Ann Thorac Surg 1997;64:1325-1330
© 1997 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Vascular Effects of Cyclosporin A and Acute Rejection in Canine Heart Transplantation
Denis Bouchard, MD,
Marc-Antoine Despatis, MD,
Josie Buluran, BSc,
Raymond Cartier, MD
Department of Surgery, Montreal Heart Institute, Montreal, Quebec, Canada
Accepted for publication May 14, 1997.
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Abstract
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Background. Alteration of coronary vascular regulation during acute rejection may induce graft dysfunction and promote the occurrence of coronary atherosclerosis in transplant recipients. We studied the effects of treated and untreated acute rejection on coronary vascular regulation.
Methods. Two groups of mongrel dogs (n = 7) underwent heterotopic heart transplantation (cervical position) and received either no treatment (group 1) or cyclosporin A (CyA), 10 mg • kg-1 • day-1 (group 2). On day 7, recipient native and transplanted hearts were harvested and studied in organ chambers for coronary vascular reactivity.
Results. Transplanted hearts from group 1 displayed grade IV histologic rejection, whereas those from group 2 displayed grade IIIA to IV rejection. Intimal hyperplasia was found in the coronary arteries of both groups. Immunoperoxidase staining revealed the presence of factor VIII and of immunoglobulin M and G antibodies on the endothelium of both groups. Coronary relaxation to thrombin was impaired in transplanted hearts compared with native hearts (p < 0.05), and this was not influenced by CyA treatment. Conversely, endothelium-dependent relaxation to 5-hydroxytryptamine was enhanced in both CyA-treated (p < 0.01) and untreated groups (p < 0.05). A facilitating effect of CyA on 5-hydroxytryptamine also was seen in transplanted hearts in group 1 versus group 2 (p < 0.05), suggesting an intrinsic effect of CyA. Endothelium-independent relaxation to sodium nitroprusside and the contractile response to prostaglandin F2
were not affected.
Conclusions. In our model, acute rejection did not specifically impair cyclic guanosine monophosphate–mediated relaxation, but it did affect, in a receptor-specific manner, endothelium-dependent relaxation. Cyclosporin A appeared to enhance coronary endothelial sensitivity to 5-hydroxytryptamine.
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Introduction
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See also page 1330.
Accelerated coronary atherosclerosis remains a major limiting factor to long-term survival in cardiac transplantation [1]. The pathogenesis of this form of coronary atherosclerosis is multifactorial, and in addition to chronic rejection, hyperlipidemia, changes in lifestyle, donor age, type of cardiomyopathy, vascular rejection, and treatment with cyclosporin A (CyA) have been suggested as causative factors [2–4]. The vascular endothelium is an important regulator of local vascular tone, mainly through the release of nitric oxide, a powerful vasorelaxant and antiplatelet agent [5]. Although coronary endothelial dysfunction has been linked to atherogenesis in native hearts, it also has been shown to occur early on in transplanted hearts, before the appearance of angiographically detectable atherosclerotic disease [6, 7]. It has been suggested that the progressive narrowing of epicardial coronary arteries documented in transplanted hearts is related to impaired endothelial function [8].
The role of acute rejection in premature coronary atherosclerosis has not been defined. Although experimental evidence suggests a direct link, clinical experience with human heart transplantation has been less convincing [9]. Through its cytotoxic process, acute rejection eventually may injure the endothelium and set the stage for eventual abnormal pathologic vascular physiology. This study was designed to investigate the effects of acute vascular rejection and immunosuppressive treatment with CyA on coronary artery endothelial reactivity in a canine model of heterotopic heart transplantation.
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Material and Methods
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Experimental Groups and Surgical Procedure
Fourteen mongrel dogs underwent heterotopic heart transplantation in the cervical position. In the first group (n = 7), transplantation was carried out and the recipient animals were kept alive for 7 days without any immunosuppressive therapy. In the second group (n = 7), an immunosuppressive regimen of CyA (10 mg • kg-1 • day-1 (Sandoz Ltd, Dorval, Quebec, Canada) was initiated on day 2 before transplantation and continued until day 7 after transplantation.
