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Ann Thorac Surg 1998;66:382-387
© 1998 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Adenosine-enhanced ischemic preconditioning decreases infarct in the regional ischemic sheep heart

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

Address reprint requests to Dr McCully, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Rm 140, Boston, MA 02115

Presented at the Poster Session of the Thirty-fourth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 26–28, 1998.

	Abstract

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Background. Recently we have reported a myoprotective protocol, adenosine-enhanced ischemic preconditioning, that extends the protection afforded by ischemic preconditioning in the isolated crystalloid-perfused heart. In this report the efficacy of adenosine-enhanced ischemic preconditioning in the in situ blood-perfused heart was investigated.

Methods. Sheep were subjected to 60 minutes of regional ischemia and 120 minutes of reperfusion. Ischemic preconditioned hearts received 5 minutes of zero flow regional ischemia and 5 minutes of reperfusion before regional ischemia. Adenosine-enhanced ischemic preconditioned hearts received a bolus injection of 10 mmol adenosine at the immediate start of ischemic preconditioning. Adenosine-treated hearts received an adenosine bolus, 10 minutes before regional ischemia. The ratio of infarct size to area at risk and mechanical function were determined.

Results. The infarct size to area at risk ratio in regional ischemia was 55.4% ± 2.1%. This ratio was significantly decreased with ischemic preconditioning and adenosine (22.2% ± 2.2% and 19.3% ± 1.4%, respectively; p < 0.001 versus regional ischemia) and adenosine-enhanced ischemic preconditioning (8.0% ± 2.0%, p < 0.001 versus regional ischemia and ischemic preconditioning, and p < 0.01 versus adenosine).

Conclusions. Adenosine-enhanced ischemic preconditioning significantly decreases infarct size in the in situ blood-perfused heart and provides superior protection compared with ischemic preconditioning.

	Introduction

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Previous reports have indicated that 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 is significantly reduced during the subsequent induction of sublethal global or regional ischemia [1, 2]. The induction of this endogenous myocardial protection, termed ischemic preconditioning (IPC), would appear to be common in all species studied in reducing myocardial infarct size. However, the effects of IPC on postischemic myocardial functional recovery have been shown to vary among species. In the rat heart the use of preconditioning has been shown to both reduce myocardial infarction and enhance postischemic myocardial functional recovery [3]. In contrast, in the rabbit heart, although preconditioning has been shown to reduce myocardial infarction, no enhancement of postischemic myocardial functional recovery occurs [4].

Recently we have reported a myoprotective protocol, adenosine-enhanced ischemic preconditioning (APC), that extends the protection afforded by IPC by both reducing myocardial infarct size and enhancing postischemic functional recovery in the isolated, perfused rabbit heart [5]. However, our previous study did not examine the efficacy of this protocol in a blood-perfused heart model.

Previous investigation has shown that IPC is effective in reducing infarct size in both the buffer-perfused and blood-perfused hearts, but infarct size in buffer-perfused hearts was found to be much greater than in crystalloid-perfused hearts [6, 7]. These data suggest that the protection afforded by IPC may be modulated in a blood-perfused model of ischemia and reperfusion [6, 7]. To determine the efficacy of APC we have used a clinically relevant blood-perfused in situ model of regional ischemia [8]. Our results indicate that APC significantly decreases the ratio of infarct size to area at risk after 60 minutes of regional ischemia in a blood-perfused in situ model and provides superior protection compared with IPC.

	Material and methods

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

Surgical preparation
Dorset or Suffolk sheep of either sex (35 to 45 kg, n = 28) 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. A tracheotomy was performed through a midline cervical incision (36F Argyle endotracheal tube) and ventilation begun with a volume-cycled ventilator (North American Drager, model Narkomed II, Telford, PA; oxygen, 40%; tidal volume, 1,400 mL; ventilation rate, 11 breaths/min; positive end-expiratory pressure 3 cm H₂O; inspiratory to expiratory time ratio, 1/2). 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, NJ; 5,000 IU intravenously) and 1% lidocaine (Abbott, Inc, North Chicago, IL; 5 mL intravenously) were given before thoracotomy. 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 (LV) to record LV pressure. Silk thread (3-0) was passed around the second or third diagonal branch of the left anterior descending coronary artery with a taper needle, and both ends of the silk tie threaded through a small vinyl tube to form a snare. The coronary artery was occluded by pulling the snare, which was then secured by clamping the tube with a mosquito clamp. Myocardial ischemia was confirmed visually by regional cyanosis of the myocardial surface. Regional myocardial function was assessed using a pulsed Doppler epicardial probe (Triton Technologies, Inc, San Diego, CA). The probes were secured with four 6-0 Prolene (Ethicon, Somerville, NJ) stitches to the periphery of the ischemic epicardial region. 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 ECG/Biotach [5].

