Ann Thorac Surg 1997;63:20-27
© 1997 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Coronary Microvascular Reactivity After Ischemic Cold Storage and Reperfusion
Charles O. Murphy, MD,
Pan-Chih, MD,
John Parker Gott, MD,
Robert A. Guyton, MD
Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine, Carlyle Fraser Heart Center-Cardiothoracic Research Laboratory, Crawford Long Hospital, Atlanta, Georgia
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Abstract
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Background. The coronary microvascular system is important in the regulation of myocardial perfusion. Preservation of microvascular reactivity may be important in those hearts undergoing ischemic storage for transplantation. Endothelium-dependent relaxation of right and left ventricular coronary microvessels was examined in a canine model of heart transplantation.
Methods. Canine hearts underwent topical cooling, antegrade arrest, and 3 hours' ischemic cold storage at 4°C using crystalloid cardioplegia (n = 8), Roe's solution (n = 8), and University of Wisconsin solution (n = 8). All groups underwent 1 hour of reperfusion in an isolated heart circuit. Noninstrumented canines were used as controls (n = 10). Coronary microvessels (100 to 200 µm in diameter) were examined in a pressurized, no-flow state with video microscopic imaging and electronic dimension analysis.
Results. Endothelium-dependent microvascular relaxation was examined in response to the receptor-dependent acetylcholine and to the receptor-independent calcium ionophore. Microvascular relaxation to acetylcholine in Roe's solution and University of Wisconsin solution was preserved (p = not significant) in the left ventricle, whereas crystalloid cardioplegia failed to preserve (p < 0.05) microvascular relaxation when compared with the control groups. Right ventricular microvascular relaxation was always (p < 0.05) less than left ventricular microvascular relaxation. Endothelium-independent microvascular relaxation to nitroprusside was similar to that in controls, indicating normal smooth muscle responsiveness.
Conclusions. Ischemic cold storage with Roe's solution and University of Wisconsin solution preserved microvascular relaxation in the left ventricle, whereas crystalloid cardioplegia failed to preserve microvascular relaxation. Right ventricular microvascular relaxation was impaired in all groups, but University of Wisconsin solution was superior to crystalloid cardioplegia and Roe's solution. This suggests that microvascular dysfunction may be partially responsible for right ventricular dysfunction after heart transplantation. The choice of preservation solution may be important in preservation of the microvascular endothelium.
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Introduction
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See also page 26.
The endothelium is an important regulator of vasomotor tone in the coronary microvasculature, and the coronary microvascular system is important in the regulation of myocardial perfusion. Reduced myocardial perfusion after cardiac operations may be related to impaired endothelium-dependent microvascular reactivity. Studies have shown the importance of protecting the microvasculature in attenuating reperfusion injury [1, 2]. Preservation of microvascular reactivity may be especially important in those hearts undergoing cold ischemic storage for transplantation. Potential impairment of the right ventricular endothelium-dependent microvascular response after harvesting and implantation [2] is also a likely contributing factor in right ventricular failure after cardiac transplantation.
Although success has been realized in cardiac transplantation, long-term success has been limited by cardiac allograft vasculopathy, a form of coronary artery disease in the transplanted heart. It is believed that endothelial cell injury initiates smooth muscle cell migration and proliferation in the transplanted coronary arteries, leading to progressive concentric narrowing [3]. In addition, right ventricular failure is common after cardiac transplantation and may be due to an increase in pulmonary vascular resistance [4], possibly due to pulmonary microvascular endothelial dysfunction [5, 6].
To date, the effect of preservation solutions for ischemic cold storage on endothelial integrity and microvascular reactivity has not been studied. In particular, the response of microvessels from the right ventricle in a heart transplantation model after cold storage and reperfusion has not been examined. In this study, we examined microvessels from branches of both the right coronary artery and the left circumflex coronary artery in a canine transplantation model to determine whether the choice of preservation solution for ischemic cold storage and reperfusion is important in endothelial preservation.