The hearts from the donor dogs (body weight, 12 to 18 kg) were removed after having received 500 mL of cold (4°C) crystalloid cardioplegic solution, composed of 130 mmol/L of Na+, 159 mmol/L of Cl-, 24 mmol/L of K+, 1 mmol/L of Ca2+, 28 mmol/L of lactate, 20 g/L of mannitol, and 170 mg/L of NaHCO3. The hearts then were preserved in a cold (4°C) Krebs-Ringer's solution, composed of 118.3 mmol/L of NaCl, 4.7 mmol/L of KCl, 1.2 mmol/L of MgSO4, 1.22 mmol/L of KH2PO4, 1.3 mmol/L of CaCl2, 25 mmol/L of NaHCO3, and 15 mmol/L of dextrose, for an ischemic period of 30 to 45 minutes before proceeding to transplantation. The jugular vein and carotid artery of the recipient dog (body weight, 20 to 30 kg) were exposed and the donor heart was transplanted by anastomosing the donor pulmonary artery to the jugular vein and the donor aorta to the carotid artery. The heart then was placed in a subcutaneous pocket.
At the end of the experiment, the grafted and native hearts were excised. The circumflex coronary artery was dissected for in vitro and histologic studies. The hearts then were fixed in paraformaldehyde for histologic studies. The cellular rejection grade was assessed by a cardiovascular pathologist according to the International Society for Heart and Lung Transplantation classification [10]. The presence of vascular rejection was evaluated by the amount of intimal lymphocyte infiltration and hyperplasia. Immunoperoxidase studies were used to detect endothelial deposit of immunoglobulin M and G antibodies and the presence of factor VIII on the endothelial surface, and they were carried out on segments taken from both the grafted (n = 2) and the native hearts (n = 2). All the animals were cared for in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised in 1985).
Organ Chamber Experiments
The circumflex arteries were divided into 3- to 4-mm rings and were attached to a strain gauge for isometric tension recording. In rings without the influence of the endothelium, the intima was removed by gentle rubbing of the endoluminal surface of the blood vessel with a pair of watchmaker's forceps. Vascular segments, with and without endothelium, were suspended in organ chambers (25 mL) that were filled with Krebs-Ringer solution (pH 7.4), maintained at 37°C, and aerated with a gas mixture of 95% oxygen and 5% carbon dioxide. Each segment was suspended by two stainless steel stirrups passed through its lumen. One stirrup was anchored to the bottom of the organ chamber and the other was connected to a strain gauge for measurement of isometric force. The segments were placed at the optimal point of their length-tension relation by progressive stretching until the contraction response to KCl (20 mmol/L) was maximal. In all experiments, the presence or absence of endothelium was confirmed by determination of the response to acetylcholine (ACH) (10-6 mol/L) in rings contracted with KCl (20 mmol/L). After optimal tension was achieved, the coronary segments were allowed to equilibrate in Krebs-Ringer solution for 30 to 45 minutes before drugs were administered.
Protocols
After precontraction to prostaglandin F2 (PGF2), 2 x 10-6, the endothelium-dependent vasodilation to ACH (10-9 to 10-4 mol/L), adenosine diphosphate (ADP) (10-9 to 10-4 mol/L), serotonin (5-hydroxytryptamine [5-HT]) (10-9 to 10-4 mol/L), and thrombin (0.01 to 10 µm/L), and the endothelium-independent relaxation to sodium nitroprusside (10-9 to 10-4 mol/L) were recorded. Vascular smooth muscle vasocontraction to PGF2 (10-9 to 10-5 mol/L) also was documented. In all experiments, indomethacin (10-5 mol/L) was added to the organ bath to prevent the synthesis of endogenous prostanoids. After each concentration-response experiment, the organ chambers and the vascular walls were washed with Krebs-Ringer's solution (37°C) and the coronary segments were allowed to equilibrate for 45 minutes before being exposed to the next agonist. All drugs were obtained from Sigma Chemicals Ltd (St. Louis, MO). The drugs were prepared daily with distilled water, except for the indomethacin, which was dissolved in NaCO3 (10-5 mol/L). The concentrations described always represent the final bath concentration obtained in 25-mL baths, expressed as molar concentrations.