Experimental protocol
Sheep were divided randomly into four groups. Regional ischemia hearts (RI hearts; n = 8) were subjected to 60 minutes of RI and 120 minutes of reperfusion. Regional ischemia was achieved by tightening the snare to occlude the second or third branch of the left coronary artery. Ischemic preconditioning hearts (IPC; n = 6) received a 10-mL saline bolus injection at the immediate start of IPC, coincident with the tightening of the snare (5 minutes of zero flow RI followed by 5 minutes of reperfusion) before 60 minutes of RI and 120 minutes of reperfusion. Adenosine-enhanced ischemic preconditioning hearts (APC; n = 8) received a 10-mmol bolus injection of adenosine (Adenoscan; Medico Research Inc, Research Triangle Park, NC) in 10 mL at the immediate start of IPC, coincident with the tightening of the snare (5 minutes of zero flow RI followed by 5 minutes of reperfusion). The bolus was injected into the left atrial appendage through a 19-gauge needle. To separate the effects of adenosine from those of APC, a control group, adenosine only (Ado; n = 6), received a 10-mmol bolus injection of adenosine, in 10 mL, 10 minutes before RI.

Functional analysis
Hemodynamic measurements, mean arterial pressure, heart rate, LV systolic pressure, LV end-diastolic pressure, and LV developed pressure were monitored continuously throughout the experiment. Regional mechanical function was assessed by sonomicrometry using two orthogonal pairs of dimension crystals arranged perpendicularly within the ischemic zone. Percent regional segment shortening was recorded continuously in both crystal sets throughout the study protocol. Percent regional segment shortening was calculated as .

Measurement of infarct size
Area at risk (AR) was delineated by monastryl blue pigment injection into the aorta after ligation of the involved artery following the end of the experiment, then the heart was rapidly removed and sliced across the long axis of the LV, from apex to base, into 1-cm-thick transverse sections; these sections were traced onto a clear acetate sheet over a glass plate under room light. The sliced hearts were incubated in 1% triphenyl tetrazolium chloride (Sigma Chemical Co., St. Louis, MO) in phosphate buffer (pH 7.4) at 38°C for 20 minutes [9, 10]. A copy of the stained heart slices were traced onto a clear acetate sheet over a glass plate under room light. The AR in the LV and the area of infarct size (IS) were measured by using planimetry. The volumes of the infarcted zone and the AR were calculated by multiplying the planimetered areas by the slice thickness. The ratio of AR to LV weight was calculated. Infarct size was expressed as a percentage of AR for each heart (IS/AR) [5].

Statistical analysis
Statistical analysis was performed with the use of the Systat for Windows version 5.0 software package (Systat, Inc, Urbana, IL). The mean ± standard error of the mean is shown for all variables. Statistical significance was determined using repeated measures analysis of variance with group as a between-subjects factor and time as a within-subjects factor. Post hoc comparisons between groups for both the average effect and at individual time points were made using a Bonferroni correction to adjust for the multiplicity of tests. A one-way analysis of variance was used for IS. Statistical significance was claimed at p less than 0.05.

	Results

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Hemodynamics (LV global function)
Hemodynamic measurements are summarized in Tables 1 and 2. Heart rate remained stable throughout the experimental protocol in all groups. No significant differences in LV systolic pressure, LV end-diastolic pressure, LV developed pressure, or mean arterial pressure were observed within or between groups during equilibrium, RI, or reperfusion.

Measurement of regional function
Regional mechanical function assessed by sonomicrometry, to determine percent segment shortening, did not discriminate between groups (Fig 1). In all experimental groups, there was systolic bulging as evidenced by a negative percent segment shortening during 0 to 30 minutes of RI. After 30 minutes of RI and during 120 minutes of reperfusion, all experimental groups demonstrated hypokinetic recovery of systolic function. No dyskinesis was observed in any of the experimental groups.