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Material and Methods
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Thirty-four Dirofilaria-free adult mongrel dogs weighing 22 to 30 kg were studied. All animals were premedicated with morphine sulfate (4 mg/kg). Anesthesia was induced with intravenous pentobarbital (20 mg/kg) and maintained with intermittent boluses (3 mg/kg). The animals were intubated endotracheally and placed on a volume ventilator. The right femoral artery was cannulated for arterial pressure monitoring. The left femoral artery was cannulated for exsanguination. In the control group (n = 10), a sternotomy was performed. The heart was excised rapidly and placed immediately in cold (1° to 4°C) Krebs/HEPES buffer solution of the following composition (in mmol/L): NaCl, 99.0; KCl, 4.7; CaCl, 2.5; MgSO4, 1.2; NaHCO3, 26.0; K2HPO4, 1.0; NaHEPES, 20.0; and glucose, 11.1. Responses of microvessels from these hearts served as nonischemic controls for the three preservation groups.
After induction of anesthesia, intubation, and preparation, arterial blood gases were measured and adjusted by ventilatory rate, tidal volume, and inspired oxygen fraction to maintain oxygenation greater than 100 mm Hg, pH between 7.35 and 7.45, and carbon dioxide tension between 30 and 45 mm Hg. A median sternotomy was used for exposure of the heart and great vessels. The great vessels were dissected and isolated with umbilical tape. The azygos vein was then ligated. The animal was given heparin at 400 U/kg. The left subclavian artery was cannulated for preservation solution inflow. The superior and inferior venae cavae were then ligated. Next, the distal aortic arch was cross-clamped and ligated. Exsanguination occurred by gravity from the left femoral artery. One of three preservation solutions (crystalloid cardioplegia [CCP], Roe's solution [ROE], or University of Wisconsin solution [UW]) was infused into the left subclavian artery to arrest the heart (Table 1
). The crystalloid solution tested is that used clinically for routine cardiac operations in our institution. The total preservation solution delivered approximated the clinical use of about 3 mL/g of heart (with the assumption that the average canine heart mass to total body mass ratio is approximately 9 g/kg). Cold topical saline slush was used to cool the heart. The cardioplegia was vented through a venotomy in the superior and inferior venae cavae. After arrest, the heart was excised with the pericardium intact and stored in an ice chest at 4°C for 3 hours. The temperature range during ischemic cold storage was approximately 0° to 4°C. The exsanguinated blood was stored at 4°C for subsequent reperfusion. The pulmonary arterial trunk was then ligated. After cold storage, air was displaced from the heart and the heart was mounted in an isolated heart circuit involving a standard roller pump, membrane oxygenator (Cobe)/heat exchanger, and venous reservoir. The circuit was primed with homologous blood and crystalloid to a hematocrit of 19% ± 0.9%. The pH was adjusted to 7.4 with sodium bicarbonate as needed. Lidocaine hydrochloride was added to a calculated therapeutic level of 3 µg/mL. Blood inflow was into the brachiocephalic artery, and outflow was from a vent in the right ventricular free wall. The apex of the left ventricle was vented. The heart underwent controlled reperfusion with normothermic (37°C) oxygenated blood at a mean aortic pressure between 50 and 80 mm Hg. The heart was electrically defibrillated as needed at 5 minutes of reperfusion and as needed if persistent ventricular fibrillation was present. The heart was not placed in a working mode. Hearts that failed to recover with a spontaneous rhythm at 60 minutes were excluded from the study. There were no significant differences between groups in the hearts that were excluded from the studies. After 60 minutes of reperfusion, the hearts were removed rapidly from the circuit and placed in cold Krebs/HEPES buffer solution.
All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication no. 85-23, revised 1985).
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Coronary Microvessel Studies
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One to two vessels from either the right or left ventricle of each heart were studied. Microarterial vessels (100 to 200 µm in internal diameter) were dissected from the right and left ventricles of the hearts from the three experimental groups using a 10 to 60x dissecting microscope. The vessels were placed in an isolated double chamber Plexiglas organ chamber, cannulated with dual glass micropipettes (tip measuring 40 to 80 µm in diameter), and secured with 10-0 nylon monofilament suture. Krebs/HEPES buffer solution warmed to 37°C was circulated continuously through both organ chambers and both reservoirs. The total volume of each organ chamber and reservoir was 100 mL. The microvessels were pressurized to 20 mm Hg in a no-flow state. With an inverted microscope connected to a video camera, we projected the vessel image onto a black and white television monitor. A Halpern video dimension analyzer (Living Systems Instrumentation, Burlington, VT) was used to measure internal lumen diameter. The vessels were allowed to bathe in the organ chamber for 30 to 120 minutes before an intervention.
