Graft Coronary Arteriosclerosis Research Articles

Inhibition of Graft Coronary Arteriosclerosis after Heart Transplantation

Graft coronary arteriosclerosis (GCA) is the leading cause of long-term mortality after heart transplantation (HTx). The goal of this study was to demonstrate that inhibition of immunemediated injury by cyclosporine (CsA) protects the allograft from GCA. ACI-to-Lewis rat allografts were disparate in major and nonmajor histocompatibility loci. Isografts (Lewis-Lewis) were controls. Treatment groups received either olive oil or CsA at 2.5, 5, 10, or 20 mg/kg/day for 3 months. Histology (elastin) and immunohistochemistry using monoclonal antibodies to CD4, CD8, CD45R, RT1B, CD11b/c, CD25, and alpha-actin was performed to examine the epicardial and intramyocardial coronary arteries. Computerized image morphometry was utilized to measure intimal and medial thickness and area. Rats receiving olive oil or CsA at 2.5 mg/kg/day had severe rejection and no graft survival. CsA at 5 mg/kg/day resulted in less severe rejection with significant intimal and medial proliferation (P < 0.001). CsA at 10-20 mg/kg/day paralleled Lewis-Lewis isograft outcomes and inhibited arteriosclerotic vascular changes in the allograft (P < 0.001). Perivascular T-helper cells and macrophages were a characteristic finding with low-dose CsA but rare with higher CsA doses. In this new model of accelerated GCA in rats, immune-mediated antigen-dependent vasculopathy as a result of inadequate immunosuppresion is fundamental in the development of GCA, which appeared equally in epicardial arteries and intramyocardial arterioles. CsA prevents GCA in a dose-dependent fashion in the rat allograft.

Cold ischemic injury and donor-recipient MHC disparity significantly increase post-transplant cardiac graft coronary arteriosclerosis

Abstract Introduction: The effects of cold ischemic preservation and degree of donor-recipient histoincompatibility on graft coronary arteriosclerosis(GCA)were examined using a rat heterotopic cardiac transplant model. Methods: Three donor-recipient rat strain combinations were utilized. Lewis-F344 rats which vary slightly in class I Major Histocompatibility (MHC) Loci genes, ACI-Lewis which vary significantly in MHC class I and II genes, and Lewis-Lewis (control), donor-recipient strain combinations were subjected to varying lengths of cold ischemic preservation prior to transplantation(0, 4, and 24h in University-of-Wisconsin solution at 4’C).There were 9 rats per group.Grafts were harvested at 90 days post-op. and sections of the epicardial arteries were examined (H&E and van Gieson elastin stains).Intimal area ratio (IAR = intimal area/area within internal elastic lamina), intimal thickness score (ITS-based on % luminal compromise, perimeter of involvement), and rejection score (RS) were determined for each specimen using computerized image morphometry. Results: IAR, ITS and RS were significantly higher at 24hrs vs. 0hrs (p ∗ . IAR (hr) LEW-LEW (%) LEW-F344 ∗ (%) LEW-ACI ∗ (%) 0 0.38 ± 0.15 0.33 ± 0.16 0.57 ± 0.16 4 0.34 ± 0.11 0.42 ± 0.21 0.72 ± 0.29 24 0.41 ± 0.18 0.63 ± 0.14 ITS (hr) 0 0.36 ± 1.00 0.67 ± 0.84 2.00 ± 1.40 4 0.14 ± 0.29 0.82 ± 0.94 2.80 ± 2.10 24 0.91 ± 0.91 1.90 ± 0.87 RS (hr) 0 0.11 ± .33 3.30 ± 0.89 3.10 ± 1.4 4 0.56 ± .88 3.80 ± 0.71 5.00 ± 0.0 24 1.10 ± 1.4 4.50 ± 0.53 4.40 ± .71 ∗ p Conclusions: GCA is significantly increased by greater MHC disparity and longer cold ischemic times. GCA may be caused by an Immune-mediated antigen dependent vasculopathy secondary to histoincompatability. In the control group, longer cold ischemic times did not have a significant effect on GCA, suggesting that better histocompatibility may mitigate the adverse effects of longer ischemic times.

