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J Thorac Cardiovasc Surg 1999;117:383-389
© 1999 Mosby, Inc.

CARDIOPULMONARY SUPPORT AND PHYSIOLOGY

ISCHEMIC PRECONDITIONING ATTENUATES POSTISCHEMIC CORONARY ARTERY ENDOTHELIAL DYSFUNCTION IN A MODEL OF MINIMALLY INVASIVE DIRECT CORONARY ARTERY BYPASS GRAFTING

From the Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine, Carlyle Fraser Heart Center-Cardiothoracic Research Laboratory, Crawford Long Hospital, Atlanta.

Presented at the Seventieth Scientific Sessions, American Heart Association, Orlando, Florida, Nov 9-12, 1997.

Address for reprints: Jakob Vinten-Johansen, PhD, Cardiothoracic Research Laboratory, Crawford Long Hospital, 550 Peachtree St, NE, Atlanta, GA 30365-2225.

	Abstract

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Objective: Unmodified reperfusion without cardioplegia in minimally invasive direct coronary artery bypass grafting procedures causes endothelial dysfunction that may predispose to polymorphonuclear neutrophil-mediated myocardial injury. This study tested the hypothesis that ischemic preconditioning in a minimally invasive direct coronary artery bypass grafting model attenuates postischemic endothelial dysfunction in coronary vessels.
Methods: In anesthetized dogs, the left anterior descending coronary artery was occluded for 30 minutes and reperfused for 3 hours without ischemic preconditioning (no-ischemic preconditioning; n = 7); in 7 dogs, the left anterior descending occlusion was preceded by 5 minutes occlusion followed by 5 minutes of reperfusion. Relaxation responses to stimulators of nitric oxide synthase were used to evaluate endothelial function in arteries from the ischemic-reperfused (left anterior descending) and nonischemic (left circumflex coronary artery) zones.
Results: Stimulated endothelial-dependent relaxation of epicardial left anterior descending artery to incremental concentrations of acetylcholine in the no-ischemic preconditioning animals was shifted to the right, and maximal relaxation was attenuated compared with the nonischemic left circumflex coronary artery (117% ± 4% vs 138% ± 5%). In contrast, acetylcholine-induced maximal relaxation was comparable in the left anterior descending artery versus left circumflex coronary artery in the ischemic preconditioning group (130% ± 6% vs 135% ± 5%). In 150- to 200-µm left anterior descending microvessels, 50% relaxation occurred with a lower concentration (log[M]) of acetylcholine in ischemic preconditioning versus no-ischemic preconditioning (–8.0 ± 0.4 vs –7.0 ± 0.1) with no group differences in smooth muscle relaxation to sodium nitroprusside, suggesting endothelial-specific damage. Adherence of fluorescent labeled polymorphonuclear neutrophils to epicardial coronary artery endothelium, used as an index of basal (unstimulated) anti–polymorphonuclear neutrophil function, was significantly attenuated by ischemic preconditioning versus no-ischemic preconditioning (293 ± 25 polymorphonuclear neutrophils/mm² vs 528 ± 29 polymorphonuclear neutrophils/mm²).
Conclusion: In this minimally invasive direct coronary artery bypass grafting model, both agonist-stimulated and basal postischemic endothelial dysfunction were attenuated by ischemic preconditioning.

	Introduction

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In 1986, Murry and colleagues ¹ reported a reduction in myocardial necrosis after repeat periods of ischemia and reperfusion in an in vivo canine model of transient coronary occlusion. Since this report, a plethora of studies have observed and characterized the "ischemic preconditioning" phenomenon. Ischemic preconditioning (IP) has been defined as an endogenous adaptation of the heart to a prolonged ischemic insult by exposing the myocardium to a brief period of ischemia before the prolonged event. IP has been found to ameliorate regional contractile dysfunction in some models, ² ischemic contracture, ² infarct size, ^1,3 and reperfusion arrhythmias. ⁴ Although the mechanisms of IP have not been clearly defined, the exogenous infusion of adenosine, ⁵ noradrenaline, ⁶ bradykinin, ⁷ nitric oxide, ⁸ and endothelin ⁹ before the occlusive event have been shown to mimic IP. Furthermore, protein kinase C and adenosine triphosphate–sensitive potassium channel–mediated mechanisms have been suggested as likely end-effectors that lead to myocardial protection. ^10,11

