PRE-CLINICAL RESEARCH: EDITORIAL COMMENT
Response to Drug-Eluting StentsDo We Need Drugs to Recompense Drug Elution?*
Georg Nickenig, MD* and
Jan-Malte Sinning, MD
Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Bonn, Germany
* Reprint requests and correspondence: Dr. Georg Nickenig, Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany (Email: georg.nickenig{at}ukb.uni-bonn.de).
Key Words: vasoconstriction • stents • smooth muscle • inflammation
Drug-eluting stents (DES) considerably reduce rates of restenosis and related target vessel revascularization compared with bare-metal stents (BMS). Although patient survival is not significantly increased by DES, concern has been growing that delayed endothelialization, incomplete neointimal healing, inflammatory events, or hypersensitivity reactions after DES implantation may lead to serious adverse events such as vasospasms and stent thrombosis, and consequently may trigger myocardial infarction and death (1).
Drugs released from DES exert distinct biological effects, such as (in)activation of signal transduction pathways and inhibition of cell proliferation. Although primarily aimed at preventing vascular smooth muscle cell (VSMC) proliferation and migration, these drugs also impair re-endothelialization and induce tissue factor expression, resulting in a prothrombogenic environment (2). DES implanted in noninjured common swine coronary arteries provoke an extensive granulomatous, eosinophil-rich inflammatory response with circumferential vessel involvement in all stented sections. Inflammation was also observed in BMS control subjects, but at a much lower prevalence and with less intensity (3). DES, but not BMS, are associated with acetylcholine- or exercise-induced paradoxical coronary vasoconstriction of the adjacent vessel segments (4,5). These observations suggest a drug-induced endothelial and/or vascular dysfunction as the underlying mechanism. Whether this effect is directly and specifically drug-induced or whether this is the result of a prolonged inflammatory response with concomitant delayed recovery of the endothelium and other vascular tissues remains unclear.
In this issue of the Journal, Shiroto et al. (6) showed that paclitaxel increases Rho-kinase (ROCK) expression and activity in cultured human coronary VSMCs. After paclitaxel- or sirolimus-eluting stent implantation in porcine coronary arteries, serotonin-mediated vasoconstriction at the stent edges was more enhanced in DES than in BMS. This hyperconstriction could be diminished by intracoronary pre-treatment with hydroxyfasudil, a selective ROCK inhibitor. Bradykinin-mediated vasodilation was not altered. Histological analyses showed a suppression of neointimal formation and re-endothelialization in DES sites compared with BMS sites. Microthrombus formation and inflammatory response at DES sites were enhanced. Immunohistological analyses also detected a higher expression of ROCK at the DES sites.
This nice work by Shiroto et al. (6) suggests that the ROCK pathway plays an important pathogenetic role in coronary hyperconstriction after DES implantation. The present study deals with a very important issue, provoking additional questions: - 1 Although it is well accepted that stent thrombosis is succeeded by serious clinical end points, it is unsettled whether vascular hyperconstriction is frequently the cause of adverse events. Coronary vasospasm has been postulated to play an important role, especially in the Japanese population (7), in variant angina, but also in unstable angina, myocardial infarction, and sudden cardiac death (8). Coronary artery spasms caused by a local hyper-reactivity of the arterial wall may contribute to the development of occlusive coronary thrombosis by fissuring a plaque or the vessel wall and by leading to blood stasis (9). However, the link between adverse clinical events and persistent abnormal vasomotion after DES implantation has yet to be established.
- 2 It would be interesting to know whether DES-induced hyperconstriction predominately occurs in individuals who are a priori predisposed to abnormal vasospasms. This could shed some light on the underlying mechanisms. Is Rho-kinase generally instrumental for the development of clinically relevant vasospasms?
- 3 Obviously, it remains to be determined whether investigation and treatment of healthy porcine vessels is transferable to the clinical scenario in humans, where we commonly deal with vascular structures severely altered by atherogenesis. So far, patients with atherosclerotic lesions may display paradoxical exercise- and acetylcholine-induced vasoconstriction of vessel segments adjacent to sirolimus-eluting stents, although the endothelium-independent dilatory response to nitroglycerin was maintained (4,5,10). The underlying mechanisms (possibly Rho?) were not clarified.