Suppression of graft coronary arteriosclerosis by gene gun-mediated CTLA4-Ig gene transfer

Suppression of graft coronary arteriosclerosis by gene gun-mediated CTLA4-Ig gene transfer

Effects of Enalapril and L-158809 on Myocardial Beta-Adrenergic Receptor Density in Transplanted Rat Hearts

Background: We compare the effects of angiotensin-converting enzyme (ACE) inhibitor or angiotensin II type 1 (AT₁) receptor blocker on density of myocardial beta-adrenergic receptors (beta-ARs) in a heterotopic heart transplantation model. Methods: Hearts of F344 rats were heterotopically transplanted into Lewis rat recipients immunosuppressed with cyclosporine (10 mg/kg/day). Recipients were treated orally with the AT₁ receptor blocker L-158809 (3 mg/kg/day, n = 6), enalapril (3 mg/kg/day, n = 6), or vehicle only (n = 6) for 90 days. Density of myocordial beta-ARs was determined with an autoradiographic technique using [³H]CGP-12177. Results: Graft status, the sum of the functional score and the score for color, was preserved better in the L-158809-treated group (5.8 ± 0.9) and in the enalapril-treated group (5.6 ± 0.8) than in the vehicle-treated group (3.8 ± 0.9, p < 0.05). The grades of graft coronary artery disease in the L-158809-treated group and in the enalapril-treated group were significantly less than that seen in the vehicle-treated group. The density of myocardial beta-AR (fmol/mg of protein) was 3.5 ± 0.5 in the L-158809-treated group (p < 0.05 vs. vehicle-treated group) and 3.2 ± 0.5 (p < 0.05) in the enalapril-treated group but was 2.2 ± 0.4 in the vehicle-treated group. Conclusion: L-158809 is as effective as enalapril in restoring myocardial beta-AR density in immunosuppressed rat transplant model, and this efficacy, as well as the prevention of graft coronary arteriosclerosis, is probably associated with the preservation of graft status.

Effects of gene transfection of human BCL-2 on graft coronary arteriosclerosis in hamster-to-rat cardiac xenografts

Effects of gene transfection of human BCL-2 on graft coronary arteriosclerosis in hamster-to-rat cardiac xenografts

Gene therapy in cardiovascular disease. Current status.

Cardiovascular disease is the leading cause of mortality and morbidity in developed countries. Most conventional therapy is often inefficacious and tends to treat the symptoms rather than the underlying causes of the disorder. Gene therapy offers a novel approach for prevention and treatment of cardiovascular diseases. Technical advances in viral vector systems and the development of fusigenic liposome vectors have been crucial to the development of effective gene therapy strategies directed at the vasculature and myocardium in animal models. Gene transfer techniques are being evaluated as potential treatment alternatives for both genetic (familial hypercholesterolemia) and acquired occlusive vascular diseases (atherosclerosis, restenosis, arterial thrombosis) as well as for cardiac disorders including heart failure, myocardial ischemia, graft coronary arteriosclerosis and hypertension. Continued technologic advances in vector systems and promising results in human and animal gene transfer studies make the use of gene therapy a promising strategy for the treatment of cardiovascular disorders.

Effects of immunosuppressants on platelet-derived growth factor-A chain mRNA expression and coronary arteriosclerosis in rat cardiac allografts

Graft coronary arteriosclerosis (GCA) that results in proliferative and obstructive lesions limits the long-term success of cardiac transplantation. Despite extensive study, the pathogenic mechanisms underlying GCA are still unclear and therapeutic strategies for this condition have been inadequate. In this study, we compared the therapeutic effectiveness of cyclosporine A (CsA), 15-deoxyspergualin (DSG), and Multiglycosidorum tripterygii (MT) on GCA. In addition, we studied the correlation between the extent of GCA and the degree of platelet-derived growth facter (PDGF)-A chain mRNA expression in cardiac grafts. Lewis rats receiving heterotropic heart transplants from Wistar King donors were treated with 10 mg kg(-1) day(-1) of CsA (n=7), 5 mg kg(-1) day(-1) of DSG (n=7) or 30 mg kg(-1) day(-1) of MT (n=7) respectively. Histological evaluation of coronary arteriosclerosis and Northern blot analysis of cardiac allograft PDGF-A chain mRNA expression were conducted on day 60 after transplantation. Varying levels of GCA were observed in the 21 transplanted hearts. Significant differences in both the degree of PDGF-A mRNA expression and the extent of GCA were found among the 3 groups. GCA was significantly reduced in allografts treated with MT or DSG in comparison with the level seen in CsA-treated grafts. A significant correlation was found between PDGF-A chain mRNA expression and the grade of arterial intimal thickening (r=0.76, p<0.05) as well as with the incidence of diseased vessels (r=0.82, p<0.01). Our results indicate that both MT and DSG are more effective in the treatment of GCA than CsA. In our cardiac allografts, the degree of PDGF-A chain mRNA expression correlated well with the extent of GCA, suggesting that PDGF-A may play an important role in the development of transplant-related GCA.

