Heterotopic Cardiac Transplant Model Research Articles

Inhibition of coronary artery transplant atherosclerosis in rabbits with angiopeptin, an octapeptide

Accelerated coronary atherosclerosis of cardiac allograft occurs in 30–40% of cardiac transplant patients and remains an unsolved clinical problem. The etiology is unknown and anti-platelet drugs are used without conspicuous success. The inhibitory effect of the octapeptide, angiopeptin on coronary atherosclerosis was studied in a previously described rabbit heterotopic cardiac transplant model where allograft rejection is prevented by daily administration of cyclosporin A (CsA, 10 mg/kg per day s.c.). Twenty male New Zealand white rabbits (2.6–2.8 kg) received a heterotopic cardiac transplant from rabbits of the same strain. Donors and recipients were fed a 0.5% cholesterol diet 1 week prior to transplantation which was continued for the recipient until death 6 weeks later. The control group (n = 16) received CsA and saline injections twice daily and the treatment group (n = 4) received CsA and angiopeptin (60 μg/rabbit daily s.c.) in 2 divided doses. The treatment began after completion of the transplantation. Coronary artery transplant atherosclerosis was uniformly distributed (tubular) in the entire length of the coronary arteries. Angiopeptin inhibited the intimal hyperplasia in the transplanted heart from 47.5 ± 2.4% (mean ± SE) to 25.0 ± 6.9% and in the native heart from 24.2 ± 1.4% to 15.7 ± 1.5%. The intimal hyperplasia is expressed as area of intimal hyperplasia/total vessel area × 100%. A similar inhibition by angiopeptin was seen in lipid deposition in the donor ascending aorta which is transplanted with the heart. Angiopeptin attenuated significantly the hyperplasia and the lipid deposition of the native coronary arteries and aorta but to a lesser extent. Whether the effect of angiopeptin is due to its properties as a somatostatin analog or whether it represents the properties of a new inhibitory peptide remains to be shown.

Experimental model of heterotopic cardiac transplantation for evaluation of graft viability and function.

An experimental model of heterotopic intrathoracic cardiac transplantation making possible an evaluation of graft viability and function has been studied. The technique requires only two anastomoses in the normothermic state without cardiopulmonary bypass. In this model, the ascending aorta of the recipient animal may be occluded completely, enabling an increasing preload on the graft. In case of adequate myocardial preservation of the cardiac graft, the aorta may be completely occluded and the recipient systemic circulation can be sustained by the graft. However, in case of inadequate graft myocardial function, or in case of size mismatch, the recipient heart alone contributes to the circulation. This technique appears quite useful because of its simplicity, the elimination of the need for extracorporeal circulation while allowing a functional evaluation following cardiac graft preservation.

移植心の全体循環維持機能検討を目的とした左心バイパス型異所性心移植モデルの開発

移植心の全体循環維持機能検討を目的とした左心バイパス型異所性心移植モデルの開発

The effect of donor specific transfusions and dietary fatty acids on rat cardiac allograft survival

A rat heterotopic cardiac transplant model was used to study the effect of dietary lipids on the immune response. Animals receiving linoleic acid (LA), oleic acid (OA), and fish oil (FO) enriched diets showed significant prolongation of allograft survival when compared to the control diet fed animals. When LA was given to animals who had received a single donor specific transfusion (DST) augmentation of the beneficial DST effect was observed, while the OA and FO fed groups showed no differences from control DST animals. Dietary regulation of the immune response, possibly through manipulation of arachidonic acid metabolism, is implied.

The detection of cardiac allograft rejection by alterations in proton NMR relaxation times.

