- Email: [email protected]
Fighting restenosis after coronary angioplasty: contemporary and future treatment options
International Journal of Cardiology 83 (2002) 199–205 www.elsevier.com / locate / ijcard
Review article
Fighting restenosis after coronary angioplasty: contemporary and future treatment options a, b c Marc Horlitz *, Ulrich Sigwart , Josef Niebauer a
Department of Cardiology, Heartcenter Wuppertal, University of Witten /Herdecke, Arrenberger Str. 20, 42117 Wuppertal, Germany b Royal Brompton Hospital, Sydney Street, London SW3 6 NP, UK c Department of Cardiology, Heartcenter Leipzig, University of Leipzig, Strumpellstr. 39, 04289 Leipzig, Germany Received 19 August 2001; received in revised form 13 January 2002; accepted 23 January 2002
Abstract Despite the widespread use of coronary stents, prevention of restenosis after percutaneous transluminal coronary angioplasty (PTCA) remains a major challenge. The restenotic process is even higher after balloon angioplasty without stenting and has been shown to be in the range of 30–50%. Experimental data suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (‘statins’) might have a beneficial effect on restenosis after coronary angioplasty. Proposed mechanisms include favorable effects on plasma lipoproteins, endothelial function, plaque architecture and stability, thrombosis and inflammation. Although statins have documented efficacy in reducing clinical events and angiographic disease progression in patients with coronary atherosclerosis, the results of subsequent large prospective clinical trials using different types of statins clearly demonstrate that statins do not have a short-to-medium term effect on prevention of restenosis after successful conventional PTCA. The underlying pathological reasons for this shortcoming as well as promising innovative approaches including gene therapy and local drug delivery of vasoactive substances will be discussed in this review. 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Angioplasty; Restenosis; Statins; Gene therapy
1. Introduction Restenosis limits the long-term beneficial effects of percutaneous transluminal coronary angioplasty (PTCA) and related procedures [1]. Prevention of restenosis after successful PTCA remains one of the most challenging issues in the treatment of obstructive coronary artery disease [2]. Since 1986, the introduction of coronary stents by Sigwart has sig-
*Corresponding author. Tel.: 149-202-896-5708 fax: 149-202-8965707. E-mail address: [email protected] (M. Horlitz).
nificantly improved the short and long-term results of interventional coronary revascularisation procedures [3]. Eight years later, two major randomised trials confirmed that stenting after PTCA indeed reduces the incidence of restenosis (the STRESS [Stent Restenosis Study] trial in the USA, the BENESTENT [Belgium Netherlands Stent Trial] study in Europe) [4–6]. Despite lowering the restenosis rate with the implantation of coronary stents and a decline in the rate of initial complications, restenosis occurs in approximately 15–20% within 6 months after intervention sometimes necessitating repeat revascularisation [7]. The cellular biological mechanisms following balloon angioplasty are only partially understood. Re-
0167-5273 / 02 / $ – see front matter 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 02 )00033-5
200
M. Horlitz et al. / International Journal of Cardiology 83 (2002) 199 – 205
stenosis after PTCA has a multifactorial aetiology involving mechanical and hemostatic factors as well as altered cell proliferation. Mechanisms identified include stent under-expansion, immediate recoil, incorporation of thrombus and the ‘normal’ healing process in response to arterial injury involving proliferation of intimal smooth muscle cells and extracellular matrix, as well as vascular remodelling [8–10]. Decreased programmed cell death (apoptosis) is also an important regulatory mechanism and may contribute to human restenosis post angioplasty by prolonging the life span of intimal cells, with their subsequent accumulation and development of hyperplastic lesions [11]. In addition to mechanical interventions, pharmacological approaches to decrease the incidence of restenosis have been assessed [12–14]. The introduction of HMG-CoA reductase inhibitors has led to a significant improvement in the primary and secondary prevention of coronary artery disease [15]. Initial studies demonstrated that statins might have a beneficial effect on the relative risk of restenosis following coronary angioplasty by reducing lipid levels or mechanisms independent of low-density lipoproteins (LDL) lowering [16–18].
2. Experimental studies In the early 1990s experimental studies have suggested that HMG-CoA reductase inhibitors (‘statins’) might reduce restenosis after balloon angioplasty. Gellman et al. randomized 38 atherosclerotic rabbits to receive either lovastatin or placebo after balloon angioplasty of the femoral artery. Treatment with lovastatin decreased the progression of disease in the rabbit-iliac model independent of an effect on LDL cholesterol [17]. Eckhardt et al. showed that lowering LDL cholesterol levels decreased rates of restenosis in the rat-carotid model [16]. Soma et al. confirmed a direct effect of statins on smooth muscle cell proliferation after carotid artery injury innormocholesterolemic rabbits [18]. Therefore, sound experimental evidence suggested that statins might have a beneficial effect on restenosis after coronary angioplasty.
