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(Circulation. 1995;92:987-993.)
© 1995 American Heart Association, Inc.

Articles

Acute Rejection Accelerates Graft Coronary Disease in Transplanted Rabbit Hearts

Tetsuro Nakagawa, MD; Galina K. Sukhova, MD; Elena Rabkin; Gayle L. Winters, MD; Frederick J. Schoen, PhD, MD; Peter Libby, MD

From Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.

Correspondence to Dr Peter Libby, Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Longwood Medical Research Center, Room 307, 221 Longwood Ave, Boston, MA 02115.

Background 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.

Methods and Results 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.

Conclusions 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.

Key Words: rejection • arteritis • cyclosporine • transplantation • arteriosclerosis

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