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Ann Thorac Surg 1999;67:699-704
© 1999 The Society of Thoracic Surgeons

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Original Articles

Adenosine-enhanced ischemic preconditioning provides myocardial protection equal to that of cold blood cardioplegia

^a Division of Cardiothoracic Surgery and Biometrics Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

Accepted for publication August 25, 1998.

Address reprint requests to Dr McCully, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 77 Ave Louis Pasteur, Room 144, Boston, MA 02115

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. We recently described a novel myoprotective protocol—adenosine-enhanced ischemic preconditioning (APC)—that extends the protection of ischemic preconditioning (IPC) by both reducing myocardial infarct size and enhancing postischemic functional recovery in the isolated perfused heart. In the present report the efficacy of APC in the blood-perfused heart was investigated and compared with that of cold blood cardioplegia (CBC).

Methods. Cardiopulmonary bypass was instituted in 21 sheep hearts. The APC hearts (n = 6) received a bolus injection of adenosine through the aortic root at the immediate start of IPC (5 minutes of zero-flow global ischemia, followed by 5 minutes of reperfusion) before 30 minutes of global ischemia and 120 minutes of reperfusion. Nine other hearts received CBC. A control group (n = 6) received IPC only.

Results. Infarct size was significantly decreased (p < 0.01) in the APC (3.0% ± 0.8%) and CBC (2.6% ± 0.2%) hearts compared with the IPC hearts (16.3% ± 1.6%). The preload recruitable stroke work relation, mean arterial pressure, and the time constant of pressure decay () were significantly preserved (p < 0.05) in APC and CBC hearts compared with IPC hearts. No significant differences were observed between APC and CBC hearts.

Conclusions. Use of APC is as effective as CBC in significantly decreasing infarct size and enhancing postischemic functional recovery.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Cold blood cardioplegia (CBC) is the standard myoprotective agent for the alleviation of surgically induced ischemic injury incurred during cardiac operative procedures, allowing for the functional preservation of the myocardium. Cardioplegia increases the available intraoperative time and has been correlated with improved postischemic myocardial functional recovery and reduced postoperative mortality. In previous reports we have shown that magnesium-supplemented potassium cardioplegia (Deaconess solution) is superior to potassium cardioplegia for the amelioration of the deleterious effects of surgically induced ischemic injury and allows for enhanced postischemic functional recovery [1]. However, the use of cardioplegia may not always be appropriate, and this limitation has led to the suggested usage of alternative myocardial protective protocols. One myoprotective protocol of current interest is ischemic preconditioning (IPC), in which the imposition of one or more brief periods of ischemia (3 to 5 minutes) followed by reperfusion "preconditions" the heart such that infarct size and myocardial necrosis are significantly reduced during the subsequent induction of sublethal ischemia [2]. Induction of this endogenous myocardial protection would appear to be common in all species studied in reducing myocardial infarct volume. However, the effects of preconditioning on postischemic myocardial functional recovery have been shown to vary among species, in contrast to the protection afforded by cardioplegia [3, 4].

We recently described a novel myocardial protective protocol, termed adenosine-enhanced ischemic preconditioning (APC) [5, 6]. We showed that in the isolated perfused rabbit heart, APC is superior to IPC, affording myocardial protection similar to that with magnesium-supplemented potassium cardioplegia [5]. Our results indicated that APC significantly extends and amends the protection afforded by IPC by both significantly decreasing myocardial infarct size (p < 0.05 vs IPC) and significantly enhancing postischemic functional recovery (p < 0.05 vs IPC) in contrast to IPC, which decreased infarct size but failed to enhance postischemic functional recovery in the isolated crystalloid-perfused rabbit heart model [5]. The effectiveness of APC in the global ischemic in situ heart model was unknown.

The purpose of the present study was to examine the efficacy of APC cardioprotection compared with that of CBC arrest and IPC in the in situ ovine heart model. Myocardial function was assessed by the preload recruitable stroke work (PRSW) relation; the lineralized Frank-Starling correlation; and , the time constant of isovolumetric pressure decay. Our results indicate that APC is superior to IPC, providing cardioprotection equal to that afforded by CBC, markedly decreasing infarct size, and greatly enhancing postischemic functional recovery after 30 minutes of hypothermic global ischemia in the in situ blood-perfused heart model. These results indicate that APC is as effective as CBC in providing an alternative myocardial protection protocol for cardiac surgical procedures.