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Study Protocol
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After equilibration, the microvessels were constricted with endothelin I (0.1 to 10 nmol/L) by 30% to 40% of the baseline diameter. Acetylcholine chloride (1 x 10-10 to 3 x 10-5 mol/L), calcium ionophore (1 x 10-10 to 3 x 10-5 mol/L), or sodium nitroprusside (1 x 10-10 to 3 x 10-5 mol/L) was applied extraluminally. The order of administration was random except for calcium ionophore, which was always administered last. The microvessels were washed and allowed to equilibrate for 10 to 15 minutes between interventions. One to four interventions were performed on each vessel, and right and left ventricular vessels were examined from each heart.
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Drugs
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Endothelin I, acetylcholine chloride, the calcium ionophore A 23187, and sodium nitroprusside were obtained from Sigma Chemical Co. (St. Louis, MO).
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Data Analysis
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Microvascular relaxation values are expressed as the percentage relaxation of the endothelin I–induced constriction of the vessel diameter [(vessel diameter after application of agonist - preconstricted diameter)/(baseline diameter - preconstricted diameter)]. Values are expressed as mean ± standard error of the mean. Statistical analyses were carried out with the aid of a statistician (R. S. Clark, PhD, Emory University). Responses of the microvessels to all drugs at all drug concentrations were compared by two-way analysis of variance with repeated measures. Whenever a significant difference was observed, Tukey's test for multiple comparisons was used to evaluate possible differences between the preservation groups. Bonferroni's test for multiple comparisons was used to determine possible differences between the preservation groups and right versus left ventricular microvessels. Statistical significance was assumed at p < 0.05.
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Results
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Initial mean aortic pressures were 92 ± 1, 102 ± 4, and 101 ± 8 mm Hg in the CCP, ROE, and UW preservation groups, respectively. Mean aortic pressure after ischemic cold storage for 3 hours, cardioplegic arrest, and 60 minutes of reperfusion was 75 ± 3, 82 ± 1, and 72 ± 4 mm Hg in the CCP, ROE, and UW groups, respectively. The combined hematocrit of all groups before harvest and cold storage was 36% ± 1%.
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Vessel Characteristics
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Microvessel size ranged between 100 and 200 µm in internal diameter in both the right and left ventricles. Average internal diameters were 143 ± 6, 197 ± 13, 181 ± 17, and 178 ± 10 µm in the control, CCP, ROE, and UW groups in the left ventricle, respectively. The right ventricular microvessels had average internal diameters of 161 ± 10, 181 ± 12, 166 ± 12, and 171 ± 18 µm in the control, CCP, ROE, and UW groups, respectively. The percentage constriction after administration of endothelin I in the left ventricular microvessels was 36% ± 1%, 34% ± 0.2%, 33% ± 0.07%, and 34% ± 0.12% in the control, CCP, ROE, and UW groups, respectively. The percentage constriction after administration of endothelin I in the right ventricular microvessels was 36% ± 1%, 36% ± 0.24%, 36% ± 0.21%, and 32% ± 0.16% in the control, CCP, ROE, and UW groups, respectively.
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Endothelium-Independent Response
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Relaxation to the endothelium-independent vasodilator sodium nitroprusside was similar in the microvasculature from the right and left ventricles of the control group and the three different preservation groups, indicating normal smooth muscle responsiveness (Table 2).
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Endothelium-Dependent Response: Right Ventricle
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Endothelium-dependent relaxation to the vasodilator acetylcholine was significantly (p < 0.05) impaired in the right ventricle in the CCP (43% ± 7%), ROE (41% ± 5%), and UW (70% ± 13%) groups when compared with the control group (100% ± 0.3%) (Fig 1). The UW response was superior (p < 0.05) to the CCP and ROE responses in the right ventricular microvessels. The endothelium-dependent response to the nonreceptor-mediated vasodilator calcium ionophore was likewise impaired significantly (p < 0.05) in the right ventricle in the CCP (36% ± 7%), ROE (42% ± 4%), and UW (65% ± 14%) groups (Fig 2) when compared with the control group (98% ± 1%). This response was also superior in the UW (p < 0.05) group when compared with the CCP response and the ROE response.
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Fig 1. . Responses to acetylcholine in vitro of canine coronary microvessels from the right ventricle in control hearts (CON; n = 10) and in hearts after 3 hours of cold ischemic storage using crystalloid cardioplegia (CCP; n = 8), Roe's solution (ROE; n = 8), or University of Wisconsin solution (UW; n = 8) followed by 1 hour of reperfusion. Microvessels were pressurized (20 mm Hg) in a no-flow state and preconstricted with endothelin I by 30% to 40% of the baseline diameter. (SEM = standard error of the mean; *p < 0.05 compared with control.)
