Acadesine (AICA-riboside) Improves Postischemic Cardiac Recovery Steven F. Bolling, MD, Mark A. Groh, MD, Ann M. Mattson, BA, Russell A. Grinage, and Kim P. Gallagher, PhD Thoracic Surgery Research Laboratory, Departments of Surgery (Thoracic Surgery)and Physiology, University of Michigan, Ann Arbor, Michigan
To test if acadesine (5-aminoimidazole-4-carboxamide riboside), a purine precursor, has cardioprotective effects, 16 dogs were placed on total cardiopulmonary bypass and subjected to global myocardial ischemia. Hemodynamic recovery was compared between a control (n = 8) group receiving standard cardioplegia and an acadesine (n = 8) group pretreated with intravenous acadesine (2.5 mg * kg-' * min-' for 5 minutes, then 0.5 mg * kg-' * min-') before ischemia, during ischemia, and until 10 minutes after removal of the aortic crossclamp. Additionally, in the acadesine group the cardioplegia also contained 20 pmolJL acadesine. While the dogs were on cardiopulmonary bypass, global warm myocardial ischemia was induced by aortic cross-clamping for 5 minutes under normothermic conditions to simulate an angioplasty accident. Five minutes after aortic crossclamping, hypothermic cardioplegia (30 mL/kg) was administered. The left anterior descending coronary artery was occluded before the first infusion of cardioplegia to simulate poor cardioplegia delivery that can occur during an emergency coronary artery bypass procedure after an angioplasty accident. The left anterior descending artery occlusion was released, and additional cardioplegia (15 mL/kg) infusions were made every 30 minutes there-
A
lthough cardioplegia-induced cardiac arrest and hypothermia provide considerable myocardial protection during ischemia, perioperative stunning, infarction, and poor postoperative ventricular function remain serious problems in cardiac surgery, especially in high-risk patients with poor preoperative ventricular function, recent myocardial infarction, or left ventricular hypertrophy. Based on reports that 5-aminoimidazole-4-carboxamide riboside or acadesine (formerly AICAr) provides myocardial protection during ischemia or augments ischemic tolerance [14], the goal of this study was to ascertain if acadesine could enhance cardiac recovery after a period of global myocardial ischemia. The specific objective was to determine if treatment with acadesine resulted Accepted lor publication Dec 17, 1991 Presented in part at the Twenty-fourth Annual Meeting of the Association of Academic Surgeons, Houston, TX, Nov 1619, 1990. Address reprint requests to Dr Bolling, Section of Thoracic Surgery, The University of Michigan Hospitals, 1500 E Medical Center Dr, 2120 Taubman Center, Box 0344, Ann Arbor, MI 48109.
0 1992 by The Society of Thoracic Surgeons
after during 120 minutes of cardioplegic ischemia. Thirty minutes after reperfusion, all animals in both groups were weaned from bypass and recovery data were obtained to compare with baseline preischemic values. There were no significant differences in heart rate, left atrial pressure, or systemic vascular resistance between groups after weaning from bypass. Peak developed pressure recovered to 79% f 19% (mean 2 standard deviation) of baseline in the acadesine group compared with 56% 2 22% in the control group ( p < 0.05). Additionally, recovery of mean arterial blood pressure (acadesine ver15% versus 45% 2 21%; p < 0.03), sus control: 71% positive first derivative of left ventricular pressure (71% 16% versus 35% 2 13%; p < 0.011, and cardiac output (109% 2 26% versus 53% f 39%; p < 0.01) were also significantly better with acadesine. Mixed venous oxygen saturation (preischemic baseline for both groups = 93%) was significantly lower in the control group (54% 2 19%) compared with the acadesine group (90% f 8%) after bypass, a difference in extraction suggesting that oxygen delivery was better when acadesine was used. We conclude that acadesine is a promising cardioprotective agent for use during global ischemia. (Ann Thorac Surg 1992;54:93-8)
*
in improved postischemic functional recovery compared with controls receiving no additional treatment in a rigorous and severely ischemic canine surgical model.
Material and Methods The study was conducted in 16 unconditioned (25 to 36 kg) mongrel dogs. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research. Anesthesia was induced with intravenous sodium pentobarbital (30 mg/kg). Additional sodium pentobarbital was administered as necessary to maintain anesthesia. Intravenous lactated Ringer's solution was infused and arterial blood gases were monitored to verify that the animals were adequately ventilated and that acid-base balance was satisfactory. A sternotomy was performed to expose the thoracic structures, and the pericardium was incised and cradled. Catheters were placed in the aorta through the femoral artery (to enable measurement of arterial blood pressure) and in the left atrium (to enable 0003-4975/92/$5.00
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BOLLING ET AL ACADESINE IMPROVES POSTBYPASS RECOVERY
measurement of the left atrial pressure). An Oximetrix Swan-Ganz catheter was passed through the jugular vein into the right side of the heart, and the tip of the catheter was positioned in the pulmonary artery. A cathetermounted micromanometer (Model PC350; Millar, Houston, TX) was positioned in the left ventricle through the left ventricular apex. The Millar micromanometer was used to obtain high-fidelity measurements of left ventricular pressure and its first derivative (dP/dt). The left anterior descending (LAD) coronary artery was dissected free and a ligature was passed around the LAD (to later produce temporary coronary occlusion) distal to the first major diagonal branch. This array of instrumentation enabled continuous monitoring of arterial blood pressure, left atrial pressure, left ventricular pressure, dP/dt, and heart rate. Injections of iced saline solution through the Swan-Ganz catheter were made in triplicate to measure cardiac output by the thermodilution technique during baseline conditions and after weaning from cardiopulmonary bypass. Mixed venous oxygen saturation of the pulmonary arterial blood was also measured continuously. After instrumentation was completed, the animals were heparinized (300 U/kg). A 16F arterial perfusion cannula (DLP, Grand Rapids, MI) was placed in the innominate artery, and a two-stage venous cannula (Sarns, Inc, Ann Arbor, MI) was inserted into the inferior vena cava through the right atrial appendage. After total cardiopulmonary bypass was initiated, a cardioplegia infusion cannula (DLP) was inserted into the ascending aorta for infusion of cardioplegia and for venting of the left ventricle. Thermistor probes were placed in the LAD (ischemic) and circumflex (nonischemic) territories to monitor intramyocardial temperatures (Yellow Springs Instrument Co, Yellow Springs, OH). Arterial and cardioplegic temperatures were monitored by in-line thermistors (Sarns, Inc). Systemic temperature was maintained at 37°C on cardiopulmonary bypass. The same experimental protocol was followed in both the control and acadesine groups (Fig 1). The agent was administered before, during, and after the ischemic episode to determine if there was any beneficial or detrimental effect of acadesine and not specifically to ascertain the optimal timing of its administration. Therefore, in the treated group acadesine was infused through the right atrial port of the Swan-Ganz catheter 30 minutes before, during, and until 10 minutes after the ischemic (aortic cross-clamp) period, and acadesine (20 pmoVL) was also delivered with the cardioplegia in the acadesine group. Based on previous experiments of canine regional ischemia [ 5 ] the loading dose of acadesine (2.5 mg kg-' min-') was infused for 5 minutes before the dogs were on cardiopulmonary bypass. Thereafter, while the dogs were on bypass (during the course of the experiment) and until 10 minutes after the aortic cross-clamp was removed, acadesine was infused at a rate of 0.5 mg * kg-' min-'. Saline solution, the vehicle for acadesine, was infused in similar volumes at similar times in the control group. Baseline measurements were obtained after instrumentation and bypass cannulations were completed. The LAD was then ligated and the aorta