THE EFFECTS OF ENALAPRIL AND L-158809 ON MYOCARDIAL BETA-ADRENERGIC RECEPTOR DENSITY IN TRANSPLANTED RAT HEARTS

190 We have previously reported that the density of myocardial beta-adrenergic receptors (beta-AR) in allografts is downregulated in the chronic phase. Inhibition of the renin-angiotensin system has been shown to restore the myocardial beta-AR density in heart failure. We compared the effects of angiotensin-converting enzyme (ACE) inhibitor or angiotensin II type 1 (AT1) receptor blocker on myocardial beta-AR density in a heterotopic heart transplantation model. Hearts of F344 rats were heterotopically transplanted into immnosuppressed Lewis rat recipients (cyclosporine 10 mg/Kg/day, postop day #0-90). Recipients were treated orally with AT1 receptor blocker L-158809 (3 mg/kg/day), enalapril (3 mg/kg/day), or vehicle only for 90 days. Histological evaluations of the rejection and coronary arterosclerosis were made 90 days after transplantation and the density of myocardial beta-AR was determined with an autoradiographic technique using [3H]CGP-12177. Graft status, as assessed by inspection at laparotomy, was preserved better in the L-158809 treated group (P <.05) and in the enalapril-treated group (P < .05) than in the vehicle-treated group. Morphometric analysis showed that rejection grades (Barak, 1988) of the heart allografts were significantly lower in the treated groups than those in vehicle only group. The grades of graft coronary artery disease (Lurie, 1981) in the L-158809 treated group (P <.05) and in the enalapril-treated group (P < .05) were significantly lower than that seen in the vehicle only group (P<.05). The density of myocardial beta-ARs (fmol/mg of protein) was 3.5 ± 0.5 in the L-158809 treated group (P < .05 versus vehicle-treated group) and 3.2 ± 0.5 (P < .05) in the enalapril treated group but was 2.2 ± 0.4 in the vehicle-treated group. CONCLUSIONS. These findings indicate that AT1 receptor blockade is as effective as ACE inhibitor in restoring the myocardial beta-AR density, and this efficacy, as well as the prevention of graft coronary arteriosclerosis, is probably associated with the preservation of the graft status in a rat heart transplantation model.

Multiglycosidorum tripterygii, a new immunosuppressant, supresses coronary arteriosclerosis after heart transplantation

Background Graft coronary arteriosclerosis is the major limiting factor for long-term survival after heart transplantation. In this study, we investigate the effect of multiglycosidorum tripterygii on graft coronary arteriosclerosis and platelet-derived growth factor A mRNA expression of transplanted hearts. % Methods: Three groups of Lewis rats (n = 7/Group) underwent heterotopic heart transplantation from Wistar–King donors and were treated with cyclosporine A (10 mg/kg/day) for 60 days (Group A) or with multiglycosidorum tripterygii (30 mg/kg/day) for 60 days (Group B) or with cyclosporine A for the first 30 days and followed by multiglycosidorum tripterygii for another 30 days (Group C). Histological evaluations of rejection and coronary arteriosclerosis, as well as Northern blot analysis on graft platelet-derived growth factor A mRNA expression were made 60 days after transplantation. Results Morphometric results indicated no significant difference in rejection among three groups. However, the extent of graft coronary arteriosclerosis in Group B (1.12 ± 0.21) and Group C (1.41 ± 0.19) was significantly less than that seen in Group A (1.72 ± 0.18) (p < 0.01 and p < 0.05, respectively). Furthermore, the incidence of diseased vessels was significantly less in Group B (29.5% ± 7.8%) and Group C (42% ± 9.1%) compared with Group A (69.1% ± 11%) (p < 0.01 and p < 0.05, respectively). The expression of platelet-derived growth factor A mRNA of cardiac allograft was also significantly suppressed in Group B (25.4 ± 6.2) and Group C (39.8 ± 9.4), when compared with Group A (62.2 ± 12.9) (p < 0.01 and p < 0.05, respectively). Conclusion Multiglycosidorum tripterygii is superior to cyclosporine in prevention and attenuation of graft coronary arteriosclerosis and this efficacy is probably associated with the depressed expression of graft platelet-derived growth factor A mRNA in the multiglycosidorum tripterygii-treated groups.