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Fig 2. . Maximum response to calcium ionophore at a maximum concentration of 3 x 10-5 mol/L in vitro of canine coronary microvessels from the right ventricle in control hearts (CON; n = 10) and in hearts after 3 hours of cold ischemic storage using crystalloid cardioplegia (CCP; n = 8), Roe's solution (ROE; n = 8), or University of Wisconsin solution (UW; n = 8) followed by 1 hour of reperfusion. (*p < 0.05 compared with control.)
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Endothelium-Dependent Response: Left Ventricle
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The endothelium-dependent response to acetylcholine was significantly (p < 0.05) reduced in the left ventricle in the CCP (52% ± 9%) group when compared with the control group (100% ± 0.3%) (Fig 3). Roe's solution (81% ± 5%) and UW (95% ± 4%) preserved (p = not significant) the endothelium-dependent response to acetylcholine in the left ventricle when compared with the control (100% ± 0.3%) response. The endothelium-dependent response to the nonreceptor-mediated vasodilator calcium ionophore was impaired (p < 0.05) in the left ventricle in the CCP (58% ± 6%) group when compared with the control (98% ± 1%) group (Fig 4). The microvessel response was preserved (p = not significant) in the ROE (74% ± 5%) and the UW (92% ± 4%) left ventricular groups when compared with control (98% ± 1%) values.
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Fig 3. . Maximum response to acetylcholine at a maximum concentration of 3 x 10-5 mol/L in vitro of canine coronary microvessels from the left ventricle in control hearts (CON; n = 10) and in hearts after 3 hours of cold ischemic storage using crystalloid cardioplegia (CCP; n = 8), Roe's solution (ROE; n = 8), or University of Wisconsin solution (UW; n = 8) followed by 1 hour of reperfusion. (*p < 0.05 compared with control.)
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Fig 4. . Maximum response to calcium ionophore at a maximum concentration of 3 x 10-5 mol/L in vitro of canine coronary microvessels from the left ventricle in control hearts (CON; n = 10) and in hearts after 3 hours of cold ischemic storage using crystalloid cardioplegia (CCP; n = 8), Roe's solution (ROE; n = 8), or University of Wisconsin solution (UW; n = 8) followed by 1 hour of reperfusion. (*p < 0.05 compared with control.)
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Endothelium-Dependent Response in All Groups: Right Versus Left Ventricle
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The endothelium-dependent response to acetylcholine was significantly (p < 0.05) lower in the combined CCP, ROE, and UW (51% ± 5.5%) right ventricular groups than in the CCP, ROE, and UW (76% ± 5%) left ventricular groups (Fig 5). The endothelium-dependent response to the nonreceptor-mediated vasodilator calcium ionophore was impaired (p < 0.05) in the combined CCP, ROE, and UW (48% ± 6%) right ventricular groups when compared with the combined response in the CCP, ROE, and UW (74% ± 5%) left ventricular groups (Fig 6).
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Fig 5. . Maximum response to acetylcholine at a maximum concentration of 3 x 10-5 mol/L in vitro of canine coronary microvessels from the right ventricle (RV) in all groups (n = 24) and the left ventricle (LV) in all groups (n = 24) after 3 hours of cold ischemic storage followed by 1 hour of reperfusion. (*p < 0.05 compared with combined left ventricular groups.)
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Fig 6. . Maximum response to calcium ionophore at a maximum concentration of 3 x 10-5 mol/L in vitro of canine coronary microvessels from the right ventricle (RV) in all groups (n = 24) and the left ventricle (LV) in all groups (n = 24) after 3 hours of cold ischemic storage followed by 1 hour of reperfusion. (*p < 0.05 compared with combined left ventricular groups.)