3. Origins, chemistry and mode of action of HMG-CoA reductase inhibitors HMG-CoA reductase inhibitors were first introduced into clinical practice in the late 1980s. Originally recovered from fungal metabolites, they are now synthetically produced. Currently there are six statins in clinical use, of which lovastatin and pravastatin are natural products of fungal origin, simvastatin is a semi-synthetic derivative, and fluvastatin, the first entirely synthetic product is derived from mevalonolactone. Recently, a new generation of highly purified, synthetic statins have been developed like atorvastatin and cerivastatin [19,20]. Statins are oral systemic agents that inhibit the rate-limiting enzyme of cholesterol synthesis in the liver, thereby decreasing the hepatic production of low-density lipoproteins (LDL) and upregulating expression of hepatic LDL receptors, thus, lowering concentrations of circulating LDL cholesterol. The activity of HMG-CoA reductase limits the rate of synthesis, not only of cholesterol, but also of a range of other molecules involved in functions such as cellular respiration and cell–cell recognition. Smooth-muscle-cell (SMC) proliferation is a feature of atherogenesis, Mevalonate and other intermediates of cholesterol biosynthesis are essential for cell growth. Therefore, drugs affecting this metabolic pathway, such as statins, may reduce SMC proliferation and subsequently the developement of restenosis after PTCA [21]. Macrophages have been involved in the pathophysiology of acute coronary syndromes by producing enzymes leading to plaque instability. Oxidized LDL attracts macrophages directly and stimulates their binding to the endothelium through induction of adhesion molecules. Statins prevent the oxidation of LDL possibly through preservation of the activity of the endogenous antioxidant system. Statins also alter macrophage handling and uptake of LDL. In addition, macrophages elaborate tissue factor, a glycoprotein that plays an important role in blood coagulation and plaque thrombogenicity. Statins inhibit tissue factor expression by cultured human macrophages, and this may reduce thrombotic events [15]. Thus, statin therapy takes also part in plaque stabilization which may attenuate atherogenesis.
M. Horlitz et al. / International Journal of Cardiology 83 (2002) 199 – 205
Nitric oxide (NO) has been shown to inhibit monocyte adherence and chemotaxis, platelet adherence and aggregation, and vascular smooth muscle proliferation. The activity of NO is reduced in hypercholesterolemia and after vascular injury [22]. Both simvastatin and lovastatin induce transcriptional activation of the NO synthase gene in human cells in vitro [23]. Therefore, the effects of statins on cholesterol lowering and enhancement of NO activity may result in significant improvement in endothelial function and could be valuable for the prevention and management of restenosis. Moreover, several studies demonstrate that statins may have additional antithrombotic actions by affecting thrombus formation, erythrocyte deformability and levels of fibrinogen. Although the precise mechanism is unclear, one mechanism may involve decreased platelet thromboxane A2 production [15]. The finding that the membrane cholesterol content of both erythrocytes and platelets is reduced in patients treated with pravastatin suggests that statins reverse the thrombotic–fibrinolytic imbalance that accompanies hypercholesterolemia [23]. Effects on inflammation have been observed in a sub-analysis of the CARE trial. Results of this study suggest that pravastatin reduces the higher risk of cardiovascular events associated with an lowering effect on the levels of C-reactive protein as an inflammatory marker [24]. Statins also reduced the incidence of organ rejection and the cytotoxicity of natural killer cells in recipients of heart and kidney transplantation [24]. In conclusion, different pharmacological effects may emphasize the tremendous impact of statins on the development of restenosis. Proposed mechanisms include not only cholesterol-lowering but additional independent effects on endothelial function, plaque stability, thrombosis and inflammation.