Effect of low molecular weight heparin on graft vascular disease in the rat cardiac allograft model

HEART transplantation is now an established therapy for irreversible end-stage heart failure. Though cyclosporine (CyA) and other immunosuppressive treatments have reduced the mortality rate of graft transplanted patients, posttransplant chronic graft vascular disease (CGVD) is still a major complication after transplantation. CyA has had minimal impact on CGVD of heart transplant patients. Therefore, new additional immunosuppressive agents are needed to decrease this complication and improve long-term survival. Nitric oxide (NO) is a mediator causing vasodilatation in vascular smooth muscle cells. CyA may not only inhibit proliferation in arterial smooth muscle cells in transplanted cardiac grafts, but it may also be an atherogenic agent, thereby affecting CGVD. Because CyA may inhibit NO synthase (NOS) activity and cause reduction of the production of NO, it may cause hypertension and CGVD in transplanted grafts. On the other hand, heparin may regulate the repair of posttransplant graft coronary arterial injury and arteriosclerosis by inhibiting smooth muscle cell proliferation through increasing NO. Heparin’s inhibitory effect may be partially reversed by NOS inhibitor, which reduces production of NO. Low molecular weight heparin (LMWH), which is depolymerized heparin, has advantages over heparin for improved bioavailability and reduced bleeding. The effect of LMWH on acute rejection and CGVD was studied in a rat cardiac allograft model. The NOS inhibitor, Nv-nitro-Larginine methyl ester (L-NAME), was used to reverse heparin’s effect.

Association between the degree of platelet-derived growth factor-A chain mRNA expression and coronary arteriosclerosis in the transplanted heart.

Although intimal and medial proliferation of smooth muscle cells is recognized as one of the key mechanisms in the development of graft coronary arteriosclerosis, the role of platelet-derived growth factor (PDGF) in this process is still uncertain, because of the undetermined pathogenesis of graft coronary arteriosclerosis (GCA). In the present study, the correlation between the extent of GCA and the degree of PDGF-A chain expression in cardiac grafts was investigated in 21 rats with GCA of varying extent. Lewis rats underwent heterotopic heart transplantation from Wistar King donors and were treated with cyclosporine A (10 mg/kg/day) (n = 7), 15-deoxyspergualin (5 mg/kg/day) (n = 7), or Multiglycosidorum tripterygii (MT) (30 mg/kg/day) (n = 7). Histological evaluations of coronary arteriosclerosis, as well as Northern blot analysis of graft PDGF-A chain expression were made, 60 days after transplantation. Graft coronary arteriosclerosis of varying extent was observed among the 21 transplanted hearts. Significant correlations were found between the PDGF-A chain mRNA expression of cardiac allograft and the grade of arterial intimal thickening (Spearman's r = 0.76, P < 0.005) as well as the incidence of diseased vessels (r = 0.82, P < 0.001). The PDGF-A chain mRNA expression of the cardiac allograft is associated with the extent of GCA, indicating that PDGF-A plays an important role in the development of GCA.

Prevention of graft coronary arteriosclerosis by antisense cdk2 kinase oligonucleotide.