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Comments
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This study examined a canine model of heart transplantation, cold ischemic storage, and reperfusion in an isolated heart circuit. The preservation solutions were studied in a model designed to simulate the clinical procurement, extended storage, and initial reperfusion of the implanted heart. The harvesting of the heart and ischemic cold storage period are nearly analogous to those in current clinical practice. The isolated heart model was used to minimize the variability inherent in the use of different animals; thus the hematocrit, acid-base balance, aortic pressure, and temperature were controlled. In addition, factors that affect cardiac function were eliminated, such as respiratory and hormonal variability, as well as the autonomic effects on the peripheral circulation. The focus of this study was microvascular reactivity, as only the coronary arteries were perfused during the reperfusion phase. Myocardial recovery was not examined in this study. Unlike other investigators who have used large conduit artery rings to determine endothelium-dependent relaxation, we examined coronary microvessels in this study. Microvessels were studied that had an internal diameter less than 200 µm. These vessels represent true coronary resistance vessels [7]. The microvessel studies were performed in vitro to eliminate any metabolic or autoregulatory influences. Although a direct correlation to in vivo regulation of myocardial coronary perfusion cannot be made, in vitro study findings have generally been in agreement with other in vivo findings in other reports [8]. The microvessels were examined in a no-flow state and drugs were infused extraluminally to eliminate the effects of flow-induced vasodilation of the microvessel. Another advantage of this study is the use of a receptor-mediated agonist (acetylcholine), a nonreceptor-mediated agonist (calcium ionophore) and a receptor-independent agonist (sodium nitroprusside) to determine whether, there are any alterations in the pathway to stimulation of production of endothelium-derived relaxing factor (EDRF). This study specifically examined the production of EDRF; because EDRF is not a product of the cyclooxygenase pathway, indomethacin was not used.
During heart transplantation, the transplanted heart sustains both ischemic and reperfusion injuries. Studies have suggested that these processes can impair the ability of the vascular endothelium to produce EDRF [9]. In addition, clinical studies have suggested endothelial dysfunction more than 2 years after heart transplantation [10, 11], and this may be associated with the development of transplant vasculopathy. Our study extends these findings to the microvasculature. This is important because endothelial dysfunction is much more likely to develop in the coronary microcirculation after ischemia and reperfusion than in larger vessels [12]. Several studies have examined the effects of preservation solutions on the endothelium-dependent response [13, 14], but these studies did not examine the microvasculature or allow for reperfusion of the heart with the animal's blood after the ischemic period.
In the present study, right and left ventricular microvessels were examined to determine endothelium-dependent relaxation after ischemic cold storage and reperfusion. We found that ischemic cold storage with ROE and UW preserved microvascular reactivity in the left ventricle when compared with the control group, whereas CCP failed to preserve the endothelium-dependent response. The right ventricular microvascular response was impaired in all groups when compared with the control group. The UW response in the right ventricle was significantly better than that in the CCP and ROE groups. In addition, the right ventricular microvascular response of all preservation groups combined was significantly less than the left ventricular microvascular response of all groups combined.
In the present study, impairment of the coronary microvascular response was demonstrated acutely after heart transplantation, due to impairment of stimulation of EDRF release. There are several possible mechanisms by which ischemic cold storage and reperfusion may impair the endothelium-dependent response. The expression of leukocyte adhesion molecules on the vascular endothelium has been implicated in the neutrophil-endothelial interaction during reperfusion [15]. This interaction results in the impairment of EDRF release. Cardiopulmonary bypass is known to produce neutrophil activation [16] and complement activation [17]. Together, these factors contribute to the "response to injury" hypothesis regarding transplant vasculopathy. The hypothesis states that endothelial cell injury initiates smooth muscle cell migration and proliferation in the transplanted coronary arteries, leading to progressive concentric narrowing [3]. The ROE and UW preservation solutions preserved the microvascular response in the left ventricle. This suggests that the choice of preservation solution may be important for the attenuation of reperfusion injury after ischemic cold storage; better endothelial preservation may lead to a reduced incidence of coronary vasculopathy.
Whereas coronary vasculopathy has limited the long-term success of cardiac transplantation, right ventricular dysfunction remains the leading cause of early death after cardiac transplantation. Our previous study demonstrated an impaired response in right ventricular microvessels after cardioplegic arrest and reperfusion [2]. The present study extends this finding to an experimental model simulating transplantation. All preservation groups had impaired endothelium-dependent responses in the right ventricular microvessels. In addition, the combined microvascular response of all preservation solutions in the right ventricle was impaired when compared with the combined endothelium-dependent response in the left ventricle, suggesting that the right ventricular microvascular response may be more vulnerable to ischemia and reperfusion injury than the left ventricular response. The cause of this increased vulnerability is uncertain. The impaired release of EDRF in the right ventricular microvessels may lead to a decreased blood flow to the right ventricular myocardium and may thereby contribute to right ventricular dysfunction early after cardiac transplantation.