4. Clinical trials Three large, randomised, placebo-controlled clinical trials using statins have clearly demonstrated the efficacy of cholesterol lowering as a risk-reduction strategy for prevention of coronary artery disease. These include one primary-prevention trial (the West of Scotland Coronary Prevention Study (WOS-
201
COPS)) and two secondary-prevention trials (the Scandinavian Simvastatin Survival Study (4S) and the Cholesterol and Recurrent Events (CARE) Trial) [25–28]. The 4S was a landmark trial that changed the treatment paradigm in coronary artery disease (CAD) by showing that lowering cholesterol levels can significantly decrease the incidence of death from CAD. A total of 4444 patients with either angina pectoris or prior myocardial infarction (MI), and serum cholesterol levels of 213–310 mg / dl were enrolled in this double-blind study. Over the 5.4 years median follow-up period, Simvastatin treatment lowered total cholesterol and LDL cholesterol levels by 25 and 35%, respectively, changes that were paralleled by a 42% reduction in the incidence of death from CAD. Other benefits of treatment included a 37% reduction in the risk of undergoing myocardial revascularisation procedures [26,27]. The CARE trial demonstrated similar benefits in 4159 post-infarction patients with coronary disease who had total plasma cholesterol values ,240 mg / dl, and LDL cholesterol values of 115–174 mg / dl. Throughout the 5 years of study follow-up, cholesterol levels in the pravastatin group were 28% lower than those in placebo-treated patients and demonstrated a significant risk reduction of 24% in the incidence of fatal coronary events and non-fatal MI [25]. The West of Scotland Coronary Prevention Study showed that the incidence of death and non-fatal MI from CAD could be decreased by reducing cholesterol levels with pravastatin. A total of 6595 men with an average age of 45–64 years, no history of MI and only moderate hypercholesterolemia (mean LDL cholesterol 192 mg / dl), were enrolled in this double-blind study. Over a follow-up period of 3–5 years, the risk of death from CAD was 33% lower in the treatment group compared with the control group. There also was a 31% reduction in non-fatal MI [28]. Despite the promising results of experimental studies and the outcome of large prospective placebocontrolled prevention trials the clinical effect of HMG-CoA reductase inhibitors to prevent or delay the process of restenosis after successful conventional PTCA remained unclear. In an initial trial Sahni et al. treated 157 patients with either lovastatin (n579; 20 mg daily if the
202
M. Horlitz et al. / International Journal of Cardiology 83 (2002) 199 – 205
serum cholesterol level was ,300 mg / dl and 40 mg daily if the serum cholesterol was higher) in addition to conventional therapy or conventional therapy alone (n578; aspirin, dipyridamole, calcium channel blocker) [14]. The serum cholesterol level in the lovastatin group significantly decreased from 212649 to 175641 mg / dl, whereas the serum cholesterol level in the control group decreased from 207649 to 196648 mg / dl. Restenosis was reported in 12% of treated and 45% of non-treated patients. However, follow-up was incomplete with only 63% of treated patients and 37% of non-treated patients undergoing follow-up angiography at an interval of 2–10 months. The study was not blinded and only 157 patients were included. These factors limit the validity of this trial. The Lovastatin Restenosis Trial (LRT) was a well designed, large multicenter, prospective, doubleblind, placebo-controlled randomised study. Treatment was commenced between 7 and 10 days before successful angioplasty and the dose of lovastatin used was 40 mg orally twice daily [29]. Of 404 patients randomly assigned to study groups, 354 patients with total cholesterol between 180 and 300 mg / dl underwent successful elective angioplasty, 321 underwent angiographic assessment at 6 months. The purpose of the study was to determine whether aggressive lipid lowering therapy would reduce the rate of restenosis through reduction of cholesterol or possibly by direct effects on endothelial healing, resulting in a decreased smooth muscle cell proliferative response to angioplasty injury. Despite a 42% lipid-lowering effect in the treatment group at 1 month, no prevention or reduction of restenosis could be demonstrated in the first 6 months. The patients in the lovastatin group and the placebo group were similar with respect to clinical, angiographic and laboratory characteristics. The mean luminal diameter reduction was 64611% in the lovastatin group, as compared with 63611% in the placebo group [30,31]. The Angioplasty Plus Probucol / Lovastatin Evaluation (APPLE) using lovastatin to lower LDL levels in combination with probucol to prevent LDL oxidation showed that this combined strategy was also ineffective in preventing restenosis or subsequent cardiac events throughout the first 6 months after PTCA [32]. A total of 239 patients were enrolled, 68% were randomised to active therapy and 32% to placebo. Patients with total cholesterol values between 150