-
-
Ann Thorac Surg 1992;54:9>8
-1
AlCAR OR SALINE INFUSION
BASELINE
37%
< 8
CARCNOPLEGIC INDUCED ISCHEMIA
d c 4 5 ' + w +
- 4
120'
REPERFUSION
-
30'
was cross-clamped for 5 minutes with the left ventricle vented. Cardioplegia (30 mL.lkg) was infused after this 5-minute normothermic global ischemia period. The LAD remained ligated during the first infusion of cardioplegia to stimulate the circumstances that could exist during an emergency coronary artery bypass procedure with poor delivery of cardioplegia to th.e ischemic area. The LAD ligature was removed after finishing the first infusion of cardioplegia and the LAD was open for the second and subsequent doses of cardioplegia, as if a successful coronary bypass graft had been constructed and cardioplegia could now be delivered to the ischemic zone. The main objective was to produce a model of severe myocardial ischemia as might be encountered in high-risk or emergency patients undergoing a coronary artery bypass procedure to rigorously test the potential efficacy of acadesine. The cardioplegia was infused at temperatures of 6" to 8°C and at a pressure of appr'oximately 100 mm Hg. The cardioplegia contained 24 mEq/L potassium chloride, 25 mEq/L sodium bicarbonate, and 5 g/L dextrose. A small amount of blood was added to the cardioplegia to obtain a hematocrit of 0.03. In the acadesine group, the cardioplegia also contained 20 btmol/L of acadesine. Additional infusions of cardioplegia (15 mg/kg) were administered at intervals of 30 minutes during ischemia. Myocardial temperatures in the LAD (ischemic) and circumflex (nonischemic) territories were recorded. At the end of the ischemic period, 50 mg of lidocaine was administered, the aortic cross-clamp was removed, and the heart was reperfused. Total ischemia time, global (5 minutes) and cardioplegic (120 minutes), was 125 minutes. Defibrillation was used as necessary when ven-
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Ann Thorac Surg 1992:54:9%8
tricular fibrillation occurred, and the number of defibrillations required was recorded. Over the next 30 minutes, the dogs were reperfused with the hearts empty and beating. After this 30-minute period the animals in both groups were all weaned at equal rates from cardiopulmonary bypass. Recovery data were obtained in both groups at the same time relative to ischemia and reperfusion and were obtained at spontaneous rhythm, when the dogs were completely off cardiopulmonary bypass. After recovery data were obtained the animals were humanely euthanized. Because of the intentionally severe ischemic insult produced in these experiments, it was not possible to precisely match cardiac volume and loading conditions after reperfusion with those observed during prebypass baseline conditions for each individual animal. Although this limits the comparison of preischemic and postischemic data, both groups of dogs underwent identical protocols and these conditions stimulate those observed in the operating room during emergency coronary artery bypass grafting after an angioplasty accident with reasonable accuracy. Data were statistically analyzed with paired t test and unpaired t tests as appropriate.
Results Data in absolute terms are summarized in Table 1. Percentage change or percentage recovery data are presented in Figures 2 through 4 and are used for convenience. Raw data analysis was identical in all conclusions and statistical validity. Results are presented as mean -+ standard deviation. There were no significant differences between the control group and acadesine for any measured parameter during baseline, preischemic conditions. Acid-base balance, cardioplegia delivery, myocardial temperatures in the LAD (ischemic) and circumflex (nonischemic) territories, and oxygenation were equally maintained in the control group versus the acadesine group during and after ischemia. After the aortic cross-clamp was removed, all 8 controls required defibrillation, the number of shocks varying from one to 12. In the acadesine group, only 4 of the 8 dogs required defibrillation and only one to three shocks were required. The difference in the number of dogs requiring defibrillation did not quite achieve statistical significance ( p = 0.077) by a two-sided Fisher's exact test. Heart rate was not significantly different after weaning the dogs from bypass in either group (see Table 1). No significant heart block was noted in either group. All dogs in both groups were successfully weaned from bypass, and recovery data were obtained in all animals. Longterm survival was not addressed in this acute experiment. Mean left atrial pressure increased significantly in both groups in the postischemic period, as compared with preischemic baseline values. The absolute increases were not significantly different between groups, averaging 6 t 5 (mean k standard deviation) mm Hg and 9 6 mm Hg in the acadesine and control groups, respectively. Although the left atrial pressure data during recovery were similar, we acknowledge that compliance may have been modified more in one group than the other, resulting in
*
Table 1. Hernodynamic Data Before and After Cardiopulmonary Bypass in the Control and Acadesine Groups" Variable Heart rate (beatsimin) Control Acadesine LAP (mm Hg) Control Acadesine MAP (mm Hg) Control Acadesine LVSP (mm Hg) Control Acadesine CO (L/min) Control Acadesine SVR (mm Hg . L- . min-') Control Acadesine MVO, Control Acadesine .
'
P
Before Bypass
After Bypass
134 2 17 145 t 24
116 t 19 133 t 14
0.04 NS
7 t 3 5 t 3
16 t 5 11 -+ 5
0.005 0.010
107 t 16 105 t 22
48 2 23 78 t 21'
0.0004 0.038
127 ? 17 130 2 23
72 t 29 101 2 15'
0.0009 0.023
Valueh
3.23 2 1.40 1.93 t 1.92 0.054 2.36 t 0.58 2.55 t 0.96 NS 41 ? 22 49 t 17 93% t 4% 93% 2 5 %
43 t 28 33 t 13
NS 0.059
54% ? 19% 0.003 90% t 8%d NS
.' Data are reported as mean
C standard deviation; n = 8 except for cardiac output, systemic vascular resistance, and mixed venous oxygen saturation (n = 7). Paired f tests were performed to compare prebypass and postbypass data. ' ' A Unpaired and paired t tests were performed comparing acadesine data against the control group data, both before and after bypass: ' p < 0.05, p < 0.001.