	Material and methods

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Animals were housed individually and provided with laboratory chow and water ad libitum. All experiments were approved by the Beth Israel Deaconess Medical Center Animal Care and Use Committee and conformed to the US National Institutes of Health guidelines regulating the care and use of laboratory animals (NIH publication 5377-3, 1996).

Surgical preparation
Dorset sheep of either sex (35 to 45 kg; n = 21) were sedated with ketamine hydrochloride (Ketaset; Fort Dodge Laboratories, Inc, Fort Dodge, IA; 20 mg/kg intramuscularly) and then anesthetized with sodium pentobarbital (Pentobarbital; Veterinary Laboratories, Inc, Lenexa, KA; 25 mg/kg intravenously). General anesthesia was maintained throughout the experiment with sodium pentobarbital. Tracheotomy was performed through a midline cervical incision (36F Argyle), and ventilation was begun with a volume-cycled ventilator (model Narkomed II; North American Drager, Telford, PA; oxygen, 40%; tidal volume, 1,400 mL; ventilation rate, 11 beats/min; positive end-expiratory pressure, 3 cm H₂O; inspiration/expiration time ratio, ). The right internal jugular vein was cannulated for intravenous access, and the right common carotid artery was cannulated for arterial blood sampling and intraarterial blood pressure monitoring (Millar Instruments, Houston, TX). Heparin sodium (Elkins-Sinn, Inc, Cherry Hill, NJ; 5,000 IU intravenously) and 1% lidocaine (Abbott, Inc, North Chicago, IL; 5 mL intravenously) were given before thoracotomy. Lidocaine was administered to prevent ventricular fibrillation occurring as a result of electric discharge from electric codarization. Heparin was administered at the same dose hourly to the end of the experiment. The pericardial sac was exposed through an anterior bilateral transverse thoracotomy and was opened to form a pericardial cradle. A catheter-tipped manometer (Millar Instruments) was introduced through the apex into the left ventricle to record left ventricular (LV) pressure. Myocardial function was assessed using three orthogonal pairs of Doppler epicardial probes (Triton Technologies Inc, San Diego, CA). The probes were secured with four 6-0 prole stitches to the epicardium. Hemodynamic variables were acquired using the PO-NE-MAH digital data acquisition system (Gould, Valley View, OH), with an Acquire Plus processor board, LV pressure analysis software, and a Gould electrocardiographic/Biotach amplifier unit [6].

Cardiopulmonary bypass was initiated at a flow rate of 75 mL · kg^-1 · min^-1, with bicaval transarterial cannulation for venous return and the left axillary artery for arterial inflow. A large-bore cannula was used to decompress the right ventricle through the pulmonary artery. To maintain hematocrit levels, cardiopulmonary bypass pumps were primed with autologous blood drawn from donor sheep just before the experimental protocol. In all studies, initial data acquisition was performed during incremental volume loading using a modified right heart bypass, as previously described [7]. In brief, inflow from the cardiopulmonary bypass machine to the left ventricle was increased from 75 to 150 mL · kg^-1 · min^-1 in increments of 25 mL · kg^-1 · min^-1. At each increment, the left ventricle was allowed to equilibrate for 1 to 2 minutes, during which pressure–volume data were recorded. Contractility was assessed with the PRSW relation, which uses the slope of the relation between preload (end-diastolic volume) and external work as an estimate of contractility [7]. Diastolic function was assessed by . All variables were acquired using the PO-NE-MAH digital data acquisition system (Gould), with an Acquire Plus processor board.