Data Analysis
All the results are expressed as mean ± standard error of the mean. In all experiments, "n" refers to the number of animals from which blood vessels were taken. The vasorelaxation response obtained from precontracted segments is expressed as the maximal relaxation obtained and the negative logarithm of the effective molar concentration of agonist that causes 50% inhibition of the contraction to PGF2 (EC50). The contractile responses to PGF2 are expressed in grams as the maximal contraction and EC50. Statistical evaluation of the data was performed by one-way analysis of variance, comparing the responses of the coronary arteries from the four groups: transplanted hearts without treatment, transplanted hearts treated with CyA, native hearts without treatment, and native hearts treated with CyA. When statistical differences were achieved, groups were compared by Bonferroni statistical analysis and results were considered significant at a p value less than 0.05.
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Results
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Histologic Studies
In the first group (without immunosuppressive treatment), all transplanted hearts (n = 7) reached a cellular rejection grade of IV according to the International Society for Heart and Lung Transplantation classification. The presence of intimal hyperplasia was found on the coronary arteries of four of the seven hearts (Fig 1
) and lymphocytic invasion of the vascular wall of the arteries was found on six of the hearts.
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Fig 1. . Light photomicrograph (Movat pentachrome) of a cross-section of the circumflex coronary artery from a transplanted heart displaying severe rejection (not treated). The right panel shows intimal hyperplasia with lymphocyte infiltration and preservation of the endothelial cells (black arrow) along with the internal lamina elastica (ILE). The upper left panel illustrates similar features with a disrupted ILE (black arrow) and lymphocyte infiltration of the underlying smooth muscle. The lower left panel depicts grade IV rejection of the myocardium with severe lymphocyte infiltration and myocyte necrosis (M).
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In the second group (immunosuppressed with CyA), in spite of an adequate CyA dosage trough level (320 ± 60 nmol/L at the end of the experiment), high rejection grades were found (IIIA in 1 heart, IIIB in 4 hearts, and IV in 2 hearts). A similar prevalence of intimal hyperplasia was observed in the coronary arteries of transplanted hearts treated with CyA (3/7 hearts).
Immunoperoxidase Studies
The sustained presence of factor VIII on the endothelial lining of the coronary arteries was found in both groups (two segments from donor hearts and two segments from native hearts for the immunosuppressed and nonimmunosuppressed groups) (Fig 2). The presence of immunoglobulins G and M on the endothelial lining was seen in the four transplanted vessels independent of CyA treatment, but could not be detected in the native coronary arteries.
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Fig 2. . Immunohistologic staining for von Willebrand factor of a coronary artery segment from an acutely rejected heart showing morphologically preserved endothelial cells (upper panel: low magnification; lower panel: high magnification).
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In Vitro Studies
ENDOTHELIUM-DEPENDENT REACTIVITY.
No difference in the endothelium-dependent relaxation to ACH and ADP was seen between the four study groups (Tables 1, 2). However, we noted a deterioration in the thrombin-mediated relaxation in the transplanted hearts without CyA treatment, as demonstrated by a rightward shift of the EC50 compared with the native hearts without CyA treatment (EC50 [-log U/L]: 1.12 ± 0.18 versus 1.67 ± 28 versus 1.67 ± 0.16; p = 0.06). Coronary arteries from the transplanted hearts with CyA treatment displayed a similar deterioration of the EC50 when compared with the native hearts with CyA treatment ([-log µm/L]: 0.99 ± 0.22 versus 1.64 ± 0.99; p = 0.02) (Fig 3), showing the specific effect of acute rejection. Treatment with CyA had no effect on this deterioration of the endothelium-dependent relaxation to thrombin.