'
LAP = mean left atrial pressure; LVSP = left CO = cardiac output; ventricular systolic pressure; MAP = mean arterial blood pressure; NS = not significant; MVO, = mixed venous oxygen saturation; SVR = systemic vascular resistance.
differences in preload. Mean arterial blood pressure was significantly reduced to 45% 21% ( p < 0.001) of baseline 26% of in the control group, whereas it was 78% baseline ( p = 0.04) in the acadesine group. The magnitude of the reduction in arterial blood pressure was significantly greater in the control group, as compared with the acadesine group. The main objective of this study focused on systolic contractile performance, and the data indicated that with the use of acadesine left ventricular peak developed pressure was 79% 17% ( p = 0.03) of the baseline level. In contrast, peak developed pressure was reduced to 56% k 22% ( p < 0.001) of baseline in the control group, a level of postischemic recovery significantly lower than in the acadesine group (see Fig 2). A similar pattern was evident in terms of peak positive dP/dt, which was reduced to 35% f 13% of baseline in the control group but maintained at 71% ? 16% ( p < 0.001 compared with the control group) in the acadesine-treated dogs (see Fig 2). Absolute cardiac output was not significantly lower than prebypass baseline in the acadesine group after weaning from bypass ( p = not significant versus before bypass). In contrast, absolute cardiac output in the con-
*
*
*
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BOLLING ET AL ACADESINE IMPROVES POSTBYPASS RECOVERY
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1992;54:93-8
100
-80
75
-60
50
8
-40
0
25
C
A
-
LVSP
0
-20 C
(+I
0 dPldt
Fig 2 . Percentage recovery of left ventricular developed pressure (LVSP) and peak positive first derivative of left ventricular pressure (dP/dt) after 125 minutes of global ischemia and weaning from cardiopulmonary bypass. Data are expressed as percentages of baseline preischemic values. Individual data points and mean values (histograms) are shown for the control (C) and acadesine (A) groups. Both peak developed pressure and peak + dPldt were significantly higher in the acadesine animals after cardiopulmonary bypass. (*p < 0.05 versus controls.)
trols was reduced considerably after weaning ( p = 0.054 versus before bypass). Furthermore, when examining the percentage recovery of cardiac output after bypass (see Fig 3) it was noted that recovery of cardiac output after 26% in the acadesine group, bypass averaged 109% whereas recovery of cardiac output after bypass in the controls averaged only 52% & 39% ( p < 0.01). Systemic vascular resistance (calculated as the ratio of mean arterial blood pressure to cardiac output) averaged 73% 2 37% and 106% k 47% of baseline in the control and acadesine groups ( p = not significant), respectively, after
*
150
100
50
0
II
I, A
Fig 3. Percentage recovery of cardiac output. Data are presented as percentages of baseline values. lndividual data points and mean values (histograms) are shown for the control (C) and acadesine-treated (A) groups. (*p < 0.05 versus controls.)
0
+20
C
A
Fig 4. Change in mixed venous oxygen saturation after 125 minutes of ischemia and weaning from cardiopulmonary bypass. Individual data points and mean values (histograms) are shown for the control (C) and acadesine-treated (A) groups. The average change (38% ? 21%) in the control group was significantly greater than that in the acadesine group (3% 6 % ) , supporting the conclusion that use of acadesine resulted in more favorable oxygen delivery after weaning from cardiopulmonary bypass. (“p < 0.05 versus controls.)
*
weaning from bypass. Additionally, there were no significant differences between groups before or after the ischemic period. Mixed venous oxygen saturation, an index of the balance between oxygen Idemand and delivery, differed substantially between groups (see Fig 4). It was not significantly changed in the acadesine group after the ischemic period and weaning from cardiopulmonary bypass. In the control group, however, mixed venous oxygen saturation was reduced significantly ( p < 0.01) to 62% k 21% of baseline, reflecting decreased cardiac output in the controls and suggesting that considerably greater utilization of extraction reserve was necessary to meet the oxygen requirements of the systemic circulation in the control group compared with the acadesine group.
Comment The objective of this study was to conduct a preliminary test on the potential efficacy of acadesine in experimental conditions designed to approximate high risk or emergency coronary artery bypass operation. The canine hearts were exposed to prolonged global ischemia with or without the use of acadesine to provide a severe test of acadesine’s potential efficacy. Because this was a preliminary investigation, acadesine was administered before, during, and after ischemia, as well as in the cardioplegia to maximize our ability to detect an effect. The rationale of administering acadesine before ischemia was in effort to ”preload” myocardial cells with acadesine before exposure to ischemic conditions, as acadesine is thought to be stored as a nucleotide precursor [ 5 ] . Under these conditions, recovery of systolic coritractile performance measured in terms of peak developed left ventricular pres-
Ann Thorac Surg 1992;54:9&8
sure, peak positive dPldt, and cardiac output was significantly better in the acadesine group than controls, leading to the conclusion that acadesine provides myocardial protection or accelerates recovery after myocardial ischemia in the dog. The mechanism by which acadesine improved ventricular functional recovery is not known with certainty. Acadesine has been advocated for use as a substrate for myocardial adenine nucleotide repletion during postischemic reperfusion [1-61. Myocardial ischemia depletes the adenine nucleotide pool because adenosine triphosphate is consumed to maintain cellular integrity and adenosine diphosphate cannot be rephosphorylated. Rather, the remaining adenosine diphosphate is transformed to adenosine monophosphate, which is converted to nucleosides that can enter the interstitial space from the cells and be washed out during reperfusion. When substrates are unavailable for the nucleotide salvage pathway, the repletion of adenosine triphosphate is dependent on the slower de novo synthetic pathway. Acadesine is easily transported into myocardial cells, is readily phosphorylated, and can be metabolized rapidly to purine nucleotides [5]. Swain and associates [l]reported enhanced repletion of adenosine triphosphate and guanosine triphosphate pools with acadesine use in dogs 24 hours after the release of a short-term (12-minute) coronary artery occlusion in a regional model of ischemia. Subsequent studies have been contradictory as to whether acadesine significantly enhances adenosine triphosphate repletion [7, 