Graft coronary arteriosclerosis, which limits the long-term survival of allograft recipients, is characterized by diffuse intimal thickening composed of proliferative smooth muscle cells. We observed that messenger RNA of the cell cycle regulatory enzyme cyclin-dependent kinase (cdk) 2 kinase, which mediates smooth muscle cell proliferation, was elevated in the thickened intima of coronary arteries of murine heterotopic cardiac allografts. We studied the effects of antisense phosphorothioate oligodeoxynucleotide (ODN) against this enzyme using gene transfer mediated by a hemagglutinating virus of Japan (HVJ)-liposome complex intraluminally delivered to inhibit the intimal hyperplasia. At 30 days after transplantation, antisense cdk2 kinase ODN treatment had dramatically inhibited neointimal formation in the allografts. Expression of vascular cell adhesion molecule-1 was also suppressed by antisense cdk2 kinase. However, these effects were not observed in the sense or scrambled ODN-treated allografts. Thus, an intraluminal administration of antisense ODN directed to a specific cell cycle regulatory gene can inhibit neointimal formation after cardiac transplantation.

Essential initial immunostimulation in graft coronary arteriosclerosis induction detected by retransplantation technique in rats: the participation of T cell subsets

Graft coronary arteriosclerosis occurs as chronic rejection after heart transplantation. In the previous studies, we have examined the minimum period of allogeneic stimulation to induce this change, using heterotopic rat heart transplantation and a retransplantation model. Retransplantation of allografts back into the donor strain did not prevent graft arteriosclerosis if the grafts had resided in the primary recipient for up to five days. In this study, the participation of the T cell subset causing graft coronary arteriosclerotic change was assessed using the same model. The transplanted rats in fully allogeneic or non-MHC antigen mismatch combinations were treated with a short-course administration of FK506. The graft was removed and retransplanted into the donor strain rats to escape from further immunological stimulation. CD4 + T cells and/or CD8 + T cells of first recipient rats in both combinations were eliminated by monoclonal antibodies. The grade of arteriosclerosis in the retransplanted hearts was evaluated on a basis of a scale from 0–4 according to the histological appearance of the vessel injury on day 40 after initial engraftment. While neither anti-CD4 nor anti-CD8 monoclonal antibody alone had little effect, the administration of both mAbs reduced this arteriosclerotic change and development. In conclusion, the T cell subsets, CD4 + T cell and CD8 + T cell play a certain role in the induction of the graft coronary arteriosclerotic change.

Recipient macrophage depletion reduces the severity of graft coronary arteriosclerosis in the rat Retransplantation model

In a series of studies, using an identical rat intestinal transplantation model, we evaluated the effects of several drugs. FK-506 caused a significant attenuation in the proliferation of allogeneic CD4+ T cells and IFN-γ secreting effector functions. FYT720 resulted in a marked reduction in the numbers of lymphocytes, associated with a reduction of T cell recruitment, in grafts. An anti-MAdCAM antibody was next reported to significantly down-regulate CD4+ T cell infiltration in intestinal grafts by blocking the adhesion molecule, and could be useful as an induction therapy. Concerning TAK-779, this CCR5 and CXCR3 antagonist diminished the number of graft-infiltrating cells by suppressing the expression of their receptors in the graft. As a result, it reduced the total number of recipient T cells involved in graft rejection.As the next step, we focused on the participation of monocytes/ macrophages in this field. PQA-18 has been the focus of a novel immunosuppressant that attenuates not only the production of various cytokines, such as IL-2 & TNF-α, on T cells, but the differentiation of macrophages by inhibiting PAK2 as well.In this report, we summarize our previous studies not only regarding the above drugs, but on an anti-complement drug and a JAK inhibitor as well.

Evidence that graft coronary arteriosclerosis begins in the early phase after transplantation and progresses without chronic immunoreaction. Histopathological analysis using a retransplantation model.

The histopathological features of chronic rejection and its initiation were assessed using rat heterotopic heart transplantation and retransplantation models. Fully allogeneic or minor, non-MHC antigen-mismatch heart grafts transplanted into recipient rats treated with a short course of FK506 showed long-term survival but developed graft atherosclerosis after 40 days posttransplantation. Retransplantation of allografts back into the original donor strain did not prevent graft atherosclerosis if the grafts had resided in the primary recipient for up to 5 days; residence in the primary allogeneic recipient for less than 4 days did not result in graft atherosclerosis in the secondary recipient. Short-course administration of FK506 did not affect the production of these changes. Graft coronary arteriosclerosis begins between 3 and 5 days posttransplantation and progresses without continuous allogeneic immunological drive. The present findings will provide a new means by which to approach the analysis of development of chronic allograft rejection.