Functional analysis
Hemodynamic measurements, mean arterial pressure, heart rate, LV systolic pressure, LV end-diastolic pressure, LV developed pressure, and were monitored continuously throughout the experiment. Blood gas and hematocrit levels were monitored every 10 to 15 minutes using a Corning 238 pH/blood gas analyzer and a Corning 270 carbon monoxide oximeter (Chiron Diagnostics, Medfield, MA). Blood gases and acid–base variables were maintained at a partial pressure of oxygen greater than 100 mm Hg, a pH of 7.3 ± 0.3, and a temperature of 37°C.

Experimental protocol
Sheep were divided randomly into three groups, and their hearts were subjected to 30 minutes of global ischemia and 120 minutes of reperfusion. The APC hearts (n = 6) received a 10-mmol/L bolus injection of adenosine (Adenoscan, Medico, Inc, Research Triangle Park, NC) in 10 mL, using a cardioplegia needle, through the aortic root, at the immediate start of IPC, coincident with the cross-clamping of the aorta (5 minutes of zero-flow global ischemia, followed by 5 minutes of reperfusion) before global ischemia and reperfusion [5, 6]. Global ischemia was achieved by cross-clamping of the aorta. The CBC hearts (n = 9) received Deaconess Surgical Associates solution (K⁺, 60 mmol/L; MgSO₄, 8 mmol/L; dextrose, 2.5 mmol/L; THAM [tris (hydroxymethyl) aminomethane], 10 mmol/L in normal saline, 0.9%) mixed (1:4, vol/vol) with cold autologous blood (procured from a donor animal). The CBC was chilled to 4°C in an icewater bath and then administered antegradely through the aortic root (20 mL/kg) to induce cardiac arrest [7]. The IPC hearts (n = 6) received a 10-mL saline bolus injection (vehicle, placebo), using a cardioplegia needle (9F ARII aortic root cannula; Medtronics DLP, Inc, Grand Rapids, MI) through the aortic root at the immediate start of IPC, coincident with cross-clamping of the aorta (5 minutes of zero-flow global ischemia, followed by 5 minutes of reperfusion) before 30 minutes of global ischemia and 120 minutes of reperfusion. All hearts received topical hypothermia during global ischemia by packing ice around the myocardium to reduce LV myocardial temperature [7]. After 30 minutes of hypothermic global ischemia, the ice packing was removed, the cross-clamp was removed, and the hearts were allowed to recover for 30 minutes. The hearts were then switched to right heart bypass, and a second incremental loading was performed to assess myocardial contractility (PRSW relation) [7]. The hearts were then returned to cardiopulmonary bypass and allowed to recover for a further 90 minutes (total, 120 minutes of reperfusion).

Measurement of infarct size
After reperfusion, hearts were excised and sliced across the long axis of the left ventricle, from apex to base, into 2-mm-thick transverse sections and then incubated in 1% triphenyl tetrazolium chloride (Sigma Chemical Co, St. Louis, MO) in phosphate buffer (pH, 7.4) at 38°C for 20 minutes [8]. Infarct areas were enhanced by storage in 10% formaldehyde solution for 24 hours before final measurement. In the globally ischemic heart, the whole ventricle is at risk of infarction, and therefore collateral flow and estimation of the area at risk were not required [8]. A copy of the stained heart slices was traced onto a clear acetate sheet over a glass plate under room light. The area of the left ventricle and the area of infarcted tissue were measured in blinded manner by an independent observer using planimetry. The volumes of the infarcted zone and the area at risk were calculated by multiplying the planimetered areas by the slice thickness. Infarct volume was expressed as a percentage of LV volume for each heart.

Comparison of wet and dry weights
Left ventricular tissue samples (approximately 0.1 g) from all experimental groups were weighed (wet weight) and dried at 80°C for 24 hours for reweighing (dry weight) and then used for the determination of dry/wet weight ratios according to previously described methods [5].

Statistical analysis
Statistical analysis was performed using Systat for Windows Version 5.0 (Systat, Urbana, IL). The mean ± standard error of the mean is shown for all variables. Statistical significance was determined using a one-way analysis of variance with Tukey post hoc comparisons between groups. Statistical significance was claimed at p < 0.05.