- 4 Is the coronary hyperconstriction, especially found at DES sites, a direct and specific drug effect of paclitaxel or sirolimus, or is it rather a result of prolonged and enhanced inflammatory response in DES? Both ROCK-messenger ribonucleic acids and ROCK-proteins are up-regulated through protein kinase C- and nuclear factor kappa B-dependent pathways by proinflammatory factors such as angiotensin II and interleukin-1 beta. The ROCK pathway modulates the phosphorylation level of myosin light chain through inhibition of myosin phosphatase and contributes to the agonist-induced calcium sensitization in smooth muscle contraction (8). Activation of the ROCK pathway down-regulates endothelial nitric oxide synthase and thereby reduces bioavailability of nitric oxide, promoting endothelial dysfunction (11). Thus, ROCK activation might be a central mechanism for both endothelial dysfunction and VSMC hyperconstriction, causing general vascular dysfunction. Because long-term inhibition of ROCK with fasudil suppresses the in-stent neointimal formation by multiple mechanisms, including inhibition of vascular inflammation, enhanced apoptosis, and reduced collagen deposition (12), increased ROCK activity at the stent site could also be an epiphenomenon of the inflammatory process of the vessel wall, which is aggravated by paclitaxel or sirolimus at the DES sites. At least, a recent study observed more extensive inflammatory reactions at DES (especially in sirolimus-eluting stents) than at BMS sites in a porcine model (3). After all, the expression of ROCK itself is accelerated by inflammatory stimuli. These inflammatory processes may partly explain the hyperconstricting responses after DES implantation.
- 5 What is the impact of anti-inflammatory treatment on the observed events? Although a recent study observed an antirestenotic efficacy of oral prednisone treatment after percutaneous coronary intervention with conventional BMS (13), the impact of steroid administration after DES implantation especially with respect to hyperconstriction is unknown, but may help to elucidate the role of the DES-induced inflammatory response of the vessel wall.
- 6 By the same token, is the inflammatory cascade directly initiated by the eluting drugs? What is the role of the polymer? The exemplary data in cultured VSMCs suggest direct effects of paclitaxel (sirolimus?). However, those cells are not comparable with the quiescent and contracting cells residing in the media of an adult vessel. In addition, in vivo hyperconstriction may not be purely mediated via VSMC action, but may also be influenced by other adjacent cells (endothelial or inflammatory cells) as well as by extracellular factors (matrix, cytokines, growth factors, and so on). If we are looking at a cell-specific mechanism taking place only in smooth muscle and not in endothelial cells, the underlying mechanisms need attention imperatively because this could guide us to the desperately needed differential vascular therapy required to selectively foster the endothelial and afflict the muscle cells. Thus, further research would need to definitely exclude the possibility that the polymer rather than the drugs is responsible for the observed hyperconstriction.
- 7 Is the pathway specific for serotonin? In coronary angiography, serotonin provokes more focal coronary vasospasm, whereas acetylcholine induces more diffuse and distal vasospasm (8,14). Obviously, coronary artery spasms frequently occur at the atherosclerotic lesions of the coronary artery. Revealing a close topological correlation between the serotonin-induced spastic site and the atherosclerotic lesion, serotonin seems to better mimic spontaneous coronary spasms than acetylcholine in vivo (8,15). It would be nice to know whether vasoconstrictors, such as norepinephrine, angiotensin II, or endothelin, also provoke hyperconstriction after DES implantation. If so, effective treatment options to test this hypothesis would be available.
- 8 Would statin treatment ameliorate the DES-associated vasoconstriction? By inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins reduce cholesterol synthesis, thus preventing the formation of geranylgeranyl pyrophosphate required for membrane translocation and activation of Rho-A, the main upstream activator of ROCK (16). Because ROCK inhibition results in the stabilization of endothelial nitric oxide synthase–messenger ribonucleic acid and an increased bioavailability of nitric oxide (17,18), this, as one of the so-called pleiotropic effects of statins, is thought to be responsible for the observed improvement in flow-mediated vasodilation by statin administration. Do we need a drug such as fasudil, with an uncertain safety profile, if we could instead select the widely used statins?
The findings of Shiroto et al. (6) add valuable information to the DES issue and underline the importance of better understanding the mechanisms responsible for the vascular performance, and supposedly, the clinical outcome after DES implantation. As almost always, we implemented with DES a treatment option in humans that we have (at best) not fully mechanistically anticipated. Although no one will dispute the clinical success of this venture, much work needs to be accomplished not only to better understand the molecular and cellular events critical for vascular pathology with or without stents, but also to develop therapeutic measures that will improve patient outcome. Certainly, the ROCK pathway is one attractive candidate.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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