and 300 mg / dl were started on active or placebo therapy between 48 h before and 24 h after successful elective PTCA. The combination of lovastatin and probucol was highly effective at reducing total cholesterol (227%) and LDL (230%), although HDL levels were also proportionately reduced (227%). At follow-up angiography there were no significant differences between the active and placebo groups with respect to restenosis. A total of 51% of patients in the active group were noted to have a minimal luminal diameter of .50% compared with 46% of the placebo-treated patients. In a multicenter, double-blind study termed ‘Prevention des Restenoses par Elisor apres Dilatation Coronaire Transluminale’ (Prevention of Restenosis by Elisor (trade name for Pravastatin) After Transluminal Coronary Angioplasty) (PREDICT) 695 patients were randomised to receive pravastatin (n5 347; 40 mg / day) or placebo (n5348) for 6 months after successful PTCA. The primary angiographic end point was minimal lumen diameter (MLD) at followup, assessed by quantitative coronary angiography [33]. A total of 556 patients were available for re-angiography and despite a significant reduction in total and low density lipoprotein cholesterol and triglyceride levels and a significant increase in HDL cholesterol levels, there was no effect on angiographic outcome at the target site. At follow-up the MLD was 1.4760.62 mm in the placebo group and 1.5460.66 mm in the pravastatin group. The restenosis rate was 43.8% in the placebo group and 39.2% in the pravastatin group. Clinical restenosis did not differ between both groups. Subsequently, a small randomized pravastatin study in a Japanese population showed no effect on angiographic restenosis either [34]. Although all HMG-CoA reductase inhibitors were found to have a direct effect on smooth muscle cell proliferation in experimental investigations fluvastatins appeared to inhibit neointimal formation to the greatest extent [35]. Whereas previous studies investigated effective lipid lowering as the antirestenosis mechanism, the multicenter Fluvastatin Angioplasty Restenosis (FLARE) trial was conceived to evaluate the direct inhibitory effect of fluvastatin 40 mg twice daily on the coronary vascular myocyte, independent of any influence on serum lipid concentrations. To ensure adaequate tissue distribution, fluvastatin was
M. Horlitz et al. / International Journal of Cardiology 83 (2002) 199 – 205
administered 2–4 weeks before angioplasty. There were 1054 patients randomised to receive either fluvastatin or placebo; 834 patients underwent successful angioplasty and angiographic follow-up at 2662 weeks was performed in 93%. The primary endpoint was angiographic restenosis. No difference in the primary endpoint (fluvastatin 0.2360.49 mm, placebo-group 0.2360.53 mm), in angiographic restenosis rate (fluvastatin 28%, placebo 31%) or in the incidence of clinical events could be detected between both treatment groups. In short, treatment with fluvastatin did not affect the process of restenosis [2,35].
203
factors, which mediate neointimal lesions characterized by abnormal migration and proliferation of vascular smooth muscle cells in the intima. Moreover, balloon injury results in the loss of endothelium-derived NO, which plays an important role as an endogenous inhibitor of vascular lesion formation because of its function in maintaining vascular homeostasis [22]. The clinical results should not be interpreted as an incentive to adopt a nihilistic attitude in patients undergoing angioplasty. Although statins do not have an effect on restenosis, their effect on the progression of atherosclerosis and on the clinical events associated with such progression is undoubted.
5. Discussion 6. Statins after coronary stenting Even though the benefits of treatment with HMGCoA reductase inhibitors in primary and secondary prevention of coronary artery disease are undisputed, no effect has been shown on clinical or angiographic medium-term (less than 1 year) restenosis after conventional PTCA. Experimentally demonstrated effects of statins on arterial smooth muscle cells failed to translate into a clinical effect. No benefit has been shown, either via an effect on lipid level, or via an effect on human monocyte proliferation. Different explanations have been provided for this shortcoming. Initially, cells in culture may not represent an appropriate model for the hypertrophic, hyperplastic myocyte changes triggered by angioplasty. Secondly, in the clinical situation, characterized by fluctuations in the drug plasma level, a steady state cannot be reached. Moreover, it seems unlikely that restenosis after conventional angioplasty and the progression of atherosclerosis have a similar pathophysiological basis. Therefore, restenosis can not be viewed simply as an acceleration of atherosclerosis in response to a severe mechanical injury. It is a much more complex process than simple cell proliferation. The cellular biological mechanisms following balloon angioplasty are only partially understood. Recent progress in molecular biology has provided a number of interactive processes like cell adhesion, coagulation, cell migration, cell proliferation and synthesis of extracellular matrix [11]. Experimental studies have demonstrated that vascular damage after dilatation may induce local expression of mitogens and chemotactic
Restenosis after coronary stenting occurs due to neointimal proliferation and it was postulated that statins might have a beneficial influence on the restenosis rate due to their known antiproliferative effect. Unfortunately, there is only little information available about the effect of statins on restenosis after stenting. Nevertheless, results of first clinical trials are promising. Walter et al. have demonstrated that HMG-CoA reductase inhibitors are associated with lower restenosis and improved clinical results in patients undergoing stent implantations [36]. In a placebo-controlled study, 525 patients were randomised to receive statins (most patients (176, 68.2%) received simvastatin, 36% (14.3%) received lovastatin, 26 (10.1%) atorvastatin, 16 (5.8%) fluvastatin and 4 (1.6%) pravastatin) or placebo (n5267) for 6 months after successful stenting. At follow-up the angiographic restenosis rate (restenosis $50%) was 38% in the placebo group and only 25% in the treated group. Larger trials are already designed to verify the promising results and to confirm the ability of statins to influence the incidence of restenosis after successful stent deployment.
