimethyl sulfoxide vehicle alone. After ischemia and reperfusion, recovery of systolic function, diastolic function, and myocardial oxygen consumption was significantly better with 5'-nucleotidase inhibition. No changes in coronary flow were noted. We speculate and are pursuing the theory that the mechanism of 5'-nucleotidase inhibition's favorable action is due to preventing the catabolism, transport, and loss of nucleotide precursors during ischemia, maintaining adenosine triphosphate precursor availability.     

Augmenting intracellular adenosine improves myocardial recovery

The objective of this study was to determine if augmentation of myocardial adenosine levels during global ischemia improves functional recovery after reperfusion. Isolated adult rabbit hearts were subjected to 120 minutes of mildly hypothermic ischemia (34 degrees C) with modified St. Thomas' Hospital cardioplegic solution used to provide myocardial protection. Myocardial adenosine levels were augmented during ischemia by providing exogenous adenosine in the cardioplegic solution or by inhibiting adenosine degradation with 2-deoxycoformycin, a noncompetitive inhibitor of adenosine deaminase. Four groups of hearts were studied: (1) control (n = 23)--cardioplegia alone; (2) adenosine group (n = 10)--adenosine 200 mumol/L added to the cardioplegic solution; (3) 2-deoxycoformycin group (n = 8)--2-deoxycoformycin 1 mumol/L added to the cardioplegic solution; and (4) a combined adenosine/deoxycoformycin group (n = 10). Recovery of developed pressure 45 minutes after reperfusion in the control group averaged only 38% +/- 4% of baseline values. Significantly better recovery was evident in the adenosine (66% +/- 7%), deoxycoformycin (59% +/- 2%), and adenosine/deoxycoformycin (75% +/- 2%) groups. The slope of the relationship between end-diastolic pressure and volume was used as an index of diastolic stiffness. The slope averaged 85 +/- 2 mm Hg/ml in the control group 45 minutes after reperfusion, significantly higher than that in the adenosine (31 +/- 6), deoxycoformycin (75 +/- 5), and adenosine/deoxycoformycin (58 +/- 5) groups; this suggests better diastolic function in the adenosine-augmented groups. During ischemia, adenosine levels were significantly elevated in the adenosine-augmented groups, whereas adenosine triphosphate decreased equally in all four groups, which indicates that augmenting myocardial adenosine had no effect on depletion of adenosine triphosphate during ischemia. After reperfusion, adenosine triphosphate levels were depressed in the control group but increased in the other groups above baseline values, which suggests that improvement in functional recovery was due to accelerated repletion of adenine nucleotide stores in the adenosine-augmented groups.     

Oxygen requirements of the isolated rat heart during hypothermic cardioplegia. Effect of oxygenation on metabolic and functional recovery after five hours of arrest

Previous studies from this laboratory demonstrated that the use of an oxygenated cardioplegic solution in the hypothermic arrested rat heart resulted in improved preservation of high-energy phosphate stores (adenosine triphosphate and creatine phosphate), mechanical recovery during reperfusion, and preservation of myocardial ultrastructure. In the current study the effect of cardioplegic solutions oxygenated with 30%, 60%, and 95% oxygen was evaluated in the isolated rat heart with reference to the maintenance of adenosine triphosphate, creatine phosphate, oxygen consumption, functional recovery, and mitochondrial oxidative phosphorylation in vitro. Results indicate that the hearts receiving cardioplegic solutions supplemented with 95% oxygen and 5% carbon dioxide maintained adenosine triphosphate and creatine phosphate at control values for at least 5 hours. The oxygen consumption during elective cardiac arrest, mechanical performance during reperfusion, and in vitro mitochondrial oxygen uptake and phosphorylation rate were highest in the hearts receiving cardioplegic solutions supplemented with 95% oxygen when compared to solutions with 30% and 60% oxygen. Addition of glucose and insulin to the cardioplegic solution (95% oxygen) increased the adenosine triphosphate levels but failed to improve function after reperfusion. Although myocardial adenosine triphosphate and creatine phosphate were well preserved by the oxygenated cardioplegic solution, there was a discrepancy between the adenosine triphosphate levels at the end of the arrest period, which represents the potential for mechanical function, and the actual function of the hearts after 5 hours.     