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Table 1. . EC50 Values for Acetylcholine, Adenosine Diphosphate, Thrombin, 5-Hydroxytryptamine, Sodium Nitroprusside, and Prostaglandin F2 Among the Four Study Groups
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Table 2. . Emax Values for Acetylcholine, Adenosine Diphosphate, Thrombin, 5-Hydroxytryptamine, Sodium Nitroprusside, and Prostaglandin F2 Among the Four Study Groupsa
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Fig 3. . Dose-response curve showing endothelium-dependent relaxation of coronary segments to thrombin. A significantly decreased response is observed among transplanted hearts regardless of the treatment supplied. (NaCyA = native hearts treated with cyclosporine; NA noTx = native hearts without treatment; TR CyA = transplanted hearts treated with cyclosporine; TR noTx = transplanted hearts without treatment.)
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The endothelium-dependent relaxation to 5-HT was enhanced in the transplanted groups with or without CyA treatment (EC50 [-log mol/L], transplanted hearts without CyA treatment: 5.96 ± 0.12 versus native hearts without CyA treatment: 5.54 ± 0.14, p = 0.046); transplanted hearts with CyA treatment: 6.65 ± 0.19 versus native hearts with CyA treatment: 5.66 ± 0.16, [p = 0.004]). Further, among the transplanted hearts, the coronary arteries from those treated with CyA displayed an increased sensitivity to 5-HT (p = 0.01) (Fig 4A). On vessel segments studied without endothelium, no specific effects related to rejection or CyA treatment were observed (Fig 4B).
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Fig 4. . (A) Dose-response curve showing endothelium-dependent relaxation of coronary artery segments to 5-hydroxytryptamine (5-HT). A significantly increased response is observed among the transplanted hearts, which was enhanced further by cyclosporine treatment. (B) Dose-response curve showing an endothelium-independent response (rings without endothelium) to 5-HT. Neither the transplant process nor the cyclosporine treatment altered the response. (NA CyA = native hearts treated with cyclosporine; NA noTx = native hearts without treatment; ns = not significant; TR CyA = transplanted hearts treated with cyclosporine; TR noTx = transplanted hearts without treatment.)
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SMOOTH MUSCLE REACTIVITY.
Endothelium-independent relaxation to the nitric oxide analogue sodium nitroprusside was not altered by either the rejection process or CyA treatment (see Tables 1, 2
). Similarly, smooth muscle contractility to the agonist PGF2 was comparable in all groups.
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Comment
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The vascular endothelium is the first biologic barrier protecting the grafted organ against the recipient's circulating lymphocytes. Effector cells, primarily T cells, natural killer cells, macrophages, and monocytes, initiate the rejection response through the expression of tissue surface antigens coded by the major histocompatibility complex present on the endothelial cell surface. Once sensitized to the donor transplantation antigens, lymphocytes release lymphokines and free radicals, directly affecting the grafted tissue [11]. Endothelial cells of donor organs are exposed directly to this process and are likely to be harmed. Allograft endothelial cells of recipient origin have been detected in the transplanted human heart, which suggests recipient reendothelialization resulting from immune-mediated vascular injury [12].
Previous experimental studies have focused on early histologic remodeling of the endothelial lining that normally follows rejection. Little emphasis has been given to the effects of acute rejection on the local vascular reactivity of the arterial network of grafted organs [13]. The current study was designed to evaluate this particular aspect. In our model, 7-day acute rejection resulted in a severe grade of cellular and humoral vascular rejection, as demonstrated by vascular wall lymphocyte infiltration, intimal hyperplasia, and immunoperoxidase staining evidence of endothelial immune complex deposition. However, preservation of the endothelial membrane proteinic structure was confirmed in all groups (by the presence of factor VIII on the endothelial cell surface) [14], and preservation of the endothelium-dependent vasodilation to ACH and ADP in the in vitro assays suggests a preserved endothelial release of nitric oxide. The cyclic guanosine monophosphate-mediated vasorelaxation also was maintained, as shown by the preservation of the endothelium-independent relaxation to the nitric oxide analogue sodium nitroprusside. However, relaxation to the endothelium-dependent agents 5-HT and thrombin was affected by the rejection process. The response to thrombin deteriorated in the hearts undergoing transplantation with or without CyA treatment compared with the native hearts, whereas the vasorelaxant response to 5-HT improved. These alterations suggest that either the specificity of endothelial receptors or the intracellular signal transduction triggered by these agonists is affected. Differences previously have been demonstrated between the G proteins associated with ADP, 5-HT, and thrombin receptors [15]. Aside from acute rejection, other phenomena have to be considered in our experiments. The ischemia-reperfusion injury that occurs after heart transplantation in dogs has been shown to cause a nonspecific endothelium-dependent disorder. This was shown with both cold ischemia for 3 hours and warm ischemia for 1 hour followed by reperfusion for 1 hour [16]. Our study did not show evidence of any alteration in the vasodilation induced by ACH and ADP demonstrated in these previous studies. This suggests that the short and cold ischemic period used in our model did not affect G protein function [17, 18]. Thus, the deficient vasorelaxation to thrombin observed in the present study does not appear to be related specifically to the ischemia-reperfusion injury itself, but mostly to the rejection phenomenon.