The ability of proton NMR relaxation times to detect cardiac allograft rejection was studied in an inbred rat heterotopic cardiac transplantation model. Hearts from 25 Lewis X Brown Norway F1 hybrid rats were anastomosed to the abdominal aorta and vena cava of Lewis recipients; 25 Lewis donor hearts served as isograft controls. Groups of five allografts and five isografts were harvested daily between two and six days post-transplant. The relaxation times T1 and T2 of the transplanted hearts were determined in vitro with a 10 MHz spectrometer. T1 and T2 values in allografts did not differ significantly from those in isografts at days 2 and 3 post-transplant. However, at days 4, 5, and 6 T1 and T2 of the allografts were significantly prolonged. This finding correlated with an elevation in tissue water content and the onset of rejection as determined histologically. An additional 21 allografts, treated with cyclosporine, were studied in the same way from four to more than 100 days post-transplant. T1 and T2 values of these treated allografts did not change significantly during the observation period and were similar to the relaxation values obtained in the isografts at days 2 to 6. These data suggest that serial measurements of myocardial T1 and T2 may be useful in detecting acute cardiac allograft rejection and monitoring the effect of antirejection treatment.

Progression and resolution of myocardial reflow injury

The development of and recovery from a severe yet nonlethal myocardial injury following hyperkalemic cardioplegia and prolonged hypothermic global ischemia was examined over 14 days in a rat model of heterotopic intraabdominal cardiac isograft transplantation. Mitochondrial enzymatic markers of myocardial ischemic injury and light microscopic signs of damage were examined. Eighteen hearts were arrested in situ using hyperkalemic cardioplegia and subjected to a mean of 38 min of ischemia at 20°C as transplantation was achieved. No changes in mitochondrial creatine kinase (CKm) activity, mitochondrial malate dehydrogenase (MDHm) activity, their ratio, or morphologic evidence of injury were found during 8 days of reperfusion. In a second group of 66 hearts, the duration of hypothermic cardioplegic ischemia was extended by 120 min before transplantation. Neither unreperfused hearts nor hearts reperfused for only 1 hr demonstrated significant depression of enzyme activities or microscopic evidence of injury. However, after 1 day of reperfusion, CKm and MDHm activities were depressed to 36 and 44% of control levels ( P < 0.05). These activities had returned to control levels by 2 days of reperfusion and remained stable for 12 days thereafter. Light microscopic analysis revealed cellular injury to be maximal at 1 to 2 days of reperfusion with gradual improvement noted over the following 12 days. These observations suggest the existence of a mitochondrial injury following prolonged cardioplegic arrest and hypothermic global ischemia that is maximal after 24 hr of reperfusion but shows evidence of improvement thereafter. These findings justify aggressive support of the poorly functioning heart for the first few days after prolonged global ischemia.

Long-term effects of cold cardioplegic myocardial protection in the rat

The long-term histologic effects of the use of two cold cardioplegic solutions (St. Thomas' and saline) were studied and compared in a model of heterotopic cardiac transplantation in rats of isogeneic strain. After cold cardioplegic arrest, hearts were stored for varying times ("minimal," 30, or 90 minutes) in one of the solution prior to transplantation, giving a total of six groups (five animals in each group). Early assessment of myocardial injury 48 hours after transplantation was by the uptake of technetium 99m pyrophosphate and by measurement of serum creatine kinase activity. Late assessment of myocardial injury at 3 months after transplantation was by quantitative histologic examination. The findings indicated that significant myocardial fibrosis occurred in hearts stored in both solutions for the longest storage period (90 minutes) and that St. Thomas' cardioplegic formula conferred better myocardial protection after 90 minutes' storage than did cold saline, as judged by the degree of histologic injury at 3 months (p less than 0.025). Significant correlation was found between long-term histologic changes at 3 months and the uptake of technetium 99m pyrophosphate (p less than 0.001) and serum creatine kinase activity (p less than 0.05) assessed at 48 hours. Uptake of technetium 99m pyrophosphate and increased serum creatine kinase activity was demonstrated 48 hours after injury in animals having no detectable histologic injury at 3 months. These observations indicate that there may be technetium 99m pyrophosphate uptake and enzyme release from reversibly damaged myocardial cells.