81. Nonetheless, treatment with acadesine has resulted in improved functional recovery in many experimental settings. Mistos and co-workers [2] demonstrated better recovery of function in globally ischemic isolated cat hearts with acadesine, despite the fact that the total adenine nucleotide pool was reduced to the same degree in acadesine-treated hearts as in controls. In a more recent study, acadesine attenuated the detrimental effects of myocardial stunning in a canine model involving brief occlusions of the LAD [4]. In this study there was better preservation of regional function in the ischemic zone with acadesine as compared with untreated controls. The mechanism of the beneficial effect was attributed to augmentation of intramyocardial adenosine levels, consistent with the findings of Gruber and associates [ 3 ] . In contrast to these positive results, Mentzer and colleagues [9] reported that acadesine did not improve functional recovery. In this study the effects of acadesine were examined in isolated rat hearts perfused at a constant coronary flow for 30 minutes followed by 10 minutes of global normothermic (37°C)ischemia. Hearts were treated with acadesine (100 pmol/L) throughout preischemic perfusion and compared with untreated controls. Acadesine failed to enhance the recovery of postischemic left ventricular developed pressure, an effect that was attributed to acadesine-induced inhibition of the enzyme adenylosuccinate lyase. Other reports have also indicated that acadesine may not be beneficial in terms of functional recovery [lo]. Despite the disparate findings and conclusions reported in the literature, we observed that functional recovery was
BOLLING ET AL ACADESINE IMPROVES POSTBYPASS RECOVERY
97
improved in a model designed to approximate operative conditions with severe ischemia. In addition, the requirement for defibrillation after removing the aortic crossclamp tended to be reduced in the acadesine-treated group, potentially consistent with recent preliminary findings that acadesine suppresses arrhythmias induced by coronary artery occlusion and reperfusion in cats [ 111. Acadesine has many profound effects, including inhibiting neutrophil and platelet aggregation, depressing the conduction system, altering glycolysis, and changing vasomotor tone [2, 3, 7, 81. The exact mechanism for the beneficial action of acadesine will require additional investigation, but maintenance or enhancement of intramyocardial adenosine may play an important role in improving postischemic myocardial recovery [3, 12-14]. In addition, we speculate that the timing of acadesine administration may be crucial, as well. In our study, the myocardium was pretreated with acadesine before the onset of ischemia, whereas studies failing to show beneficial effects of acadesine were those in which acadesine was administered during the ischemic period alone, during reperfusion, or both. In conclusion, pretreatment with acadesine may represent a practical means of enhancing the ability of the myocardium to withstand ischemia in the operative setting. Administration of acadesine, perhaps during induction of anesthesia, could lead to enhanced ischemic tolerance. Regardless of the mechanism of acadesine's beneficial effect, it appears to be a promising cardioprotective agent and warrants additional investigation. Supported in part by grant HL32043 from the National Institutes of Health and a grant from Gensia Pharmaceuticals, Inc, San Diego, CA.
References 1. Swain JL, Hines JJ, Sabina RL, Holmes EW. Accelerated repletion of ATP and GTP pools in postischemic canine myocardium using a precursor of purine de novo synthesis. Circ Res 1982;51:102-5. 2. Mitsos SE, Jolly SR, Lucchesi BR. Protective effects of AICAriboside in the globally ischemic isolated cat heart. Pharmacology 1985;31:121-31. 3. Gruber HE, Hoffer ME, McAllister DR, et al. Increased adenosine concentration in blood from ischemic myocardium by AICA riboside. Effects on flow, granulocytes and injury. Circulation 1989;80:1400-11. 4. Hori M, Kitakaze M, Takashima S. AICA-riboside (5-amino4-imidazole careboxamide riboside 100). A novel adenosine potentiator attenuates myocardial stunning. Circulation 1990;82(Suppl3):466. 5. Young MA, Mullane KM. Progressive cardiac dysfunction with repeated pacing-induced ischemia: protection by AICAriboside. Am J Physiol (Heart Circ Physiol) (in press). 6. Sabina RL, Kernstine KH, Boyd RL, Holmes EW, Swain JL. Metabolism of 5-aminoimidazole-4-carboxamideriboside in cardiac and skeletal muscle. Effects on purine nucleotide synthesis. J Biol Chem 1982;257:1017-8. 7. Mauser M, Hoffmeister HM, Nienaber C, Schaper W. Influence of ribose, adenosine, and "AICAR' on the rate of myocardial adenosine triphosphate synthesis during reperfusion after coronary artery occlusion in the dog. Circ Res
1985;56:220-30.
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ACADESINE IMPROVES POSTBYPASS RECOVERY
8. Hoffmeister HM, Mauser M, Schaper W. Effect of adenosine and AICAR on ATP content and regional contractile function in reperfused canine myocardium. Bas Res Cardiol 1985;80: 445-58. 9. Mentzer RM Jr, Ely SW, Lasley RD, Berne RM. The acute effects of AICAR on purine nucleotide metabolism and postischemic cardiac function. J Thorac Cardiovasc Surg 1989;95:286-93. 10. Ambrosio G, Jacobus WE, Mitchell MC, Litt MR, Becker LC. Effects of ATP precursors on ATP and free ADP content and functional recovery of postischemic hearts. Am J Physiol (Heart Circ Physiol) 1989;256(Heart Circ Physiol):H560-6. 11. Molina-Viamonte V, Rosen MR. AICA-riboside suppresses
arrhythmias induced by coronary artery occlusion and reperfusion. Circulation 1990;82(Suppl 3):645. 12. Rosenkranz ER, Okamoto F, Buckberg GD, et al. Biochemical studies: failure of tissue adenosine triphosphate levels to predict recovery of contractile function after controlled reperfusion. J Thorac Cardiovasc Surg 1986;92:48%501. 13. Bolling SF, Bies LE, Bove EL, Gallagher KP. Augmenting intracellular adenosine improves myocardial recovery. J Thorac Cardiovasc Surg 1990;99:469-74. 14. Bolling SF, Bies LE, Gallagher KP, Bove EL. Enhanced myocardial protection with adenosine. Ann Thorac Surg 1989;47:809-15.
Notice From the Southern Thoracic Surgical Association The Thirty-ninth Annual Meeting of the Southern Thoracic Surgical Association will be held at the Saddlebrook Golf and Tennis Resort, Wesley Chapel (near Tampa), Florida, November 5-7, 1992. The Postgraduate Course will be held the morning of Thursday, November 5, 1992, and will provide in-depth coverage of thoracic surgical topics selected primarily as a means to enhance and b r o a d e n the knowledge of practicing thoracic a n d cardiac
surgeons.
Applications for membership should be completed by
August 1, 1992, a n d forwarded to John P. Clarke, MD, Membership Committee Chairman, Southern Thoracic Surgical Association, 401 N o r t h Michigan Avenue, Chicago, IL 60611-4267.