Acute Rejection Accelerates Graft Coronary Disease in Transplanted Rabbit Hearts

The relation between episodes of acute rejection and the development of graft coronary arteriosclerosis remains controversial. We examined the hypothesis that acute rejection episodes accelerate graft coronary arteriosclerosis lesion formation in rabbit allografts. A control group (n = 5) received cyclosporine 5 mg.kg-1.d-1 for 6 weeks after heterotopic heart transplantation. In a rejection group (n = 5), cyclosporine was omitted for 4 days at 1 and 4 weeks after transplantation. We studied cross sections of grafted hearts at 6 weeks and evaluated myocardial rejection grade, incidence, and severity and cell composition of intimal lesions in multiple coronary artery profiles. Episodic withdrawal of cyclosporine augmented myocardial rejection (International Society for Heart and Lung Transplantation grades 0, 0, 0, 0, and 1A in the control group to grades 1A, 1B, 2, 3A, and 3B in the rejection group). Episodes of acute rejection significantly increased the incidence (7.8 +/- 2.7% to 49.7 +/- 1.9%) and severity (from grade 0.10 +/- 0.04 to 0.79 +/- 0.24) of intimal thickening in graft coronary arteries. Most intimal lesions consisted of smooth muscle cells and contained various degrees of T-lymphocyte infiltration but sparse macrophages. In this experimental model, episodes of acute rejection precipitated by cyclosporine withdrawal accelerated the development of graft vascular lesion formation. Activation of vascular cells and leukocyte recruitment during acute rejection may thus contribute to the pathogenesis of graft arteriosclerosis.

The present state of heart transplantation

After more than 25 years, including long periods of scepticism, heart transplantation, with the introduction of several fundamental innovations, has become a routine clinical procedure for treating life-threatening end-stage heart failure. Annually, 3000–4000 transplantations are performed worldwide. Heart transplantation has been performed successfully in patients of almost all ages, from newborn babies with untreatable heart defects to 70-year-olds. Transplant organs are explanted from deceased donors who have suffered brain death. The circulation is kept stable for several hours during which time a well-functioning heart can be excised. In Europe, as a rule, donor organs are matched to recipients by national or multinational organ-sharing organisations. ‘Eurotransplant’, for example, serves medical institutions in Germany, Austria, and the Benelux states. This enables 500–600 hearts to be transplanted in Germany each year. Since 1986, 650 heart transplantations have been performed at the German Heart Institute Berlin (GHIB) and more than 100 are performed per year. In recent years, heart-lung, single-, and double-lung transplantations have been added to the GHIB's surgical program, accounting for more than 40 operations since the institute's inception. Patients at the GHIB have ranged in age from 8 days to 68 years, including 48 patients under the age of 16 years. Approximately two-thirds of the patients suffered from dilated cardiomyopathy and one-third from coronary artery disease. Smaller groups of patients suffered from valvular or congenital heart disease. Patients were selected for heart transplantation when heart failure was untreatable by other means and when their life expectancy was estimated to be 6 months or less. Due to a shortage of donor organs, 30–50% of heart transplant candidates die before undergoing surgery. The 1-year survival rate for heart transplant recipients is 85–90% and remains above 70% after 5 years. The patients have been capable of near-normal levels of physical activity and the fact that most are able to return to work or school or active retirement has been very encouraging. Current immunosuppressive treatment consists of low dosages of cyclosporine A, azathioprine, and steroids. Additional immunosuppression is administered if rejection becomes apparent. Traditionally, rejection monitoring has been based upon frequent endomyocardial biopsies, initially performed weekly with a gradual increase in the interval over time. The GHIB has developed an electrophysiological method for recording the voltage of the intramyocardial action potential by means of a telemetric pacemaker system. This allows for daily recording and transmission of data via a telephone modem connection. In this manner, not only cellular but also humoral rejection can be detected. Biopsies, therefore, have become very rare while cases of fatal rejection remain extremely low. However, the long-term fate of heart transplant recipients is overshadowed by the development of accelerated graft coronary arteriosclerosis which is obviously related to chronic endothelial rejection. Thus, far less than 10% of the patients at the GHIB have exhibited this complication. Nevertheless, the development of graft disease has to be observed carefully. To reduce the frequency of death among heart transplantation candidates, mechanical cardiovascular support has been used to treat patients until a suitable donor heart became available, a concept termed ‘bridge-to-transplant’. The GHIB exclusively uses the ‘Berlin Heart’, a pneumatically-driven extracorporeal pulsatile system which is also the only commercially available system in Europe. Bridge-to-transplant was applied in more than 100 cases, the largest series of any single institution worldwide. Since the GHIB began employing this concept, 64 patients have been transplanted after support periods of up to 4 months. Although it is a successful addition to the heart transplantation process, the bridge-to-transplant concept cannot overcome the ever-widening gap between the number of patients requiring transplant and the number of donor organs. Presently, efforts are being made in Germany to pass legislation which require considering all brain-dead bodies as a potential source of donor organs and, thus, increase the number of transplant organs available. In the interim, however, the current dilemma calls for considering alternative solutions, such as xenotransplantation and the permanent artificial heart.