	Results

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Hemodynamic variables before and after ischemia
Hemodynamic data before and after ischemia are summarized in Table 1. No significant difference in heart rate, LV peak developed pressure, or mean arterial pressure was observed between groups before the onset of global ischemia. After 30 minutes of hypothermic global ischemia and 30 minutes of normothermic reperfusion, LV peak developed pressure and mean arterial pressure were significantly decreased (p < 0.05) in IPC compared with CBC and APC hearts. There was no significant difference before and after ischemia in heart rate, LV peak developed pressure, or mean arterial pressure within or between CBC and APC hearts. Hematocrit levels were 19.6% ± 0.9% in CBC hearts, 20.7% ± 0.6% in APC hearts, and 20.3% ± 1.9% in IPC hearts. No significant difference in hematocrit levels between groups was observed.

Infarct size
Infarct size after 30 minutes of normothermic global ischemia and 120 minutes of reperfusion is shown in Figure 1. Infarct size was significantly increased (p < 0.001) in IPC hearts (16.3% ± 1.6%) compared with CBC (2.6% ± 0.2%) and APC (3.0% ± 0.8%) hearts. There was no significant difference in infarct size between CBC and APC hearts after 30 minutes of normothermic global ischemia and 120 minutes of reperfusion. No significant difference in dry weight/wet weight ratio was observed between groups (results not shown).

View larger version (11K): [in this window] [in a new window]   Fig 1. Effects of adenosine-enhanced ischemic preconditioning (APC), cold blood cardioplegia (CBC), and ischemic preconditioning (IPC) on infarct size (percent of left ventricular volume) after 30 minutes of hypothermic global ischemia and 120 minutes of reperfusion. Results are shown as mean ± standard error of the mean for n = 6 to 9 for each group. Asterisk indicates significant differences at p < 0.05 versus APC and CBC hearts. There was no significant difference between APC and CBC hearts.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Previous investigation, comparing crystalloid- and blood-perfused rabbit hearts has shown that blood-perfused hearts exhibit a greater resistance to ischemia and a superior response to cardioplegia than crystalloid-perfused hearts [9]. Sandhu and colleagues [10] have shown that IPC is effective in reducing infarct size in both the buffer-perfused and blood-perfused hearts compared with hearts that received global ischemia only, but that infarct size in buffer-perfused hearts was much greater than that in blood-perfused hearts. However, no significant improvement in postischemic function was observed with IPC in either buffer-perfused or blood-perfused hearts. In the present report we used the in situ blood-perfused heart model to compare the efficacy of APC with that of CBC and IPC. Our results using the in situ blood-perfused heart model recapitulate our results in the crystalloid-perfused heart model and indicate that APC and CBC are superior to IPC, significantly preserving the PRSW relation, mean arterial pressure, and , with only minimal infarct size observable after 30 minutes of hypothermic global ischemia. Importantly, our results show that no marked difference exists in the myocardial protection afforded by APC versus CBC.

At present the mechanism by which a bolus injection of adenosine into the myocardium coincident with IPC (ie, APC) confers superior cardioprotection remains to be fully elucidated, but previous investigators have suggested that adenosine plays a central role, both as a mediator and a trigger in the cardioprotection afforded by IPC, and continued occupancy of adenosine receptors during ischemia is required before preconditioning can be achieved [3]. We speculate that the bolus injection of adenosine into the myocardium allows for the rapid binding and activation of myocardial adenosine receptors during the ischemic phase of IPC, thus allowing maximal preconditioning of the myocardium.

Several potential beneficial effects of preconditioning have been ascribed to adenosine. Adenosine, by its property to antagonize calcium channels, has been shown to inhibit the sinoatrial and atrioventricular nodes and myocardial contraction, thereby inducing cardiac arrest [11]. Adenosine has also been implicated in the protection afforded against myocardial infarction ("second window of protection") observed 24 hours after the imposition of IPC [12]. In rabbit hearts it has been shown that a 5-minute infusion with adenosine followed by a 10-minute washout period before ischemia reduced infarct size from 41% to 25% compared with 10% in IPC-treated hearts [4]. However, the transient infusion of adenosine followed by washout has been shown to be ineffectual in attenuating myocardial stunning [13].