Hendrick B. Barner, M D Secretary-Treasurer Southern Thoracic Surgical Association 401 North Michigan Avenue Chicago, IL 6061 1-4267
To test if acadesine (5-aminoimidazole-4-carboxamide riboside), a purine precursor, has cardioprotective effects, 16 dogs were placed on total cardiopulmonary bypass and subjected to global myocardial ischemia. Hemodynamic recovery was compared between a control (n = 8) group receiving standard cardioplegia and an acadesine (n = 8) group pretreated with intravenous acadesine (2.5 mg * kg-' * min-' for 5 minutes, then 0.5 mg * kg-' * min-') before ischemia, during ischemia, and until 10 minutes after removal of the aortic crossclamp. Additionally, in the acadesine group the cardioplegia also contained 20 pmolJL acadesine. While the dogs were on cardiopulmonary bypass, global warm myocardial ischemia was induced by aortic cross-clamping for 5 minutes under normothermic conditions to simulate an angioplasty accident. Five minutes after aortic crossclamping, hypothermic cardioplegia (30 mL/kg) was administered. The left anterior descending coronary artery was occluded before the first infusion of cardioplegia to simulate poor cardioplegia delivery that can occur during an emergency coronary artery bypass procedure after an angioplasty accident. The left anterior descending artery occlusion was released, and additional cardioplegia (15 mL/kg) infusions were made every 30 minutes there-
A
lthough cardioplegia-induced cardiac arrest and hypothermia provide considerable myocardial protection during ischemia, perioperative stunning, infarction, and poor postoperative ventricular function remain serious problems in cardiac surgery, especially in high-risk patients with poor preoperative ventricular function, recent myocardial infarction, or left ventricular hypertrophy. Based on reports that 5-aminoimidazole-4-carboxamide riboside or acadesine (formerly AICAr) provides myocardial protection during ischemia or augments ischemic tolerance [14], the goal of this study was to ascertain if acadesine could enhance cardiac recovery after a period of global myocardial ischemia. The specific objective was to determine if treatment with acadesine resulted Accepted lor publication Dec 17, 1991 Presented in part at the Twenty-fourth Annual Meeting of the Association of Academic Surgeons, Houston, TX, Nov 1619, 1990. Address reprint requests to Dr Bolling, Section of Thoracic Surgery, The University of Michigan Hospitals, 1500 E Medical Center Dr, 2120 Taubman Center, Box 0344, Ann Arbor, MI 48109.
0 1992 by The Society of Thoracic Surgeons
after during 120 minutes of cardioplegic ischemia. Thirty minutes after reperfusion, all animals in both groups were weaned from bypass and recovery data were obtained to compare with baseline preischemic values. There were no significant differences in heart rate, left atrial pressure, or systemic vascular resistance between groups after weaning from bypass. Peak developed pressure recovered to 79% f 19% (mean 2 standard deviation) of baseline in the acadesine group compared with 56% 2 22% in the control group ( p < 0.05). Additionally, recovery of mean arterial blood pressure (acadesine ver15% versus 45% 2 21%; p < 0.03), sus control: 71% positive first derivative of left ventricular pressure (71% 16% versus 35% 2 13%; p < 0.011, and cardiac output (109% 2 26% versus 53% f 39%; p < 0.01) were also significantly better with acadesine. Mixed venous oxygen saturation (preischemic baseline for both groups = 93%) was significantly lower in the control group (54% 2 19%) compared with the acadesine group (90% f 8%) after bypass, a difference in extraction suggesting that oxygen delivery was better when acadesine was used. We conclude that acadesine is a promising cardioprotective agent for use during global ischemia. (Ann Thorac Surg 1992;54:93-8)
*
in improved postischemic functional recovery compared with controls receiving no additional treatment in a rigorous and severely ischemic canine surgical model.
Material and Methods The study was conducted in 16 unconditioned (25 to 36 kg) mongrel dogs. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research. Anesthesia was induced with intravenous sodium pentobarbital (30 mg/kg). Additional sodium pentobarbital was administered as necessary to maintain anesthesia. Intravenous lactated Ringer's solution was infused and arterial blood gases were monitored to verify that the animals were adequately ventilated and that acid-base balance was satisfactory. A sternotomy was performed to expose the thoracic structures, and the pericardium was incised and cradled. Catheters were placed in the aorta through the femoral artery (to enable measurement of arterial blood pressure) and in the left atrium (to enable 0003-4975/92/$5.00
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measurement of the left atrial pressure). An Oximetrix Swan-Ganz catheter was passed through the jugular vein into the right side of the heart, and the tip of the catheter was positioned in the pulmonary artery. A cathetermounted micromanometer (Model PC350; Millar, Houston, TX) was positioned in the left ventricle through the left ventricular apex. The Millar micromanometer was used to obtain high-fidelity measurements of left ventricular pressure and its first derivative (dP/dt). The left anterior descending (LAD) coronary artery was dissected free and a ligature was passed around the LAD (to later produce temporary coronary occlusion) distal to the first major diagonal branch. This array of instrumentation enabled continuous monitoring of arterial blood pressure, left atrial pressure, left ventricular pressure, dP/dt, and heart rate. Injections of iced saline solution through the Swan-Ganz catheter were made in triplicate to measure cardiac output by the thermodilution technique during baseline conditions and after weaning from cardiopulmonary bypass. Mixed venous oxygen saturation of the pulmonary arterial blood was also measured continuously. After instrumentation was completed, the animals were heparinized (300 U/kg). A 16F arterial perfusion cannula (DLP, Grand Rapids, MI) was placed in the innominate artery, and a two-stage venous cannula (Sarns, Inc, Ann Arbor, MI) was inserted into the inferior vena cava through the right atrial appendage. After total cardiopulmonary bypass was initiated, a cardioplegia infusion cannula (DLP) was inserted into the ascending aorta for infusion of cardioplegia and for venting of the left ventricle. Thermistor probes were placed in the LAD (ischemic) and circumflex (nonischemic) territories to monitor intramyocardial temperatures (Yellow Springs Instrument Co, Yellow Springs, OH). Arterial and cardioplegic temperatures were monitored by in-line thermistors (Sarns, Inc). Systemic temperature was maintained at 37°C on cardiopulmonary bypass. The same experimental protocol was followed in both the control and acadesine groups (Fig 1). The agent was administered before, during, and after the ischemic episode to determine if there was any beneficial or detrimental effect of acadesine and not specifically to ascertain the optimal timing of its administration. Therefore, in the treated group acadesine was infused through the right atrial port of the Swan-Ganz catheter 30 minutes before, during, and until 10 minutes after the ischemic (aortic cross-clamp) period, and acadesine (20 pmoVL) was also delivered with the cardioplegia in the acadesine group. Based on previous experiments of canine regional ischemia [ 5 ] the loading dose of acadesine (2.5 mg kg-' min-') was infused for 5 minutes before the dogs were on cardiopulmonary bypass. Thereafter, while the dogs were on bypass (during the course of the experiment) and until 10 minutes after the aortic cross-clamp was removed, acadesine was infused at a rate of 0.5 mg * kg-' min-'. Saline solution, the vehicle for acadesine, was infused in similar volumes at similar times in the control group. Baseline measurements were obtained after instrumentation and bypass cannulations were completed. The LAD was then ligated and the aorta