7. Vascular gene therapy Our review demonstrates clearly that statins do not prevent restenosis in clinical trials. Therefore, restenosis after PTCA remains a burning issue and is
204
M. Horlitz et al. / International Journal of Cardiology 83 (2002) 199 – 205
still the major limitation of short-to-medium term success of this procedure. A large number of alternative approaches have been already conducted but only few interventions have appeared to be effective. In this context, the vessel wall as a target for gene therapy may yield more promising results in future [37]. Vascular gene therapy is a new area where only a few preliminary results from human trials are available. Most of the experimental studies have been targeted to affect endothelial regeneration and angiogenesis including transfection of vascular smooth muscle cells with plasmid constructs encoding ‘vasoprotective’ genes to enhance endothelial regeneration and vascular generation of nitric oxide (NO) to inhibit myointimal hyperplasia and migration after balloon injury [38,39]. Niebauer et al. could demonstrate that human endothelial cells generate more NO when transfected with a plasmid construct encoding nitric oxide synthase. The increase of NO was associated with a reduction of endothelial adhesiveness for monocytes and an enhanced resistance to cytokine induced adhesiveness [37]. The underlying mechanism may be multifactorial. NO inhibits monocyte adhesion to the endothelium, mediated by cGMP modulation of adhesion signaling. Moreover, NO down-regulates the endothelial expression of monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) [22]. Therefore, NO exerts massive protective effect on human endothelial cells by playing a critical role in monocyte-vessel wall interaction. These data suggest the possibility of NOS transfection as a potential therapeutic approach to treat restenosis and in-stent restenosis following angioplasty. Supplementation of L-arginine as the substrate for the enzyme nitric oxide synthase chronically enhances vascular NO generation, resulting in inhibition of neointimal lesion formation, attenuation of macrophage infiltration, and improved vasomotion in hypercholesteolemic rabbits [40]. Intramural delivery of L-arginine (the precursor of NO) following angioplasty causes a sustained increase in NO elaboration, associated with an attenuation of endothelial monocyte adherence and an enhanced apoptosis of vascular cells [41]. Moreover, it could be demonstrated for the first time that intramural delivery of L-arginine induces apoptosis of resident macrophages in vivo as a
underlying mechanism of reduced rate of restenosis in the L-arginine treated vessels [22]. Even though gene therapy has demonstrated promising results for the treatment of restenosis and the application of therapeutic angiogenesis, further developments in gene transfer vectors, gene delivery techniques and identification of effective treatment genes will be required before the full value of gene therapy can be assessed.
8. Conclusion The results of the present clinical studies suggest that HMG-CoA reductase inhibitors have no short-tomedium term effects on angiographic restenosis or clinical events after successful conventional PTCA despite their proven benefits in primary and secondary prevention of atherosclerosis and their significant effect on reduction in lipids. Statins may affect restenosis after coronary stenting although there is still no evidence for this at the moment. A better understanding of the pathophysiology of restenosis, improved experimental models and alternative approaches, such as targeting expression and activities of specific cell molecules, are required to facilitate the development of therapeutic agents which are effective in preventing restenosis. Innovative approaches including gene therapy and local drug delivery appear to be effective in future and may yield more promising results. The endothelium may be genetically engineered to have local effects on the vessel wall or to secrete substances to have systemic effects. Accordingly, new clinical trials with the intention to affect the process of restenosis are already underway.
References [1] Landau C, Lange RA, Hillis DL. Percutaneous transluminal coronary angioplasty. New Engl J Med 1994;330:981–93. [2] Foley DP, Bonnier H, Jackson G et al. Prevention of restenosis after coronary balloon angioplasty: rationale and design of the Fluvastatin Angioplasty Restenosis (FLARE) Trial. Am J Cardiol 1994;73:50D–61D. [3] Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. New Engl J Med 1987;316:701–6.