Ischemia-reperfusion has been demonstrated to reduce vascular endothelial-dependent vasoactive properties in both in vitro ¹² and in vivo ¹³ animal models. Injury to vascular endothelium increases polymorphonuclear neutrophil (PMN) adherence (basal function) and decreases the ability of coronary vessels to vasorelax in response to agonist stimulators of nitric oxide synthase (stimulated function). Although therapeutic strategies (adenosine, nitric oxide) have attenuated PMN attachment and PMN-mediated damage to the endothelium at reperfusion, ^14,15 few studies have examined IP's potential protective effects on the coronary endothelium, and the results of these studies are discrepant. ^16-20 DeFily and Chilian ¹⁷ have reported that IP reduces endothelial dysfunction of coronary arterioles in intact beating canine hearts after reperfusion injury. In contrast, Bauer and colleagues, ²⁰ in an in vivo canine model, have shown that IP did not reduce endothelium-dependent coronary vasorelaxation. Therefore the effects of preconditioning on the endothelial cell have not been clearly defined. Furthermore, because coronary epicardial macrovessels and microvessels differ in their normal physiologic features and responses to ischemia and reperfusion, ²¹ with the microvascular endothelium being more vulnerable to injury, further studies on the effects of IP on the endothelium in both vascular tissues are warranted.

The present study tests the hypothesis that IP attenuates postischemic endothelial dysfunction in epicardial macrovessels and microvessels in a model of minimally invasive direct coronary artery bypass grafting (MIDCABG) in which short-term occlusions simulate transient intraoperative vessel occlusion during anastomosis.

	Methods

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General
All dogs were handled in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH Publication #86-23, revised in 1985) and the Institutional Animal Care and Use Committee of Emory University.

Fourteen heartworm-free dogs of either sex were initially anesthetized with pentobarbital (20 mg/kg) and endotracheally intubated. Anesthesia was supplemented with fentanyl citrate (0.3 µg/kg/min) and diazepam (0.03 µg/kg/min) administered intravenously as needed to maintain deep anesthesia. The dogs were ventilated with a volume-cycled respirator with oxygen-enriched room air. Serial arterial blood gases were measured to maintain the arterial oxygen tension above 100 mm Hg and arterial carbon dioxide tension between 30 and 40 mm Hg. A standard lead II electrocardiogram was monitored throughout the experimental protocol. Polyethylene catheters were inserted into the right femoral artery and vein.A median sternotomy incision was used to expose the heart. Millar catheter-tipped pressure transducers (Millar Instruments, Houston, Texas) were placed in the proximal aorta and left ventricular cavity to measure aortic and left ventricular pressures, respectively. The left anterior descending (LAD) coronary artery distal to the first marginal branch was dissected and loosely encircled with 2-0 silk suture.

The dogs were randomized to a 2-group paradigm comparing preconditioning and no-preconditioning involving 30 minutes of LAD occlusion and 3 hours of reperfusion, as described previously. ²² In the group without IP (no-IP), the LAD artery was occluded for 30 minutes and reperfused for 3 hours. In the preconditioning group (IP), animals underwent 5 minutes of LAD occlusion followed by 5 minutes of reperfusion and then 30 minutes of LAD occlusion. After 3 hours of reperfusion, the experiment was terminated with a bolus of intravenous pentobarbital (100 mg/kg). The heart was immediately excised and placed into ice-cold Krebs-Henseleit buffer of the following composition: 118 mmol/L NaCl, 4.7 mmol/L KCl, 1.2 mmol/L KH₂PO₄, 1.2 mmol/L MgSO₄ · 7H₂O, 2.5 mmol/L CaCl₂ · 2H₂O, 12.5 mmol/L NaHCO₃, and 11 mmol/L glucose at pH 7.4. After excision of the coronary artery segments in selected experiments, the hearts were sliced transversely and incubated in 1% triphenyltetrazolium chloride solution (37°C) for 10 minutes to visualize necrotic myocardium within the area at risk. Necrosis was not observed by triphenyltetrazolium chloride staining. Three ex vivo bioassays were used to interrogate the effects of in vivo IP on endothelial function.