-
-
Ann Thorac Surg 1992;54:9>8
-1
AlCAR OR SALINE INFUSION
BASELINE
37%
< 8
CARCNOPLEGIC INDUCED ISCHEMIA
d c 4 5 ' + w +
- 4
120'
REPERFUSION
-
30'
was cross-clamped for 5 minutes with the left ventricle vented. Cardioplegia (30 mL.lkg) was infused after this 5-minute normothermic global ischemia period. The LAD remained ligated during the first infusion of cardioplegia to stimulate the circumstances that could exist during an emergency coronary artery bypass procedure with poor delivery of cardioplegia to th.e ischemic area. The LAD ligature was removed after finishing the first infusion of cardioplegia and the LAD was open for the second and subsequent doses of cardioplegia, as if a successful coronary bypass graft had been constructed and cardioplegia could now be delivered to the ischemic zone. The main objective was to produce a model of severe myocardial ischemia as might be encountered in high-risk or emergency patients undergoing a coronary artery bypass procedure to rigorously test the potential efficacy of acadesine. The cardioplegia was infused at temperatures of 6" to 8°C and at a pressure of appr'oximately 100 mm Hg. The cardioplegia contained 24 mEq/L potassium chloride, 25 mEq/L sodium bicarbonate, and 5 g/L dextrose. A small amount of blood was added to the cardioplegia to obtain a hematocrit of 0.03. In the acadesine group, the cardioplegia also contained 20 btmol/L of acadesine. Additional infusions of cardioplegia (15 mg/kg) were administered at intervals of 30 minutes during ischemia. Myocardial temperatures in the LAD (ischemic) and circumflex (nonischemic) territories were recorded. At the end of the ischemic period, 50 mg of lidocaine was administered, the aortic cross-clamp was removed, and the heart was reperfused. Total ischemia time, global (5 minutes) and cardioplegic (120 minutes), was 125 minutes. Defibrillation was used as necessary when ven-
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Ann Thorac Surg 1992:54:9%8
tricular fibrillation occurred, and the number of defibrillations required was recorded. Over the next 30 minutes, the dogs were reperfused with the hearts empty and beating. After this 30-minute period the animals in both groups were all weaned at equal rates from cardiopulmonary bypass. Recovery data were obtained in both groups at the same time relative to ischemia and reperfusion and were obtained at spontaneous rhythm, when the dogs were completely off cardiopulmonary bypass. After recovery data were obtained the animals were humanely euthanized. Because of the intentionally severe ischemic insult produced in these experiments, it was not possible to precisely match cardiac volume and loading conditions after reperfusion with those observed during prebypass baseline conditions for each individual animal. Although this limits the comparison of preischemic and postischemic data, both groups of dogs underwent identical protocols and these conditions stimulate those observed in the operating room during emergency coronary artery bypass grafting after an angioplasty accident with reasonable accuracy. Data were statistically analyzed with paired t test and unpaired t tests as appropriate.
Results Data in absolute terms are summarized in Table 1. Percentage change or percentage recovery data are presented in Figures 2 through 4 and are used for convenience. Raw data analysis was identical in all conclusions and statistical validity. Results are presented as mean -+ standard deviation. There were no significant differences between the control group and acadesine for any measured parameter during baseline, preischemic conditions. Acid-base balance, cardioplegia delivery, myocardial temperatures in the LAD (ischemic) and circumflex (nonischemic) territories, and oxygenation were equally maintained in the control group versus the acadesine group during and after ischemia. After the aortic cross-clamp was removed, all 8 controls required defibrillation, the number of shocks varying from one to 12. In the acadesine group, only 4 of the 8 dogs required defibrillation and only one to three shocks were required. The difference in the number of dogs requiring defibrillation did not quite achieve statistical significance ( p = 0.077) by a two-sided Fisher's exact test. Heart rate was not significantly different after weaning the dogs from bypass in either group (see Table 1). No significant heart block was noted in either group. All dogs in both groups were successfully weaned from bypass, and recovery data were obtained in all animals. Longterm survival was not addressed in this acute experiment. Mean left atrial pressure increased significantly in both groups in the postischemic period, as compared with preischemic baseline values. The absolute increases were not significantly different between groups, averaging 6 t 5 (mean k standard deviation) mm Hg and 9 6 mm Hg in the acadesine and control groups, respectively. Although the left atrial pressure data during recovery were similar, we acknowledge that compliance may have been modified more in one group than the other, resulting in
*
Table 1. Hernodynamic Data Before and After Cardiopulmonary Bypass in the Control and Acadesine Groups" Variable Heart rate (beatsimin) Control Acadesine LAP (mm Hg) Control Acadesine MAP (mm Hg) Control Acadesine LVSP (mm Hg) Control Acadesine CO (L/min) Control Acadesine SVR (mm Hg . L- . min-') Control Acadesine MVO, Control Acadesine .
'
P
Before Bypass
After Bypass
134 2 17 145 t 24
116 t 19 133 t 14
0.04 NS
7 t 3 5 t 3
16 t 5 11 -+ 5
0.005 0.010
107 t 16 105 t 22
48 2 23 78 t 21'
0.0004 0.038
127 ? 17 130 2 23
72 t 29 101 2 15'
0.0009 0.023
Valueh
3.23 2 1.40 1.93 t 1.92 0.054 2.36 t 0.58 2.55 t 0.96 NS 41 ? 22 49 t 17 93% t 4% 93% 2 5 %
43 t 28 33 t 13
NS 0.059
54% ? 19% 0.003 90% t 8%d NS
.' Data are reported as mean
C standard deviation; n = 8 except for cardiac output, systemic vascular resistance, and mixed venous oxygen saturation (n = 7). Paired f tests were performed to compare prebypass and postbypass data. ' ' A Unpaired and paired t tests were performed comparing acadesine data against the control group data, both before and after bypass: ' p < 0.05, p < 0.001.