Similarly, the enhancement of endothelium-mediated relaxation to 5-HT observed is contrary to the decrease in 5-HT–related vasorelaxation observed by Pearson and colleagues [19] in a canine model using 45 minutes of ischemia followed by 60 minutes of reperfusion, which argues in favor of an endothelial dysfunction not related to ischemia-reperfusion. The reason for the 5-HT enhancement observed in the transplanted group is not clear. However, the hypotheses suggested include general enhancement of the endothelial signal transduction associated with a rejection-selective endothelial receptor attrition or increased nitric oxide synthase activity.
The current study also was designed to evaluate the effects of immunosuppressive treatment with CyA on coronary vascular reactivity early after heart transplantation. Treatment with CyA did not prevent deterioration in the vasodilatory response to thrombin. Unfortunately, CyA did affect the rejection grade slightly (rejection grade IIIA to IV compared with grade IV only) despite the fact that a therapeutic CyA plasma level was reached during the rejection period. The enhancement in sensitivity to the 5-HT–mediated vasodilation observed in our untreated groups was enhanced further in the CyA-treated group, suggesting a CyA-related facilitating effect on serotoninergic endothelial receptors.
Cyclosporin A previously has been recognized to influence local and systemic vascular tone by different mechanisms. Increased sympathetic activity, increased renal liberation of endothelin, and increased sensitivity to catecholamine all are previously described CyA vascular effects [20–22]. In a previous study performed on conductance vessels such as rat thoracic aorta, we observed a CyA-induced facilitation of endothelium-dependent relaxation to ADP and histamine, whereas relaxation to ACH was impeded [23]. This facilitating effect appeared to be dose-dependent and related primarily to a very high concentration of CyA. However, in humans, O'Neil and associates [24] found no deleterious effect on coronary endothelial function with long-term CyA administration at a therapeutic dosage.
These changes in the endothelium-dependent vasodilatory response in this heterotopic canine heart transplant model suggest significant modifications of coronary artery endothelial function attributable to the phenomenon of rejection itself. The clinical significance of these alterations and their implication in the development of accelerated atherosclerosis remain to be defined. These results were unexpected; we anticipated an early abolition of endothelial reactivity during the acute rejection process. Therefore, this suggests that endothelial function might be more resistant to acute immunologic aggression than previously postulated. Interestingly, although experimental evidence supports an immune mechanism in the pathogenesis of early graft arteriosclerosis, the association between acute rejection and graft vasculopathy remains controversial [25, 26]. Consequently, we hypothesize that promptly treated, an acute rejection episode may not impede endothelial function and cause additional risk for early graft coronary atherosclerosis. However, further investigation is needed to clarify the functional aspect of the endothelium in rejection and its role in the pathogenesis of the phenomenon of accelerated atherosclerosis.
In conclusion, in the canine heterotopic heart transplant model, acute rejection was found to affect coronary artery endothelial reactivity in a receptor-specific manner without any impairment of the cyclic guanosine monophosphate pathway. Treatment with CyA appeared to enhance endothelial sensitivity to 5-HT.
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Acknowledgments
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This study was supported by the Heart and Stroke Foundation of Canada.
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Footnotes
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Address reprint requests to Dr Cartier, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec, Canada H1T 1C8.
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References
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Abstract
Introduction