It has been previously noted that although endogenous adenosine accumulation is central to the cardioprotection afforded by ischemic preconditioning, endogenous concentration may not be sufficient to allow for maximal cardioprotection because the administration of exogenous adenosine or its analogues increases the degree of cardioprotection [14]. This observation would agree with those of Lasley and associates [4] who suggested that it is the interstitial fluid levels of adenosine that attenuate infarct size. Although we did not determine the effect of APC on interstitial adenosine levels, we speculate that APC rapidly increases interstitial adenosine levels greater than that able to be achieved by either IPC induction or steady-state adenosine infusion, allowing for the rapid saturation of myocardial adenosine receptors, and that the level of adenosine receptor saturation may be directly correlated with both the reduction in myocardial infarct size and the degree of postischemic functional recovery attained.

The mode of adenosine augmentation and the method of its administration would appear to be of primary importance in allowing for enhanced infarct size limitation and enhanced postischemic functional recovery. Previous reports have used either adenosine or adenosine-regulating agents to enhance the infarct-size limiting effects of IPC, but the effect of such protocols has varied [15, 16]. It has also been shown that there are differential responses to steady-state adenosine compared with responses to bolus adenosine injections. Langerqvist and colleagues [17] showed that adenosine, when delivered by steady-state intracoronary infusion, was associated with myocardial ischemia, as determined by lactate production, ST segment depression, and chest pain. The delivery of adenosine by intracoronary bolus injection was found to obviate these effects.

Recently, Cohen and associates [18] reported that the use of an intravenous bolus injection of adenosine through the jugular vein (0.2 mg/kg) resulted in a minimal but significant reduction in infarct size; however, higher adenosine concentrations (0.4 mg/kg) provided no protection and were associated with cardiac slowing and marked hypotension. In the present report, the concentration of adenosine used was 10 mmol/L [6] injected directly into the myocardium through the aortic root. Using this technique for adenosine administration we showed that the systemic effects associated with infusion through the jugular vein are obviated, and only transient, nonsignificant decreases in LV systolic pressure, LV developed pressure, and mean arterial pressure occur, and these hemodynamic alterations are eliminated 2.4 ± 0.3 minutes after the bolus injection [6].

Intrinsic to the development of new myoprotective protocols for use in cardiac surgical procedures are the requirements of new protocols to be equal to or better than conventional cardioplegia in providing enhanced postischemic functional recovery and decreased myocardial infarct size. Our data suggest that APC, in which a bolus injection of adenosine into the myocardium is used coincidently with IPC, would meet these requirements and provide cardioprotection equal to that of CBC, markedly decrease myocardial infarct size, and greatly enhance postischemic myocardial functional recovery. These results further suggest that APC may provide an effective alternative myocardial protective protocol, allowing for the reduction of morbidity and mortality in cardiac surgical procedures.

In the present report we used 30 minutes of hypothermic global ischemia during which the whole heart is at risk [8]. The reason for this time limit was the need for a viable control population. In preliminary studies it was found that hearts receiving IPC were unable to be resuscitated after 60 minutes of hypothermic global ischemia (results not shown).

Previous investigation has shown that the use of topical hypothermia reduces myocardial infarct size [19]. In the present report we attempted to replicate our clinical procedures using Deaconess Surgical Associates solution with topical hypothermia and tepid systemic perfusate. The effect of topical hypothermia alone was not investigated; however, topical hypothermia was used in all groups, and therefore any intervening factors would be accounted for in our results.

It should also be noted that we used 2 hours of reperfusion after 30 minutes of hypothermic global ischemia before estimation of infarct size by triphenyl tetrazolium chloride staining. Recently, Birnbaum and colleagues [20] suggested that 3 hours of reperfusion is required to allow for the proper estimation of infarct size in the in situ rabbit heart after 30 minutes of regional ischemia. It is possible that our results may underestimate infarct size; however, we must assume that this underestimation would be proportional and therefore would not bias the overall import of our findings.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This study was supported by the National Institutes of Health (HL 29077 and HL 59542) and the American Heart Association.

	References

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