'
LAP = mean left atrial pressure; LVSP = left CO = cardiac output; ventricular systolic pressure; MAP = mean arterial blood pressure; NS = not significant; MVO, = mixed venous oxygen saturation; SVR = systemic vascular resistance.
differences in preload. Mean arterial blood pressure was significantly reduced to 45% 21% ( p < 0.001) of baseline 26% of in the control group, whereas it was 78% baseline ( p = 0.04) in the acadesine group. The magnitude of the reduction in arterial blood pressure was significantly greater in the control group, as compared with the acadesine group. The main objective of this study focused on systolic contractile performance, and the data indicated that with the use of acadesine left ventricular peak developed pressure was 79% 17% ( p = 0.03) of the baseline level. In contrast, peak developed pressure was reduced to 56% k 22% ( p < 0.001) of baseline in the control group, a level of postischemic recovery significantly lower than in the acadesine group (see Fig 2). A similar pattern was evident in terms of peak positive dP/dt, which was reduced to 35% f 13% of baseline in the control group but maintained at 71% ? 16% ( p < 0.001 compared with the control group) in the acadesine-treated dogs (see Fig 2). Absolute cardiac output was not significantly lower than prebypass baseline in the acadesine group after weaning from bypass ( p = not significant versus before bypass). In contrast, absolute cardiac output in the con-
*
*
*
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BOLLING ET AL ACADESINE IMPROVES POSTBYPASS RECOVERY
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!
1992;54:93-8
100
-80
75
-60
50
8
-40
0
25
C
A
-
LVSP
0
-20 C
(+I
0 dPldt
Fig 2 . Percentage recovery of left ventricular developed pressure (LVSP) and peak positive first derivative of left ventricular pressure (dP/dt) after 125 minutes of global ischemia and weaning from cardiopulmonary bypass. Data are expressed as percentages of baseline preischemic values. Individual data points and mean values (histograms) are shown for the control (C) and acadesine (A) groups. Both peak developed pressure and peak + dPldt were significantly higher in the acadesine animals after cardiopulmonary bypass. (*p < 0.05 versus controls.)
trols was reduced considerably after weaning ( p = 0.054 versus before bypass). Furthermore, when examining the percentage recovery of cardiac output after bypass (see Fig 3) it was noted that recovery of cardiac output after 26% in the acadesine group, bypass averaged 109% whereas recovery of cardiac output after bypass in the controls averaged only 52% & 39% ( p < 0.01). Systemic vascular resistance (calculated as the ratio of mean arterial blood pressure to cardiac output) averaged 73% 2 37% and 106% k 47% of baseline in the control and acadesine groups ( p = not significant), respectively, after
*
150
100
50
0
II
I, A
Fig 3. Percentage recovery of cardiac output. Data are presented as percentages of baseline values. lndividual data points and mean values (histograms) are shown for the control (C) and acadesine-treated (A) groups. (*p < 0.05 versus controls.)
0
+20
C
A
Fig 4. Change in mixed venous oxygen saturation after 125 minutes of ischemia and weaning from cardiopulmonary bypass. Individual data points and mean values (histograms) are shown for the control (C) and acadesine-treated (A) groups. The average change (38% ? 21%) in the control group was significantly greater than that in the acadesine group (3% 6 % ) , supporting the conclusion that use of acadesine resulted in more favorable oxygen delivery after weaning from cardiopulmonary bypass. (“p < 0.05 versus controls.)
*
weaning from bypass. Additionally, there were no significant differences between groups before or after the ischemic period. Mixed venous oxygen saturation, an index of the balance between oxygen Idemand and delivery, differed substantially between groups (see Fig 4). It was not significantly changed in the acadesine group after the ischemic period and weaning from cardiopulmonary bypass. In the control group, however, mixed venous oxygen saturation was reduced significantly ( p < 0.01) to 62% k 21% of baseline, reflecting decreased cardiac output in the controls and suggesting that considerably greater utilization of extraction reserve was necessary to meet the oxygen requirements of the systemic circulation in the control group compared with the acadesine group.
Comment The objective of this study was to conduct a preliminary test on the potential efficacy of acadesine in experimental conditions designed to approximate high risk or emergency coronary artery bypass operation. The canine hearts were exposed to prolonged global ischemia with or without the use of acadesine to provide a severe test of acadesine’s potential efficacy. Because this was a preliminary investigation, acadesine was administered before, during, and after ischemia, as well as in the cardioplegia to maximize our ability to detect an effect. The rationale of administering acadesine before ischemia was in effort to ”preload” myocardial cells with acadesine before exposure to ischemic conditions, as acadesine is thought to be stored as a nucleotide precursor [ 5 ] . Under these conditions, recovery of systolic coritractile performance measured in terms of peak developed left ventricular pres-
Ann Thorac Surg 1992;54:9&8
sure, peak positive dPldt, and cardiac output was significantly better in the acadesine group than controls, leading to the conclusion that acadesine provides myocardial protection or accelerates recovery after myocardial ischemia in the dog. The mechanism by which acadesine improved ventricular functional recovery is not known with certainty. Acadesine has been advocated for use as a substrate for myocardial adenine nucleotide repletion during postischemic reperfusion [1-61. Myocardial ischemia depletes the adenine nucleotide pool because adenosine triphosphate is consumed to maintain cellular integrity and adenosine diphosphate cannot be rephosphorylated. Rather, the remaining adenosine diphosphate is transformed to adenosine monophosphate, which is converted to nucleosides that can enter the interstitial space from the cells and be washed out during reperfusion. When substrates are unavailable for the nucleotide salvage pathway, the repletion of adenosine triphosphate is dependent on the slower de novo synthetic pathway. Acadesine is easily transported into myocardial cells, is readily phosphorylated, and can be metabolized rapidly to purine nucleotides [5]. Swain and associates [l]reported enhanced repletion of adenosine triphosphate and guanosine triphosphate pools with acadesine use in dogs 24 hours after the release of a short-term (12-minute) coronary artery occlusion in a regional model of ischemia. Subsequent studies have been contradictory as to whether acadesine significantly enhances adenosine triphosphate repletion [7, 81. Nonetheless, treatment with acadesine has resulted in