M. Horlitz et al. / International Journal of Cardiology 83 (2002) 199 – 205 [4] Fischman DL, Leon MB, Baim DS et al. A randomized comparison of coronary stent placement and balloon angioplasty in the treatment of coronary artery disease. (The STRESS trial). New Engl J Med 1994;331:496–501. [5] Serruys PW, de Jaegere P, Kiemeneij F et al. A comparison of balloon expandable stent implantation with balloon angioplasty in patients with coronary artery disease. (The Benestent study). New Engl J Med 1994;331:489–95. [6] Serruys PW, Macaya C, de Jaegere P et al. Interim analysis of the Benestent trial (abstract). Circulation 1993;88:I594. [7] Haude M, Erbel R, Hafner G et al. Multizentrische Ergebnisse der koronaren Implantation von Ballon expandierbaren Palmaz-Schatz¨ ¨ Gefaß-Stutzen. Z Kardiol 1993;82:77–86. [8] Chesebro KST, Lam JYT, Badimon L, Fuster V. Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia. Circulation 1987;60:10B–6B. [9] Guiteras VP, Bourassa MG, David PR et al. Restenosis after successful percutaneous transluminal coronary angioplasty: The Montreal Heart Institute experience. Am J Cardiol 1987;60:50B–5B. [10] Liu MW, Roubin GS, King III SB. Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia. Circulation 1989;79:1374–87. ¨ [11] Luescher TF, Oemar BS, Yang Z, Noll G. Molekulare und zellulare ¨ Mechanismen der Arteriosklerose und Restenose: M.oglichkeiten der Gentherpie. Z Kardiol 1996;85:495–508. [12] Califf RM, Fortin DF, Frid DJ et al. Restenosis after coronary angioplasty: an overview. J Am Cardiol 1991;17:2B–13B. [13] Hermans WRM, Rensing BJ, Strauss BH, Serruys PW. Prevention of restenosis after percutaneous transluminal coronary angioplasty: the search for a ‘magic bullet’. Am Heart J 1991;122:171–87. [14] Sahni R, Maniet AR, Voci G, Banka VS. Prevention of restenosis by lovastatin after successful coronary angioplasty. Am Heart J 1991;121:1600–8. [15] Vaughan CJ, Gotto AM, Basson CTB. The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol 2000;35:1– 10. [16] Eckardt H, Voelker W, Bruenning T, Buddecke E. Lovastatin reduces myointimal proliferation after vascular injury (abstract). Eur Heart J 1991;12(Suppl. 9). [17] Gellman J, Ezekowitz MD, Sarembock IJ et al. Effect of lovastatin on intimal hyperplasia after balloon angioplasty: a study in an atherosclerotic hypercholesterolemic rabbit. J Am Coll Cardiol 1991;17:251–9. [18] Soma MR, Donetti E, Parolini C, Mazzini G, Ferrari C, Fumagalli R. HMG-CoA reductase inhibitors: In vivo effects on carotid intimal thickening in normocholesterolaemic rabbits. Arterioscler Thromb 1993;13:71–8. [19] Endo A, Kuroda M, Tsujita Y. ML-236A, ML-236B, ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinum. J Antibiot 1976;29:1346–8. [20] Farnier M, Davignon J. Current and future treatment of hyperlipidemia: The role of statins. Am J Cardiol 1998;82:3J–10J. [21] Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. Lancet 1996;348:1079–82. [22] Niebauer J, Schwarzacher SP, Hayase M et al. Local L-arginine delivery after balloon angioplasty reduces monocyte binding and induces apoptosis. Circulation 1999;100:1830–5. [23] Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000;101:207–13. [24] Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999;100:230–5.