Studies also suggest that right ventricular dysfunction after cardiac transplantation may be related to pulmonary hypertension [18]. Although pulmonary microvessels were not examined in this study, Shafique and associates [5] demonstrated that cardiopulmonary bypass with associated reductions in pulmonary perfusion results in a decrease in the pulmonary microvascular reactivity related to a reduction in the release of EDRF. Kimblad and associates [6] demonstrated that pulmonary endothelial dysfunction appears to contribute to the increase in pulmonary vascular resistance. The vulnerability of the right ventricular microvessels to ischemic cold storage and reperfusion injury in addition to the altered pulmonary microvascular reactivity may contribute markedly to right ventricular dysfunction after cardiac transplantation.
This study shows the importance of the choice of preservation solutions. Although all groups had impaired endothelium-dependent reactivity in the right ventricular microvessels when compared with the control group, the UW response was significantly better than the CCP or ROE response in the right ventricle. The preservation of the left ventricular microvascular response in the ROE and UW groups and the superior response in the right ventricular microvessels in the UW group may be related to the composition of the preservation solution. The UW preservation solution has sodium (Na+) and potassium (K+) concentrations that are similar to those found in the intracellular space. The potential advantage of intracellular solutions over extracellular solutions such as CCP is that the intracellular solution minimizes the reequilibration of normal ion gradients that are required during reperfusion [19]. The intracellular solutions used for preservation of organs for transplantation accomplish most closely the critical principles for successful cold storage outlined by Belzer and Southard [20]: prevention of cold-induced cellular swelling, prevention of intracellular acidosis, reduction of interstitial fluid, reduction of free-radical injury, and provision of substrate for cellular energy production during reperfusion. The absence of specific compounds in the CCP known to have a role in reduction of free-radical formation or in suppression of their deleterious effects may help explain its impairment of the endothelium-dependent response in the right and left ventricular microvessels. In contrast, the ROE solution contains some compounds that help to stabilize cellular membranes to prevent cellular edema and intracellular acidosis (Solu-Medrol [methylprednisolone sodium succinate; Upjohn, Kalamazoo, MI], magnesium sulfate).
The increased vulnerability of the right ventricular microvessels to ischemia and reperfusion injury as compared with the left ventricular microvessels [2] led to the demonstration of a significant difference between the UW and ROE groups. The inclusion of additional compounds in the UW solution resulted in a superior response in the right ventricle when compared with both the CCP and ROE groups. The xanthine oxidase inhibitor allopurinol reduces the production of free radicals, and glutathione replenishes this intracellular antioxidant. The inclusion of precursors (adenosine) for high-energy compound synthesis during reperfusion has been shown to attenuate the injury sustained at reperfusion [21]. In addition, UW solution incorporates osmotically active and metabolically inactive impermeants to prevent interstitial edema. These considerations may contribute to the superior response in the right ventricular microvessels with UW preservation as compared with CCP or ROE preservation.
The results of this study suggest that dysfunction of endothelium-dependent microvascular relaxation may be partially related to the choice of preservation solution for heart transplantation. In addition, the choice of preservation solution for ischemic cold storage and reperfusion is pivotal in the preservation of endothelium-dependent microvascular response and, possibly, the subsequent cardiac function, particularly right heart function, after heart transplantation.
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Footnotes
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Presented at the Thirty-second Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 29–31, 1996.
Address reprint requests to Dr Guyton, Carlyle Fraser Heart Center, Crawford Long Hospital of Emory University, 550 Peachtree St NE, Suite 4356, Atlanta, GA 30365-2225.
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References
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- Hosenpud JD, Shipley GD, Wagner CR. Cardiac allograft vasculopathy: current concepts, recent developments, and future directions. J Heart Lung Transplant1992;11:9–23.[Medline]
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V. H. Thourani, M. Nakamura, I. G. Duarte, B. L. Bufkin, Z.-Q. Zhao, J. E. Jordan, S. T. Shearer, R. A. Guyton, and J. Vinten-Johansen
ISCHEMIC PRECONDITIONING ATTENUATES POSTISCHEMIC CORONARY ARTERY ENDOTHELIAL DYSFUNCTION IN A MODEL OF MINIMALLY INVASIVE DIRECT CORONARY ARTERY BYPASS GRAFTING
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Abstract
Introduction
