Author + information
- Received October 17, 1991
- Revision received January 28, 1992
- Accepted February 21, 1992
- Published online August 1, 1992.
- David W.M. Muller, MBBS, FRACP, FACCa,
- Eric J. Topol, MD, FACCa,
- Gerald D. Abrams, MDa,
- Kim P. Gallagher, PhDb and
- Stephen G. Ellis, MD, FACCc,∗
- ↵∗Address for correspondence: David W. M. Muller, MBBS, Division of Cardiology, B1 F245, University of Michigan Medical Center, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-0022.
Objectives. The study was performed to test the hypothesis that high local, intramural concentrations of antineoplastic agents at the site of balloon injury inhibit vascular smooth muscle cell proliferation without systemic toxicity.
Background. The predominant mechanism for recurrent stenosis after coronary balloon angioplasty is neointimal thickening due to medial smooth muscle cell proliferation. The clinical use of potent antiproliferative agents to prevent restenosis has been limited by the potential for severe systemic side effects. Local therapy with these agents may be effective and free of systemic complications.
Methods. After bilateral balloon angioplasty of the carotid arteries of 14 juvenile farm pigs, the dilated arterial segments were treated locally with methotrexate (6.25 mg/ml, total dose 25 mg) or 0.9% saline solution through a perforated balloon catheter. The animals were then killed 30 days after balloon injury to determine the effects of this therapy on neointimal thickness. In an additional six animals, tritium-labeled methotrexate was used to determine the concentration and duration of detectability of methotrexate in the wall of the treated arteries and in the systemic circulation.
Results. Two hours after drug instillation the concentration of labeled drug was > 1,000-fold greater in the wall of the treated artery than in circulating blood, and this ratio remained between 50 and 100 for at least 7 days. Despite this difference, the mean intimal thickness 30 days after the procedure was similar in the 10 methotrexate-treated arteries and the 18 saline-treated arteries (59 ± 30 vs. 56 ± 25 μm, p = 0.6). The morphologic appearance of the neointima was similar in each group and suggested an important role for mural thrombus in the genesis of the intimal thickening.
Conclusions. Treatment with intramural methotrexate, delivered through a perforated balloon catheter at the selected concentration and total dose, failed to prevent intimal thickening after balloon injury. Nonetheless, the perforated balloon catheter appears to be a promising means of delivering a high local concentration of drugs with potentially life-threatening systemic side effects. The optimal concentrations and combinations of candidate drug therapies warrant further evaluation.
☆ This study was supported in part by Grants HL 38529-01 and HL 32043 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland and by grants from USCI Division of CR Bard Inc., Billerica, Massachusetts.
- Received October 17, 1991.
- Revision received January 28, 1992.
- Accepted February 21, 1992.