205
[25] Sacks FM, Pfeffer MA, Moye LA et al. For the cholersterol and recurrent events trial investigators. New Engl J Med 1996;335:1001–9. [26] Scandinavian Simvastatin Survival Study Group. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S). Lancet 1995;345:1274–5. [27] Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Study (4S). Lancet 1994;344:1383–9. [28] West of Scotland Coronary Prevention Study Group, Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. New Engl J Med 995;1333:1301–7. [29] the Lovastatin Restenosis Trial Study Group, Weintraub WS, Boccuzzi SJ, Brown CL et al. Background and methods for the Lovastatin restenosis trial after percutaneous transluminal coronary angioplasty. Am J Cardiol 1992;70:293–9. [30] Lovastatin restenosis trial study group. Lovastatin Restenosis trial: final results (abstract). Circulation 1993;88:I–506. [31] the Lovastatin Restenosis Trial Study Group, Weintraub WS, Boccuzzi SJ, Klein JL et al. Lack of effect of lovastatin on restenosis after coronary angioplasty. New Engl J Med 1994;331:1331–7. [32] O’Keefe JH, Stone GW, McCallister BD et al. Lovastatin plus probucol for prevention of restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol 1996;77:649–52. [33] for the PREDICT Trial Investigators, Bertrand ME, McFadden EP, Fruchart J-C et al. Effect of pravastatin on angiographic restenosis after coronary balloon angioplasty. J Am Coll Cardiol 1997;30:863– 9. [34] Onaka H, Hirota Y, Kita Y. The effect of pravastatin on prevention of restenosis after successful percutaneous coronary angioplasty. Jpn Circ J 1994;58:100–6. [35] Serruys PW, Foley DP, Jackson G et al. A randomized placebocontrolled trial of fluvastatin for prevention of restenosis after successful coronary balloon angioplasty. Final results of the fluvastatin angiographic restenosis (FLARE) trial. Eur Heart J 1999;20:58–69. ¨ [36] Walter DH, Schachinger M, Elsner M et al. Effect of statin therapy on restenosis after coronary stent implantation. Am J Cardiol 2000;85:962–8. [37] Niebauer J, Dulak J, Chan JR, Tsao PS, Cooke JP. Gene transfer of nitric oxide synthase. Effects on endothelial biology. J Am Coll Cardiol 1999;34:1201–7. [38] Von der Leyen HE, Braun-Dullaeus R, Mann MJ, Zhang L, Niebauer J, Dzau VJ. A pressure-mediated non-viral method for efficient arterial gene and oligonucleotide transfer. Hum Gene Ther 1999;10:2355–64. [39] Von der Leyen HE, Gibbons GH, Morishita R et al. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Natl Acad Sci USA 1995;92:1137–41. [40] Wang BY, Candipan RC, Arjomandi M, Hsiun PT, Tsao PS, Cooke JP. Arginine restores nitric oxide activity and inhibits monocyte accumulation after vascular injury in hypercholesterolemic rabbits. J Am Coll Cardiol 1996;28:1573–9. [41] Schwarzacher SP, Lim TT, Wang BY et al. Local intramural delivery of L-arginine enhances nitric oxide generation and inhibits lesion formation after balloon angioplasty. Circulation 1997;95:1863–9.
Review article
Fighting restenosis after coronary angioplasty: contemporary and future treatment options a, b c Marc Horlitz *, Ulrich Sigwart , Josef Niebauer a
Department of Cardiology, Heartcenter Wuppertal, University of Witten /Herdecke, Arrenberger Str. 20, 42117 Wuppertal, Germany b Royal Brompton Hospital, Sydney Street, London SW3 6 NP, UK c Department of Cardiology, Heartcenter Leipzig, University of Leipzig, Strumpellstr. 39, 04289 Leipzig, Germany Received 19 August 2001; received in revised form 13 January 2002; accepted 23 January 2002
Abstract Despite the widespread use of coronary stents, prevention of restenosis after percutaneous transluminal coronary angioplasty (PTCA) remains a major challenge. The restenotic process is even higher after balloon angioplasty without stenting and has been shown to be in the range of 30–50%. Experimental data suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (‘statins’) might have a beneficial effect on restenosis after coronary angioplasty. Proposed mechanisms include favorable effects on plasma lipoproteins, endothelial function, plaque architecture and stability, thrombosis and inflammation. Although statins have documented efficacy in reducing clinical events and angiographic disease progression in patients with coronary atherosclerosis, the results of subsequent large prospective clinical trials using different types of statins clearly demonstrate that statins do not have a short-to-medium term effect on prevention of restenosis after successful conventional PTCA. The underlying pathological reasons for this shortcoming as well as promising innovative approaches including gene therapy and local drug delivery of vasoactive substances will be discussed in this review. 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Angioplasty; Restenosis; Statins; Gene therapy
1. Introduction Restenosis limits the long-term beneficial effects of percutaneous transluminal coronary angioplasty (PTCA) and related procedures [1]. Prevention of restenosis after successful PTCA remains one of the most challenging issues in the treatment of obstructive coronary artery disease [2]. Since 1986, the introduction of coronary stents by Sigwart has sig-
*Corresponding author. Tel.: 149-202-896-5708 fax: 149-202-8965707. E-mail address: [email protected] (M. Horlitz).