Dose Response of Fish Oil Versus Safflower Oil on Graft Arteriosclerosis in Rabbit Heterotopic Cardiac Allografts

With the advent of cyclosporin A, accelerated coronary arteriosclerosis has become the major impediment to the long-term survival of heart transplant recipients. Due to epidemiologic reports suggesting a salutary effect of fish oil, the dose response of fish oil on graft coronary arteriosclerosis in a rabbit heterotopic cardiac allograft model was assessed using safflower oil as a caloric control. Seven groups of New Zealand White rabbits (n = 10/group) received heterotropic heart transplants from Dutch-Belted donors and were immunosuppressed with low-dose cyclosporin A (7.5 mg/kg/day). Group 1 animals were fed a normal diet and served as control. Group 2, 3, and 4 animals received a daily supplement of low- (0.25 mL/kg/day), medium- (0.75 mL/kg/day), and high- (1.5 mL/kg/day) dose fish oil (116 mg n-3 polyunsaturated fatty acid/mL), respectively. Group 5, 6, and 7 animals were supplemented with equivalent dose of safflower oil (i.e., 0.25, 0.75, and 1.5 mL/kg/day). Oil-supplemented rabbits were pretreated for 3 weeks before transplantation and maintained on the same diet for 6 weeks after operation. The extent of graft coronary arteriosclerosis was quantified using computer-assisted, morphometric planimetry. When the animals were killed, cyclosporin A was associated with elevated plasma total cholesterol and triglyceride levels in the control group. While safflower oil prevented the increase in plasma lipids at all dosages, fish oil ameliorated the cyclosporin-induced increase in total cholesterol only with high doses. Compared to control animals, there was a trend for more graft vessel disease with increasing fish oil dose, as assessed by mean luminal occlusion and intimal thickness. A steeper trend was observed for increasing doses of safflower oil; compared to the high-dose safflower oil group, animals supplemented with low-dose safflower oil had less mean luminal occlusion (16.3% +/- 5.9% versus 41.4% +/- 7.6%, p less than 0.017) and intimal thickness (7.9 +/- 1.9 microns versus 34.0 +/- 13.0 microns, analysis of variance: p = 0.054). Low-dose safflower oil also had a slight, but nonsignificant, beneficial effect on graft vessel disease when compared to control rabbits. The same trends were observed in the degree of histologic rejection (0 = none to 3 = severe) in fish oil- and safflower oil-treated animals. Rejection score correlated weakly but significantly (p = 0.0001) with mean luminal occlusion (r = 0.52) and intimal thickness (r = 0.46). Therefore allograft coronary disease in this model appeared to exhibit an unfavorable, direct-dose response to fish oil and safflower oil, independent of effects on plasma lipids.(ABSTRACT TRUNCATED AT 400 WORDS)