Active matrix metalloproteinases 3 and 9 are independently associated with coronary artery in-stent restenosis
Introduction
In-stent restenosis (ISR) is regarded to be a major limiting factor of bare-metal coronary stenting [1], and while drug-eluting stents have reduced the rates of ISR, they are still significant [2]. Concern over very late/late stent thrombosis and bleeding with prolonged dual antiplatelet therapy has led to proposals that patients be risk profiled for selective use of drug-eluting stents [3]. The ability to more reliably predict the risk of ISR would be an important part of the decision making process to optimise patient management.
Models of arterial injury have revealed that matrix metalloproteinase (MMP) genes [4] and plasma concentrations are up-regulated in a time and location specific manner [5], [6]. Over-expression of tissue inhibitors of metalloproteinases (TIMPs) reduced smooth muscle cell (SMC) migration [7], and MMP-9 in particular is critical for the proliferation and migration of SMC [8]. The levels of various MMPs appear to be raised after stent implantation in humans [9], [10], and there is some evidence that MMPs are linked to restenosis of carotid endarterectomy [11] and after coronary stenting [12]. The association of MMPs and vascular injury is consistent in both animal and human studies, and suggest that levels of MMPs may be increased with the development of restenosis after coronary stent implantation.
In this study, circulating plasma levels of four active isoforms (MMP-1, -2, -3 and -9) and TIMP-1 were assayed in patients who had previously undergone bare-metal stent placement to determine if individual or combined levels of these isoforms were predictors of ISR.
Section snippets
Subjects
Patients with coronary bare-metal stent placements were recruited retrospectively from the Dunedin Hospital Cardiology Clinical database as previously described [13]. A group of 152 patients with a history of symptomatic, angiographically proven, ISR were compared with 151 patients who were angina free for more than 1 year following their stent placement (non-ISR). At the time of study all subjects in the ISR group had undergone revascularisation with either repeat percutaneous intervention or
Demographic factors associated with ISR
Patients with ISR had significantly greater waist circumference, BMI and high-sensitivity CRP, significantly lower HDL-cholesterol and were more medicated compared with those with no history of ISR (online Table 1). Patients with ISR also had a higher rate of triple vessel disease and significantly more complex ACC/AHA lesion score and stent characteristics (online Table 2). There were no other significant differences between the two patient groups demographic variables.
Plasma MMP levels
Plasma active MMP-3 and
Discussion
This study evaluated circulating levels of multiple MMP related markers in patients who had undergone coronary bare-metal stent placement, with a specific emphasis on the active forms of MMP-1, -2, -3 and -9. Circulating levels of active forms of MMP-3 and -9 were significantly higher in patients with a history of ISR. In addition there appeared to be an additive association with regard to patients with multiple ISR lesions. Importantly, these associations remained significant despite
Acknowledgements
We gratefully acknowledge the funding support of the Heart Foundation of New Zealand. The assistance of Mr Andrew Gray with the statistical analysis in this study is greatly appreciated.
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