Neutrophil-endothelial cell adhesion studies
Neutrophil isolation. Neutrophil isolation was performed with techniques previously described. ¹⁴ Briefly, peripheral arterial blood was sampled from the femoral artery before the median sternotomy and PMNs were isolated by the Ficoll-Pacque (Sigma Chemical, St. Louis, Mo) density gradient technique. In our hands, the isolated cell preparation contains greater than 95% PMNs, and cell viability is greater than 90% (trypan blue exclusion). ¹⁴

Neutrophil adherence to coronary artery endothelium. The adherence of unstimulated neutrophils to canine epicardial coronary arteries was assessed with neutrophils labeled with Zynaxis PKH26 vital fluorescent dye (Zynaxis Cell Science, Malvern, Pa). In validation studies performed with the labeling procedure, unlabeled and labeled neutrophils demonstrated 95% and 97% viability, respectively, using trypan blue excision. ¹⁴

After the experiment, LAD (ischemic-reperfused LAD) and left circumflex coronary artery (LCx; nonischemic LCx) segments were isolated after the heart was harvested, cut into 3-mm segments, and carefully opened to expose the endothelium while being submerged in ice-cold Krebs-Henseleit buffer. The segments were then placed in dishes containing Krebs-Henseleit buffer at 37°C. Unstimulated, fluorescent-labeled neutrophils were added to the baths containing the artery segments (final concentration 1 x 10⁶ cells/dish) for 15 minutes. After incubation, coronary segments were washed of nonadherent PMNs by carefully being dipped in Krebs-Henseleit buffer 3 times. The segments were mounted on glass slides, and adherent neutrophils were counted under epifluorescence microscopy (490-nm excitation; 504-nm emission).

Agonist-stimulated vascular relaxation
MACROVESSEL STUDIES. Vasoreactivity in epicardial macrovessels was interrogated as described previously. ¹⁴ Briefly, LAD and LCx segments were carefully transected into 2- to 3-mm rings and placed into organ chambers (Radnoti Glass, Monrovia, Calif) containing oxygenated (95% oxygen and 5% carbon dioxide) Krebs-Henseleit solution at 37°C. Indomethacin (10 µmol/L) was used to inhibit the release of prostaglandins. ¹⁴ The coronary rings were precontracted with an optimal concentration of thromboxane A₂ mimetic agent, U-46619, determined for each experiment (approximately 5 nmol/L). Endothelial function was assessed by comparing the vasorelaxation responses with incremental concentrations of acetylcholine (10 to 685 µmol/L) and A23187 (1-91 µmol/L), whereas smooth muscle responses were assessed with sodium nitroprusside (1-381 µmol/L). The order of dilator agent administration was random, except for A23187, which was always administered last because this causes the acute loss of responsiveness to other endothelial agonists.

MICROVESSEL STUDIES. Coronary microvessels were studied as previously described. ²³ Briefly, 1 or 2 myocardial arterial microvessels (150-200 µm in internal diameter) were dissected from the LAD distribution within the ischemic zone. The vessels were placed in a circulating organ bath (Krebs-Henseleit buffer, 37°C), cannulated with dual glass micropipettes, and secured with monofilament suture. The microvessels were pressurized to 20 mm Hg in a no-flow state. With an inverted microscope connected to a video camera (IX50-S8F; Olympus Optical Company, Ltd, Japan), the vessel was projected onto a television monitor. A video dimension analyzer (Halern; Living Systems Instrumentation, Burlington, Vt), with edge detection algorithms, was used to measure internal lumen diameter.

After 60 minutes of equilibration, the microvessels were preconstricted with U-46619 (5 nmol/L) and dilated in a dose-response fashion with acetylcholine (1 x 1010–3 x 105 mol/L), A23187 (1 x 1010–3 x 105 mol/L), or sodium nitroprusside (1 x 1010–3 x 105 mol/L). The order of dilator agent administration was random, except for A23187, which was always administered last.