View larger version (20K): [in this window] [in a new window]   Fig 1. Regional dimensional changes during 60 minutes of normothermic regional ischemia and 120 minutes of reperfusion. Experimental group designation is indicated as follows: regional ischemia (RI), ischemic preconditioning (IPC), adenosine-enhanced ischemic preconditioning (APC), and adenosine alone (Ado). Results are shown as the mean ± standard error of the mean for n = 6 to 8 for all groups. Regional mechanical function assessed by sonomicrometry to determine percent segment shortening did not discriminate between groups. (EDL = end-diastolic regional length; ESL = end-systolic regional length.)

Myocardial infarct size
No significant difference in LV weight or AR was observed between groups (Table 3). Ischemic preconditioning significantly decreased IS/AR to 22.2% ± 2.2% compared with 55.4% ± 2.1% in RI hearts (p < 0.001). In Ado hearts IS/AR was significantly decreased to 19.3% ± 1.4% (p < 0.001 versus RI hearts). No significant difference in IS/AR was observed between IPC and Ado hearts. In APC hearts, IS/AR was significantly decreased to 8.0% ± 2.0% (p < 0.001 versus RI and IPC hearts, and p < 0.01 versus Ado hearts; Fig 2).

View larger version (12K): [in this window] [in a new window]   Fig 2. The effects of adenosine-enhanced ischemic preconditioning (APC), ischemic preconditioning (IPC), and adenosine (Ado) on infarct size to area at risk ratio after 60 minutes of regional ischemia (RI) of the left anterior descending artery and 120 minutes of reperfusion. Results are shown as the mean ± standard error of the mean for n = 6 to 8 for all groups. (*, significant differences from RI at p < 0.001; **, significant differences from IPC at p < 0.001; , significant differences from Ado at p < 0.01; no significant difference between IPC and Ado was observed.)

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Recently we have described a myoprotective protocol, adenosine-enhanced ischemic preconditioning, that extends the protection afforded by IPC by both reducing myocardial IS and enhancing postischemic functional recovery in the isolated crystalloid-perfused rabbit heart [5]. In this report the efficacy of this protocol was compared with IPC using the in situ blood-perfused, RI sheep heart model. Our results indicate that the use of APC significantly decreases IS after 1 hour of RI in the in situ blood-perfused sheep heart and is superior to IPC.

In this report we have used the single-cycle ischemic preconditioning protocol using 5 minutes of zero flow RI followed by 5 minutes of reperfusion before 60 minutes of prolonged RI and 120 minutes of reperfusion as described previously [5]. In a previous report using the same in situ blood-perfused, RI sheep heart model, but with three cycles of 5 minutes of zero flow RI followed by 5 minutes of reperfusion, IS/AR was 25% ± 4% compared with 52% ± 10% in RI hearts (note values reported as mean ± SD) [11]. Using single-cycle IPC, our data indicate that IS/AR was 22.2% ± 2.2% compared with 55.4% ± 2.1% in RI hearts (p < 0.001) (Fig 2). The use of a bolus injection of Ado (10 mmol in 10 mL) coincident with the tightening of the snare in concert with IPC (APC) was found to significantly decrease IS/AR to 8.0% ± 2.0% (p < 0.001 versus RI and IPC hearts). Although it is difficult to extrapolate between species (rabbit versus sheep), it would appear that the myoprotective benefits of APC in reducing IS are not compromised by blood perfusion [5, 11]. These data also suggest that the use of single-cycle IPC is at least as effective as three-cycle IPC, in agreement with previous reports [12].

In our in situ blood-perfused sheep heart model, RI was achieved by occlusion of the second or third branch of left anterior descending coronary artery. This procedure induced an AR of 9.0% ± 0.7% with no significant difference in AR between groups (Table 3). Our results indicate that this small AR did not adversely affect global heart function, but was of sufficient magnitude to induce alterations in regional function as evidenced by regional systolic bulging during ischemia. It must be noted that although the ovine model has limited native collateral coronary circulation to allow for amelioration of IS [13], in our study no attempt was made to heat or cool the animals during ischemia and reperfusion and the animals were allowed to cool to room temperature (22° ± 2°C) during ischemia and reperfusion. This methodology was used so as to replicate operating conditions and as such may have contributed to IS limitation.

