Early Plus Delayed Hirudin Reduces Restenosis in the Atherosclerotic Rabbit More Than Early Administration Alone

Abstract

Background-A 2-hour infusion of r-hirudin at the time of balloon angioplasty limits restenosis in atherosclerotic rabbits.Because thrombin activity in the vessel wall after angioplasty remains high for 48 to 72 hours, we hypothesized that a second infusion of hirudin at 24 hours would reduce restenosis more than early treatment alone. Methods and Results-Femoral atherosclerosis was induced in 35 rabbits by air desiccation injury and a high-cholesterol diet. At the time of angioplasty, rabbits were randomly assigned to 1 of 4 groups: controls: heparin bolus, saline infusion at 24 hours; early hirudin: hirudin bolusϩ2 hours' infusion, saline infusion at 24 hours; delayed hirudin: heparin bolus, hirudin infusionϮbolus at 24 hours; and earlyϩdelayed hirudin: hirudin bolusϩ2 hours' infusion, hirudin infusionϮbolus at 24 hours. Rabbits were euthanized after 28 days. The earlyϩdelayed hirudin treatment group had less loss of minimal lumen diameter by angiography at 28 days. By histomorphometry, cross-sectional area narrowing by plaque was least in the earlyϩdelayed treatment group compared with controls (Pϭ0.0001), early hirudin (Pϭ0.01), or delayed hirudin (Pϭ0.001). The earlyϩdelayed hirudin group also had a significant reduction in absolute plaque area and an improvement in lumen area compared with the other groups. No differences were observed between treatment groups with respect to the cross-sectional area encompassed by the internal or external elastic laminae. Conclusions-Combined earlyϩdelayed administration of hirudin significantly reduces angiographic restenosis and cross-sectional area narrowing by plaque compared with early or late treatment alone. These results suggest that restenosis after balloon angioplasty is markedly influenced by thrombin-mediated events not only occurring early but also extending beyond the first 24 hours in this model. (Circulation. 1998;98:2301-2306.)

Hirulog-Like Peptide Reduces Balloon Catheter Injury Induced Neointima Formation in Rat Carotid Artery without Increase in Bleeding Tendency

“…Previous studies demonstrated that early started and prolonged infusions of hirudin improved its effect on the prevention of angioplasty-induced restenosis in atherosclerotic rabbits [8]. Our earlier studies indicated that multiple infusions of hirulog-1 (1 mg/kg/h for 4 h × 6 times), but not one or two infusions, significantly reduced balloon injury induced neointima formation in rats [12].…”

“…A long-term beneficial effect of thrombin inhibitors on restenosis has not been shown in humans [5, 6]. Recent studies demonstrated that the modification of the administration of hirudin through early and/or prolonged infusions substantially improved its preventive effects on the development of restenosis in experimental animal models [7, 8]. Results of phase III clinical trials indicated that hirudin significantly increased the frequency of intracerebral or major hemorrhage [9]which limits its clinical application.…”

The critical role of the intrinsic VSMC proliferation and death programs in injury-induced neointimal hyperplasia

“…Although we have shown here that the in vitro responses of Harlan and Sasco CAVSMCs to growth and cytotoxic stimuli are entirely concordant with in vivo phenotypes of Harlan and Sasco rats in response to balloon vascular injury, the current data do not completely exclude the possibility that the phenotypic differences between Harlan and Sasco carotid arteries were also contributed by factors other than VSMCs, such as responses of platelets, leukocyte, coagulation cascades, and growth-factor production in the setting of vascular injury, all of which have been shown to play critical roles in the pathogenesis of restenosis (5,11,14,28,31). Nevertheless, the current work, to our knowledge, is the first to report restenosis-prone and -resistant rat substrains that originated from the same ancestrous strain (i.e., Sasco and Harlan Sprague-Dawley rats) and to suggest that a difference in the genetic (intrinsic) program on proliferation and cell death (Fig.…”

Local Adenovirus-Mediated Delivery of Hirudin in a Rabbit Arterial Injury Model

“…In rabbit and porcine models, hirudin, a potent direct thrombin inhibitor, given at the time of balloon angioplasty (BA) has been shown to reduce neointimal hyperplasia [5, 6, 7]. However, subsequent human trials with both hirudin and hirulog, a synthetic hirudin-like antithrombin, have not demonstrated a reduction in restenosis despite a reduction in acute thrombotic events [8, 9].…”

“…The rabbit is a particularly appropriate model to test the efficacy of Ad-Hir because prior studies have consistently shown that thrombin inhibition with systemic hirudin at the time of balloon injury limits neointimal growth [5, 14, 15]. More recently, pulse dosing of hirudin at the time of balloon injury and 24 h later has been shown to incrementally reduce the arterial response to injury in the rabbit model [6]. Our hypothesis was that the combination of early hirudin infusion plus successful transduction of the hirudin gene using an adenovirus vector would provide sustained thrombin inhibition over days and limit neointimal growth compared to early hirudin alone after BA in femoral arteries of cholesterol-fed rabbits.…”