Chemical preparation
Acetylcholine chloride, the calcium ionophore A23187, sodium nitroprusside, and indomethacin were obtained from Sigma Chemical Company (St Louis, Mo). The final concentrations of acetylcholine, A23187, sodium nitroprusside, indomethacin, and U-46619 were determined from a previous study. ¹⁴ The thromboxane A₂ mimetic, U-46619, was donated from Upjohn Pharmaceuticals, Inc (Kalamazoo, Mich). Ca²⁺- and Mg²⁺-free Hanks' balanced salt solution 1X was purchased from Cellgro (Mediatech, Inc, Herndon, Va).

Statistical analysis
An 1-way analysis of variance was used to determine whether group-related differences occurred. If significant interactions were found, Tukey's or Student-Newman-Keuls post hoc multiple comparisons tests were applied to locate the sources of differences. The mean ± standard error of the mean are reported.

	Results

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Neutrophil adherence to coronary endothelium
After the experiment, unstimulated, fluorescent-labeled neutrophils were coincubated with epicardial coronary arterial segments from both the ischemic-reperfused LAD artery and the nonischemic-reperfused LCx (Fig 1). In the no-IP group, neutrophil adherence was significantly greater by 29% in the LAD segments as compared with the LCx segments (528 ± 29 vs 409 ± 25 neutrophils/mm², respectively; P = .004). In contrast, in the ischemic-preconditioned group neutrophil adherence in the ischemic-reperfused LAD coronary segments was comparable to that observed in the nonischemic-reperfused LCx segments of the same group and was reduced by 44% compared with no-IP LAD segments (293 ± 25 vs 528 ± 29 neutrophils/mm², respectively; P < .001).

View larger version (20K): [in this window] [in a new window]   Fig. 1. Adherence of neutrophils to coronary artery endothelium with IP or no-IP. Labeled neutrophils were quantified with epifluorescence microscopy and are represented as the sum of neutrophils adhering to the endothelial surface per square millimeter of endothelium. Values are mean ± standard error of the mean.

View larger version (29K): [in this window] [in a new window]   Fig. 2. Response curves to incremental concentrations of acetylcholine (ACh) to coronary macrovessels precontracted with U46619, which were treated with no-IP (A) or IP (B). Responses are expressed as percent relaxation from precontracted tension. Values are mean ± standard error of the mean. The number of coronary rings in each group is given in parentheses. *P < .05 versus LCx.

View larger version (25K): [in this window] [in a new window]   Fig. 3. Response curves to incremental concentrations of acetylcholine (ACh; A), calcium ionophore (A23187; B), and sodium nitroprusside (NP; C) to LAD microvessels (150-200 µmol/L) precontracted with U46619, which were treated with no-IP or IP. Responses are expressed as percent relaxation from precontracted tension. Values are mean ± standard error of the mean. The number of microvessels in each group is given in parentheses. *P < .05 versus no-IP.

	Discussion

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Since the initial report of IP by Murry and colleagues, ¹ a considerable amount of literature regarding this phenomenon has been published focusing primarily on the end points of contractile function and infarct size. Although IP reduces myocyte necrosis resulting from a prolonged ischemia, the effects of preconditioning on the coronary vascular endothelium is less well defined. In 1993, DeFily and Chilian, ¹⁷ measuring vasodilator reserve in in vivo canine coronary arterioles, demonstrated that IP preserved endothelial-dependent vasodilation after myocardial ischemia-reperfusion. Similar endothelial protection with IP was reported by Richard and colleagues. ¹⁸ Conversely, Bauer and colleagues ²⁰ reported that although IP significantly reduced myocardial infarct size, the protective effects did not extend to the coronary endothelium because IP did not significantly improve postischemic endothelium-dependent responses to acetylcholine. More recently, Kaeffer and colleagues ¹⁶ showed that endothelial dysfunction as the result of ischemia-reperfusion persisted for at least 1 month and that IP attenuated this prolonged endothelial dysfunction. The present study showed that IP preserved acute endothelial function in both epicardial coronary macrovessels and microvessels in agreement with DeFily and Chilian ¹⁷ and others ^16,18-20 and extended these observations by demonstrating a reduction in neutrophil adherence with IP. However, it is not known whether endothelial dysfunction in postischemic macrovessels and microvessels is a long-term event in this MIDCABG model, or whether IP offers sustained protection.