Recently, Birnbaum and colleagues [14] have suggested that 3 hours of reperfusion is required to allow for the proper estimation of IS in the in situ rabbit heart after 30 minutes of RI. In our investigation we have used 2 hours of reperfusion after 30 minutes of RI before estimation of IS by triphenyl tetrazolium chloride staining. It is possible that our results may underestimate IS; however, we must assume that this underestimate would be proportional and therefore would not bias the overall import of our findings. Of importance, our results indicate that APC provides for significantly decreased IS as compared with IPC or Ado after RI and reperfusion.

Although APC, IPC, and Ado provided significant reduction of IS from the deleterious effects of regional myocardial ischemia, analysis of mechanical function using regional sonomicrometry crystals failed to distinguish the myoprotective benefits of increased myocyte survival (Fig 1). This lack of discrimination between protocols may be related to the delayed response time of the stunned myocardium. In previous reports it has been shown that regional stunning may exist more than 24 hours after the initial insult [15, 16]. Owing to the limitations of our model we were unable to investigate regional mechanical function at these time points, but it is reasonable to speculate that the significant decreases in myocyte necrosis may be of benefit to the recovery of the regionally stunned myocardium. It is further speculated that the significantly greater reduction in myocyte necrosis provided by APC as compared with IPC and Ado would be of greater benefit to the myocardium, in agreement with our previous observations [15].

Previous reports have used either Ado or Ado-regulating agents to enhance the IS-limiting effects of IPC [17, 18]. Cohen and coworkers [19] have recently reported that the use of an intravenous bolus injection of Ado through the jugular vein (0.2 mg/kg) resulted in a minimal but significant reduction in infarct size; however, higher Ado concentrations (0.4 mg/kg) provided no protection and were associated with cardiac slowing and marked hypotension. In this report, the concentration of Ado used was 10 mmol based on the mean LV weight of 103.8 ± 2.7 g (n = 28). The concentration of the Ado bolus used was determined from preliminary studies, indicating that Ado concentrations less than 2.5 mmol but greater than 0.1 mmol were more effective than steady-state infusion and that 1 mmol Ado per 10 g LV mass was required to allow for enhanced postischemic functional recovery and reduced IS in the rabbit heart [5]. In our study we have injected the bolus of Ado into the atrium rather than through the jugular vein. Our results indicate that using this method of injection the systemic effects as described by Cohen and associates [19] are mostly obviated. The use of a bolus injection of 10 mmol Ado was found to induce a transient decrease in LV systolic pressure, LV developed pressure, and mean arterial pressure, with maximal pressure decreases occurring 1.4 ± 0.3 minutes after the bolus injection. This decrease in pressure did not reach statistical significance, and no statistical difference either within or between groups was observed after the bolus injection of Ado. It is important to note that all pressures returned to equilibrium levels by 2.4 ± 0.3 minutes after the bolus injection. These data would agree with previous reports, which have shown that Ado evokes a rapid but transient (50 seconds) decline in blood pressure [20]. We did not investigate the use of reduced Ado concentrations, but our results would indicate that the use of 10 mmol Ado as a bolus injection when injected directly into the myocardium does not detrimentally affect myocardial function. Although the mechanism of APC cardioprotection remains to be elucidated, we speculate that the use of a bolus injection of Ado at the immediate start of IPC allows for full activation of myocardial Ado receptors and thus enhances the native endogenous cardioprotection afforded by IPC.

In conclusion our data indicate that a bolus injection of Ado used in concert with a single-cycle of IPC (APC) significantly decreases IS after 60 minutes of RI and 120 minutes of reperfusion. In addition our results indicate that APC is superior to IPC or Ado alone. However, no difference in regional mechanical function between groups could be determined. These data suggest that APC provides a powerful myoprotective alternative protocol to reduce myocardial necrosis. In addition the beneficial effects of APC in reducing myocardial IS previously shown in the crystalloid-perfused heart would appear to be preserved in the in situ blood-perfused model.

	Acknowledgments

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

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Jari O. Laurikka Sidney Levitsky Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Uematsu, M. Articles by McCully, J. D. Search for Related Content PubMed PubMed Citation Articles by Uematsu, M. Articles by McCully, J. D.