improved functional recovery in many experimental settings. Mistos and co-workers [2] demonstrated better recovery of function in globally ischemic isolated cat hearts with acadesine, despite the fact that the total adenine nucleotide pool was reduced to the same degree in acadesine-treated hearts as in controls. In a more recent study, acadesine attenuated the detrimental effects of myocardial stunning in a canine model involving brief occlusions of the LAD [4]. In this study there was better preservation of regional function in the ischemic zone with acadesine as compared with untreated controls. The mechanism of the beneficial effect was attributed to augmentation of intramyocardial adenosine levels, consistent with the findings of Gruber and associates [ 3 ] . In contrast to these positive results, Mentzer and colleagues [9] reported that acadesine did not improve functional recovery. In this study the effects of acadesine were examined in isolated rat hearts perfused at a constant coronary flow for 30 minutes followed by 10 minutes of global normothermic (37°C)ischemia. Hearts were treated with acadesine (100 pmol/L) throughout preischemic perfusion and compared with untreated controls. Acadesine failed to enhance the recovery of postischemic left ventricular developed pressure, an effect that was attributed to acadesine-induced inhibition of the enzyme adenylosuccinate lyase. Other reports have also indicated that acadesine may not be beneficial in terms of functional recovery [lo]. Despite the disparate findings and conclusions reported in the literature, we observed that functional recovery was
BOLLING ET AL ACADESINE IMPROVES POSTBYPASS RECOVERY
97
improved in a model designed to approximate operative conditions with severe ischemia. In addition, the requirement for defibrillation after removing the aortic crossclamp tended to be reduced in the acadesine-treated group, potentially consistent with recent preliminary findings that acadesine suppresses arrhythmias induced by coronary artery occlusion and reperfusion in cats [ 111. Acadesine has many profound effects, including inhibiting neutrophil and platelet aggregation, depressing the conduction system, altering glycolysis, and changing vasomotor tone [2, 3, 7, 81. The exact mechanism for the beneficial action of acadesine will require additional investigation, but maintenance or enhancement of intramyocardial adenosine may play an important role in improving postischemic myocardial recovery [3, 12-14]. In addition, we speculate that the timing of acadesine administration may be crucial, as well. In our study, the myocardium was pretreated with acadesine before the onset of ischemia, whereas studies failing to show beneficial effects of acadesine were those in which acadesine was administered during the ischemic period alone, during reperfusion, or both. In conclusion, pretreatment with acadesine may represent a practical means of enhancing the ability of the myocardium to withstand ischemia in the operative setting. Administration of acadesine, perhaps during induction of anesthesia, could lead to enhanced ischemic tolerance. Regardless of the mechanism of acadesine's beneficial effect, it appears to be a promising cardioprotective agent and warrants additional investigation. Supported in part by grant HL32043 from the National Institutes of Health and a grant from Gensia Pharmaceuticals, Inc, San Diego, CA.
References 1. Swain JL, Hines JJ, Sabina RL, Holmes EW. Accelerated repletion of ATP and GTP pools in postischemic canine myocardium using a precursor of purine de novo synthesis. Circ Res 1982;51:102-5. 2. Mitsos SE, Jolly SR, Lucchesi BR. Protective effects of AICAriboside in the globally ischemic isolated cat heart. Pharmacology 1985;31:121-31. 3. Gruber HE, Hoffer ME, McAllister DR, et al. Increased adenosine concentration in blood from ischemic myocardium by AICA riboside. Effects on flow, granulocytes and injury. Circulation 1989;80:1400-11. 4. Hori M, Kitakaze M, Takashima S. AICA-riboside (5-amino4-imidazole careboxamide riboside 100). A novel adenosine potentiator attenuates myocardial stunning. Circulation 1990;82(Suppl3):466. 5. Young MA, Mullane KM. Progressive cardiac dysfunction with repeated pacing-induced ischemia: protection by AICAriboside. Am J Physiol (Heart Circ Physiol) (in press). 6. Sabina RL, Kernstine KH, Boyd RL, Holmes EW, Swain JL. Metabolism of 5-aminoimidazole-4-carboxamideriboside in cardiac and skeletal muscle. Effects on purine nucleotide synthesis. J Biol Chem 1982;257:1017-8. 7. Mauser M, Hoffmeister HM, Nienaber C, Schaper W. Influence of ribose, adenosine, and "AICAR' on the rate of myocardial adenosine triphosphate synthesis during reperfusion after coronary artery occlusion in the dog. Circ Res
1985;56:220-30.
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8. Hoffmeister HM, Mauser M, Schaper W. Effect of adenosine and AICAR on ATP content and regional contractile function in reperfused canine myocardium. Bas Res Cardiol 1985;80: 445-58. 9. Mentzer RM Jr, Ely SW, Lasley RD, Berne RM. The acute effects of AICAR on purine nucleotide metabolism and postischemic cardiac function. J Thorac Cardiovasc Surg 1989;95:286-93. 10. Ambrosio G, Jacobus WE, Mitchell MC, Litt MR, Becker LC. Effects of ATP precursors on ATP and free ADP content and functional recovery of postischemic hearts. Am J Physiol (Heart Circ Physiol) 1989;256(Heart Circ Physiol):H560-6. 11. Molina-Viamonte V, Rosen MR. AICA-riboside suppresses
arrhythmias induced by coronary artery occlusion and reperfusion. Circulation 1990;82(Suppl 3):645. 12. Rosenkranz ER, Okamoto F, Buckberg GD, et al. Biochemical studies: failure of tissue adenosine triphosphate levels to predict recovery of contractile function after controlled reperfusion. J Thorac Cardiovasc Surg 1986;92:48%501. 13. Bolling SF, Bies LE, Bove EL, Gallagher KP. Augmenting intracellular adenosine improves myocardial recovery. J Thorac Cardiovasc Surg 1990;99:469-74. 14. Bolling SF, Bies LE, Gallagher KP, Bove EL. Enhanced myocardial protection with adenosine. Ann Thorac Surg 1989;47:809-15.
Notice From the Southern Thoracic Surgical Association The Thirty-ninth Annual Meeting of the Southern Thoracic Surgical Association will be held at the Saddlebrook Golf and Tennis Resort, Wesley Chapel (near Tampa), Florida, November 5-7, 1992. The Postgraduate Course will be held the morning of Thursday, November 5, 1992, and will provide in-depth coverage of thoracic surgical topics selected primarily as a means to enhance and b r o a d e n the knowledge of practicing thoracic a n d cardiac
surgeons.
Applications for membership should be completed by
August 1, 1992, a n d forwarded to John P. Clarke, MD, Membership Committee Chairman, Southern Thoracic Surgical Association, 401 N o r t h Michigan Avenue, Chicago, IL 60611-4267.
Hendrick B. Barner, M D Secretary-Treasurer Southern Thoracic Surgical Association 401 North Michigan Avenue Chicago, IL 6061 1-4267