The time course of myocardial high-energy phosphate degradation during potassium cardioplegic arrest

Myocardial high-energy phosphate and glucose-6-phosphate levels were determined in the in vivo pig heart model during ischemic arrest and reperfusion to determine the effectiveness of potassium cardioplegia in myocardial protection. Thirty-five pigs were divided into six experimental groups consisting of 2-hour normothermic arrest, 2-hour hypothemic arrest, 2-hour normothermic cardioplegic arrest, and 1-, 2-, and 3-hour hypothermic cardioplegic arrest. Myocardial biopsies from the left ventricle were obtained prior to arrest, every 30 minutes during the arrest interval, and at 30 and 60 minutes of reperfusion. The measurement of adenosine triphosphate and creatine phosphate showed that (1) cardioplegic arrest requires hypothermia to preserve high-energy phosphate levels in myocardial tissue; (2) hypothermia, while not completely protective alone, is more effective than potassium cardioplegia alone in providing myocardial preservation during 2-hour ischemic arrest; (3) the combination of potassium cardioplegia and hypothermia is additive in providing an effective means of maintaining myocardial high-energy phosphate stores during 1, 2, and 3 hours of ischemic arrest; (4) myocardial reperfusion does not allow a return to preischemic adenosine triphosphate (ATP) levels after 2 hours of arrest, except following hypothermic cardioplegia; and (5) extension of the duration of ischemic arrest to 3 hours using hypothermic cardioplegia prevents recovery of high-energy phosphate stores to preischemic levels during reperfusion. Optimal preservation can be achieved during 2 hours of ischemic arrest by using hypothermic potassium cardioplegia. The effects of myocardial reperfusion, however, prevent full ATP and creatine phosphate (CP) recovery following 3 hours of arrest. No other technique studied was as effective in providing myocardial preservation.     

Enhanced myocardial preservation by nicotinic acid, an antilipolytic compound. Improved cardiac performance after hypothermic cardioplegic arrest

The effect of nicotinic acid, an antilipolytic drug, on myocardial preservation was studied on the basis of cardiac performance after 2 hours of cardioplegic arrest. Isolated in situ pig hearts were subjected to 120 minutes of hypothermic potassium (35 mEq) crystalloid cardioplegic arrest followed by 60 minutes of reperfusion. The experimental group received nicotinic acid 0.08 mmol/L 15 minutes before cardioplegic arrest, whereas the control group received 15 minutes of unmodified perfusion. There was a marked decline in myocardial creatine phosphate levels during cardioplegic arrest in both groups that returned to the baseline level during reperfusion without a significant intergroup difference, and adenosine triphosphate levels remained stable throughout the experiment in both groups. Myocardial oxygen consumption during reperfusion was significantly higher in hearts treated with nicotinic acid, which was consistent with a significantly greater cardiac contractile force as evaluated by isovolumetric left ventricular pressure measurements. There appeared to be less cardiac membrane damage as measured by creatine kinase release during reperfusion, which was significantly inhibited by treatment with nicotinic acid. The present study supports the conclusion that nicotinic acid improves cardiac performance after hypothermic cardioplegic arrest.     

Myocardial protection during prolonged aortic cross-clamping. Comparison of blood and crystalloid cardioplegia

We compared the ability of blood and crystalloid cardioplegia to protect the myocardium during prolonged arrest. Twelve dogs underwent 180 minutes of continuous arrest. Group I (six dogs) received 750 ml of blood cardioplegic solution (potassium chloride 30 mEq/L) initially and every 30 minutes. Group II (six dogs) received an identical amount of crystalloid cardioplegic solution (potassium chloride 30 mEq, methylprednisolone 1 gm, and 50% dextrose in water 16 ml/L of electrolyte solution). Temperature was 10 degrees C and pH 8.0 in both groups. Studies of myocardial biochemistry, physiology, and ultrastructure were completed before arrest and 30 minutes after normothermic reperfusion. Biopsy specimens for determination of adenosine triphosphate were obtained before, during, and after the arrest interval. Regional myocardial blood flow, total coronary blood flow, and myocardial oxygen consumption were statistically unchanged in Group I (p greater than 0.05). Total coronary blood flow rose 196% +/- 49% in Group II (p less than 0.005), and left ventricular endocardial/epicardial flow ratio fell significantly in this group from 1.51 +/- 0.18 to 0.8 +/- 0.09, p less than 0.01 (mean +/- standard error of the mean. The rise in myocardial oxygen consumption was not significant in this group (34% +/- 36%, p greater than 0.05). Ventricular function and compliance were statistically unchanged in both groups. In Group II, adenosine triphosphate fell 18% +/- 3.4% (p less than 0.005) after 30 minutes of reperfusion; it was unchanged in Group I. Ultrastructural appearance in both groups correlated with these changes. We conclude that blood cardioplegia offers several distinct advantages over crystalloid cardioplegia during prolonged arrest.     

