Potential role of Chinese medicinal herbs in the prevention of coronary artery restenosis

Percutaneous coronary intervention (PCI) especially stent implantation has now become a mainstay of therapeutic armamentarium in the treatment of patients with coronary artery disease even at clinically or angiographically high risk. However, restenosis requiring reintervention remains a major limitation and a challenging problem of percutaneous revascularization. 1 Despite the use of coronary stents, the rate of restenosis is still relatively high, affecting a quarter or more of overall patients treated by bare- metal stents and around 10% of those treated by drug- eluting stents, which may be even higher for complex PCI (long lesion, bifurcation, small vessel disease) or at unfavorable clinical conditions (diabetes, chronic renal failure). 2,3 Although the pathophysiology of restenosis may involve a complex interplay of several different aspects, migration and proliferation of medial vascular smooth muscle cells (VSMCs) is the predominant mechanism of neointimal hyperplasia leading to in-stent stenosis. 4 Systemic medical therapies targeting different mechanisms of restenosis have been studied previously, including antiplatelet and anticoagulant agents, calcium antagonists, angiotensin-coverting enzyme inhibitors, vitamins, antiproliferative or immunosuppressive drugs, and statins. For most of these approaches, initial positive results in animal models of vascular injury and/or small pilot studies have been followed by conflicting or even disappointing results and more side-effects in large clinical trials.5 Drug-eluting stent with local drug release provides the antirestenotic agents exactly where it is needed. It also makes us possible use the smallest effective dose required to achieve sufficient drug concentration at the vessel wall to prevent neointimal hyperplasia, producing better outcome and less side-effects than systemic or oral treatment with the identical compounds. 6 Although rapamycin or paclitaxel drug-eluting stents have been, at the present time, considered as “golden standard” for prevention of restenosis after PCI, a synergistic inhibitory effect of local and systemic therapeutic strategies on different mechanisms of restenosis may be desirable. 7,8 With this regard, the recent findings of some studies on Chinese medical herbs have been promising in the inhibition of neointimal formation and occurrence of restenosis after PCI.9-11 Emodin, an anthraquinone derivative isolated from the rhizomes of Rheum palmatum, selectively inhibits the activity of casein kinase II as a competitive inhibitor.12 In an experiment of inhibitory effects of emodin on human VSMCs proliferation, the percentage of the cells in G0/G1 phase was increased but those in S phase was decreased for emodin group documented by flow cytometry. Emodin also reduced cyclin D1 expression by Western-blot technique, suggesting that emodin may be an effective drug for the inhibition of VSMC proliferation.9 Triptolide is a novel immunosuppressive and anti-inflammatory agent purified from Chinese medical herb Trifterygium wilfordii hook F. 10 In our laboratory, we have previously assessed its effects and mechanism on proliferation of VSMCs in vitro using cultured aortic smooth muscle cells of rats. The effects of triptolide on VSMCs were compared with rapamycin using direct cell counting, and their difference in influence of VSMCs cell cycle was evaluated with flow cytometry. The effect of triptolide on c-fos mRNA expression was measured by RT-PCR technique. We found that both triptolide and rapamycin had comparable inhibitory effect on proliferation of VSMCs by blocking cell cycle from G0/G1 phase to S phase, and the former also inhibited c-fos mRNA expression in a concentration dependent manner. These findings indicate that down-regulation of proto-oncogene c-fos mRNA expression by triptolide may be one of the mechanisms with which it exerts its inhibitory effect on VSMCs. 11 In this issue of Chinese Medical Journal, Chen et al 13 have conducted a multi-center, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of XS0601 in the prevention of restenosis after PCI. This compound consists of active ingredients (chuangxiongol and paeoniflorin) and has been shown to hamper pathological vascular remodeling by inhibiting arterial neointimal hyperplasia in animal model and in preliminary clinical studies 14. After successful PCI, patients were randomly allocated to either XS0601 (n=166; 500 mg, three times daily) or placebo (n=169). Clinical follow-up was performed at 1, 3, 6 months after PCI, and 47% of patients underwent repeat angiography at 6 months. The restenosis rate was significantly reduced (26.0% vs 47.2%, P<0.05), and the minimum lumen diameter was greater [(2.08±0.89)mm vs (1.73± 0.94)mm, P<0.05] in the XS0601 group as compared with placebo. During follow-up, the incidence of major adverse cardiac events (death, nonfatal myocardial infarction, target lesion revascularization) was lower in the XS0601group than in placebo (10.4% vs 22.7%, P<0.01), with reduced reoccurrence rate of angina. Interestingly, all patients well tolerated this medication. The study reported by Chen et al 13 certainly has some clinical implications. This is probably the first randomized clinical trial, which addresses specifically the issue concerning the utility of Chinese herbal medicine in the prevention of restenosis after PCI. The patient population was selected as majority of patients included suffered from unstable angina or acute myocardial infarction, and had one or more risk factors for coronary disease; almost 20% had diabetes. Despite some limitations of this study due to the different types of PCI procedure and stents used and insufficient number of patients with follow-up angiography, the results suggest that XS0601 could be used as a therapeutic agent in preventing restenosis after PCI. The mechanism by which XS0601 treatment resulted in reduced restenosis after PCI cannot be discerned from the present study, but it may be related to anti-platelet and anti-inflammatory actions of multiple components of the compound. This study was also underpowered to assess treatment effects in patients with multi-vessel disease and complex lesions. Thus, further studies are indicated to determine the place of treatment with Chinese herbal medicine in the broad spectrum of patients undergoing coronary stent implantation, particularly in those receiving drug-eluting stents. While our understanding of the pathophysiology of restenosis after PCI is increasing and new approaches are being developed and evaluated to slow its progression, more could be accomplished by applying current knowledge regarding early detection and more intense anti-inflammatory and anti-proliferative response and control of other cardiovascular risk factors. With this regard, Chinese herbal medicine with multiple biologically active components may have great potential in dealing with the restenotic process as a whole. In future, great efforts should be made to define which biological component is the most active and what mechanism could possibly be involved in restenosis prevention with each medical herb used. Furthermore, despite continuation of search for identification and optimization of suitable compounds for systemic anti-proliferative vascular pharmacotherapy, the “golden standard” for prevention of restenosis has already been set by drug-eluting stents. 2,3 From current perspective, stents coated with biologically active component (s) extracted from Chinese medical herbs may be promising in the reduction of overall restenosis rate after PCI by means of rapid endothelialization and prolonged inhibition of migration and proliferation of VSMCs, leading to an improvement of clinical outcome of the patients.