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Experimental graft coronary artery disease in a murine heterotopic cardiac transplant model
T Hirozane1, A Matsumori, Y Furukawa
1Department of Internal Medicine, Faculty of Medicine, Kyoto University, Japan.
Insights
This study developed a mouse model for cardiac allograft vasculopathy, a form of coronary artery disease (CAD) in transplanted hearts. Low-dose cyclosporine showed limited benefit in reducing arterial lesions in this model.
Area of Science:
- Transplantation immunology
- Cardiovascular pathology
- Animal modeling
Background:
- Acute rejection of cardiac allografts has decreased due to immunosuppression.
- Coronary artery disease (CAD) in the graft is a primary cause of late mortality and retransplantation.
- The mechanisms and treatment of graft CAD remain unclear.
Purpose of the Study:
- To establish a mouse model for studying cardiac allograft vasculopathy (CAV), a form of CAD in transplanted hearts.
- To investigate the efficacy of low-dose cyclosporine in mitigating CAV progression.
Main Methods:
- Vascularized heterotopic cardiac transplantation was performed using DBA/2 donor and B10.D2 recipient mice.
- Mice shared major histocompatibility antigens but differed in minor antigens.
- Graft survival, histology, and intimal hyperplasia were assessed, with and without cyclosporine treatment.
Main Results:
- Allografts surviving >4 weeks showed significant intimal hyperplasia compared to syngeneic grafts (42% vs 13%).
- Low-dose cyclosporine (40 mg/kg/day) reduced intimal area to 34% but did not affect lesion incidence.
- Histopathological findings in the mouse model mimicked human cardiac allograft CAD.
Conclusions:
- The DBA/2 to B10.D2 mouse cardiac transplant model effectively replicates human graft CAD.
- Low-dose cyclosporine demonstrates a limited beneficial effect on reducing intimal thickening in this model.
- This model is valuable for future research into the pathogenesis and treatment of graft CAD.
Background:
The development of immunosuppressive therapy has brought about a remarkable decrease in the risk of acute cardiac allograft rejection; however, the major cause of patient death or retransplantation after the first postoperative year is coronary artery disease (CAD) in the graft. The pathogenesis and management of CAD are still not clearly established.
Methods And Results:
To make an animal model of CAD, we performed primary vascularized heterotopic cardiac transplantation using mice. Inbred strains, sharing major histocompatibility antigens but differing in minor antigens, were selected. DBA/2 mice (H-2d) served as donors and B10.D2 mice (H-2d) as recipients. Viability of the cardiac grafts was assessed by abdominal palpation. Eight of twelve cardiac allografts (67%) survived for 10 weeks after operation without any immunosuppressive therapy. Allografts rejected within 4 weeks showed acute rejection histologically, whereas allografts surviving more than 4 weeks displayed intimal hyperplasia in the coronary arteries, together with interstitial and perivascular fibrosis. The severity of intimal thickening in the graft coronary artery was then assessed by point counting. In allografts surviving for 70 days, intima comprised approximately 42% of the graft arterial wall, whereas in DBA/2 and B10.D2 syngeneic grafts, it comprised approximately 13%. A significant difference in percentage was observed between the intima area of allografts and that of syngrafts (P < .01, ANOVA). Long-term oral administration of cyclosporine at a dose of 40 mg/kg per day decreased the intima area to 34% (P < .05 versus nontreated allografts, ANOVA); however, this dose did not affect the incidence of arterial lesions.
Conclusions:
The histopathological features of DBA/2 allografts surviving for 10 weeks in B10.D2 recipient mice mimicked those in human CAD. Using this animal model, the beneficial effect of low-dose cyclosporine therapy on CAD was demonstrated, although this effect seemed to be limited. This DBA/2-B10.D2 mouse heterotypic cardiac transplant model provides valuable results for future studies of the disease.