It is well established that under basal conditions, normal endothelium releases nitric oxide, which acts to tonically retard the adherence of neutrophils to coronary endothelium. In response to myocardial ischemia-reperfusion, the ability to synthesize and release nitric oxide is impaired in relation to the degree of endothelial injury, which leads to increased basal neutrophil adherence and reduced vascular relaxation responses to agonist stimulators of nitric oxide synthase. In our study, we demonstrated that myocardial stunning increases basal neutrophil-coronary endothelial adherence in ischemic LAD when compared with the neutrophil-endothelial adherence in the nonischemic LCx. Although it is well established that the interaction between PMN and coronary vascular endothelium at reperfusion leads to endothelial dysfunction, ^24,25 which can largely be attenuated by anti-PMN therapy (nitric oxide, adenosine, monoclonal antibodies), ^14,15,26 it is not clear from our study whether IP reduced endothelial dysfunction by directly protecting the endothelium or by directly attenuating neutrophil activation and adherence. If the preconditioning response is mediated, in part by adenosine, then both cell types may be effected directly. However, it would be interesting to determine whether endothelial protection by IP involved attenuation of neutrophil events at reperfusion. Nevertheless, the protection afforded to the endothelium is manifested in part by inhibiting PMN adherence.

Study limitations
Although the beneficial effects of IP have not been found in all species, many studies have reported the beneficial effects of IP in both canine and human patients. It is possible that the degree of injury and the effectiveness of IP may be blunted in human patients. ²⁷ The effects of IP on human myocardium may depend on whether the ischemia is local (ie, coronary occlusion) or global. In addition, our studies were performed in normal coronary vessels. However, in instances where underlying pathologic conditions such as atherosclerosis, diabetes mellitus, or hypercholesterolemia may significantly impact the ability of the endothelium to produce endogenous protection with ischemic or chemical preconditioning, the protection afforded by preconditioning may be less than in normal vessels. Further studies interrogating the effects of IP on endothelial function in humans undergoing coronary artery bypass grafting are warranted. Another consideration is the clinical relevance of the duration of LAD occlusion used in the present study. In a large study of MIDCABG procedures, the time to completion of target vessel anastomosis averaged 23 minutes. ²⁸ In the present study, the duration of regional ischemia (30 minutes) is only somewhat longer than that encountered during completion of anastomoses in MIDCABG operations. Whether shorter periods of coronary occlusion in patients with underlying disease causes endothelial dysfunction needs to be determined.

In summary, the present study used a canine model of transient coronary occlusion to evaluate the effect of IP on coronary artery endothelium. We conclude that IP attenuated endothelial dysfunction expressed as neutrophil adherence to the ischemic-reperfused LAD and attenuated endothelial dysfunction in both coronary macrovessels and microvessels, which may have implications for the long-term patency of grafts and myocardial viability. Furthermore, we have demonstrated that IP reduces neutrophil adherence to vascular endothelium, which is consistent with an attenuation of neutrophil accumulation in ischemic-reperfused areas at risk observed in a previous study with the same model. ²² This study may be clinically important for the practicing cardiac surgeon, because protection of coronary vascular endothelial function by IP may diminish reperfusion injury, reduce vascular permeability and myocardial edema, and possibly reduce end-artery thrombosis and its associated complications.

	Acknowledgments

 
We thank Ms Gail Nechtman for formatting the manuscript; Mrs Susan Schmarkey, Ms Sara Katzmark, and Ms Jill Robinson from the Cardiothoracic Research Laboratory for technical support; the Carlyle Fraser Heart Center at Emory University School of Medicine for its continued support of the research effort; and Ron Shebusky, PhD, (Pharmacia-Upjohn Pharmaceutics) for the gift of U46619.

	References

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