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

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

Metabolic enhancement of myocardial preservation during cardioplegic arrest

An experimental study was undertaken to evaluate the relative efficacy of oxygenated versus unoxygenated cardioplegic solutions and to determine if the addition of certain metabolically active substrates to cardioplegic solutions had any effect on myocardial preservation. Sixty-one pigs were divided into seven groups of animals (5 to 15 animals per group). The impact of different cardioplegic vehicles, i.e., crystalloid versus the oxygen-carrying vehicles, blood and Fluosol-DA, on preservation of high-energy phosphates (adenosine triphosphate and creatine phosphate) was examined in the first three animal groups. The influence of Krebs cycle intermediates, i.e., glutamate, malate, succinate and fumarate, on adenosine triphosphate and creatine phosphate preservation was evaluated in the other four animal groups. All hearts underwent 120 minutes of hypothermic cardioplegic arrest at 15 degrees C followed by 60 minutes of normothermic reperfusion. Higher adenosine triphosphate and creatine phosphate levels were maintained during arrest when oxygenated solutions were used as the cardioplegic vehicle and when any of the four intermediates were added to the crystalloid cardioplegic solution, especially succinate and fumarate. During reperfusion, however, adenosine triphosphate levels were uniformly lower than control whereas creatine phosphate levels rose to either control levels or higher in all groups. No significant intergroup difference could be identified during reperfusion. These findings lead to the conclusion that the presence of either oxygen or certain Krebs cycle intermediates enhances the protective effect of hyperkalemic hypothermic cardioplegia on high-energy phosphates during the arrest period only. This enhancement is not maintained during the reperfusion period.     

A Comparison of Intermittent and Continuous Arrest for Prolonged Hypothermic Cardioplegia

A study was carried out to evaluate the best method of myocardial preservation in the pig-heart model. Two techniques for employing hypothermic potassium cardioplegia during prolonged ischemic arrest were compared. One entailed three one-hour periods of arrest interrupted with 30-minute intervals of reperfusion (intermittent arrest), and the other involved a single period of continuous hypothermic cardioplegic arrest (continuous arrest) of three hours' duration. In order to evaluate intermittent versus continuous cardioplegic arrest, prearrest and postarrest contractility, compliance, myocardial perfusion, and left ventricular adenosine triphosphate (ATP) and creatine phosphate (CP) levels were compared in 28 animals.The results show significant deterioration in myocardial contractility and compliance following three-hour cardioplegic arrest whether the arrest was intermittent or continuous. However, there were significant differences between the two groups studied. The animal having continuous arrest had less functional impairment than the animal having intermittent arrest. Myocardial perfusion 30 minutes following continuous arrest returned to prearrest levels whereas there was significant depression in perfusion in the group with intermittent arrest. This represented severe coronary vasoconstriction. The ATP level after completion of arrest is significantly higher in the group having continuous arrest and remains higher throughout the final reperfusion period.On the basis of these studies, it is thought that intermittent reperfusion may lead to a reperfusion injury, which is primarily reflected in decreased perfusion, contractility, and compliance. While hypothermic potassium cardioplegia does not optimally protect the myocardium during prolonged (three hour) ischemic arrest, the alternative of intermittent arrest provides poorer myocardial preservation.     

The effect of ischemia/reperfusion on adenine nucleotide metabolism and xanthine oxidase production in skeletal muscle

Prolonged ischemia to skeletal muscle as occurs after an acute arterial occlusion results in alterations in adenine nucleotide metabolism. Adenosine triphosphate continues to be used for cellular functions, and an ischemia-induced degradation of phosphorylated adenine nucleotides is initiated. In this experiment we demonstrated the time-dependent aspect of adenine nucleotide depletion during ischemia and the production of large quantities of soluble precursors. In addition, we studied the rate of conversion of xanthine dehydrogenase to xanthine oxidase, a potential source of oxygen-free radicals, after controlled periods of total normothermic ischemia (4 hours and 5 hours) and during the reperfusion phase. During ischemia complete depletion of creatine phosphate occurred in both groups, and adenosine triphosphate fell from 22.1 +/- 1.3 to 10.3 +/- 1.4 mumol/gm dry weight after 4 hours and from 21.6 +/- 0.7 to 3.9 +/- 0.8 mumol/gm dry weight after 5 hours (p less than 0.05). During reperfusion, creatine phosphokinase resynthesis occurred in both groups, but adenosine triphosphate levels were not significantly increased (p greater than 0.05). A washout of lipid soluble products of adenine nucleotide metabolism occurred equally in both groups. The relationship between phosphorylated adenine nucleotides as measured by the energy charge potential fell significantly in both groups (p less than 0.05), but after the shorter period of ischemia (4 hours it returned to normal during early reperfusion but did not after 5 hours of ischemia. There was 21% +/- 4% necrosis after 4 hours and 51% +/- 8% after 5 hours of ischemic stress when assessed at 48 hours. In conclusion, the degree of adenine nucleotide degeneration as determined primarily by the length of the ischemic period, may be the most important determinant of the ultimate extent of skeletal muscle ischemic necrosis that results from an acute interruption of circulation.