nificantly improved the short and long-term results of interventional coronary revascularisation procedures [3]. Eight years later, two major randomised trials confirmed that stenting after PTCA indeed reduces the incidence of restenosis (the STRESS [Stent Restenosis Study] trial in the USA, the BENESTENT [Belgium Netherlands Stent Trial] study in Europe) [4–6]. Despite lowering the restenosis rate with the implantation of coronary stents and a decline in the rate of initial complications, restenosis occurs in approximately 15–20% within 6 months after intervention sometimes necessitating repeat revascularisation [7]. The cellular biological mechanisms following balloon angioplasty are only partially understood. Re-
0167-5273 / 02 / $ – see front matter 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 02 )00033-5
200
M. Horlitz et al. / International Journal of Cardiology 83 (2002) 199 – 205
stenosis after PTCA has a multifactorial aetiology involving mechanical and hemostatic factors as well as altered cell proliferation. Mechanisms identified include stent under-expansion, immediate recoil, incorporation of thrombus and the ‘normal’ healing process in response to arterial injury involving proliferation of intimal smooth muscle cells and extracellular matrix, as well as vascular remodelling [8–10]. Decreased programmed cell death (apoptosis) is also an important regulatory mechanism and may contribute to human restenosis post angioplasty by prolonging the life span of intimal cells, with their subsequent accumulation and development of hyperplastic lesions [11]. In addition to mechanical interventions, pharmacological approaches to decrease the incidence of restenosis have been assessed [12–14]. The introduction of HMG-CoA reductase inhibitors has led to a significant improvement in the primary and secondary prevention of coronary artery disease [15]. Initial studies demonstrated that statins might have a beneficial effect on the relative risk of restenosis following coronary angioplasty by reducing lipid levels or mechanisms independent of low-density lipoproteins (LDL) lowering [16–18].
2. Experimental studies In the early 1990s experimental studies have suggested that HMG-CoA reductase inhibitors (‘statins’) might reduce restenosis after balloon angioplasty. Gellman et al. randomized 38 atherosclerotic rabbits to receive either lovastatin or placebo after balloon angioplasty of the femoral artery. Treatment with lovastatin decreased the progression of disease in the rabbit-iliac model independent of an effect on LDL cholesterol [17]. Eckhardt et al. showed that lowering LDL cholesterol levels decreased rates of restenosis in the rat-carotid model [16]. Soma et al. confirmed a direct effect of statins on smooth muscle cell proliferation after carotid artery injury innormocholesterolemic rabbits [18]. Therefore, sound experimental evidence suggested that statins might have a beneficial effect on restenosis after coronary angioplasty.
3. Origins, chemistry and mode of action of HMG-CoA reductase inhibitors HMG-CoA reductase inhibitors were first introduced into clinical practice in the late 1980s. Originally recovered from fungal metabolites, they are now synthetically produced. Currently there are six statins in clinical use, of which lovastatin and pravastatin are natural products of fungal origin, simvastatin is a semi-synthetic derivative, and fluvastatin, the first entirely synthetic product is derived from mevalonolactone. Recently, a new generation of highly purified, synthetic statins have been developed like atorvastatin and cerivastatin [19,20]. Statins are oral systemic agents that inhibit the rate-limiting enzyme of cholesterol synthesis in the liver, thereby decreasing the hepatic production of low-density lipoproteins (LDL) and upregulating expression of hepatic LDL receptors, thus, lowering concentrations of circulating LDL cholesterol. The activity of HMG-CoA reductase limits the rate of synthesis, not only of cholesterol, but also of a range of other molecules involved in functions such as cellular respiration and cell–cell recognition. Smooth-muscle-cell (SMC) proliferation is a feature of atherogenesis, Mevalonate and other intermediates of cholesterol biosynthesis are essential for cell growth. Therefore, drugs affecting this metabolic pathway, such as statins, may reduce SMC proliferation and subsequently the developement of restenosis after PTCA [21]. Macrophages have been involved in the pathophysiology of acute coronary syndromes by producing enzymes leading to plaque instability. Oxidized LDL attracts macrophages directly and stimulates their binding to the endothelium through induction of adhesion molecules. Statins prevent the oxidation of LDL possibly through preservation of the activity of the endogenous antioxidant system. Statins also alter macrophage handling and uptake of LDL. In addition, macrophages elaborate tissue factor, a glycoprotein that plays an important role in blood coagulation and plaque thrombogenicity. Statins inhibit tissue factor expression by cultured human macrophages, and this may reduce thrombotic events [15]. Thus, statin therapy takes also part in plaque stabilization which may attenuate atherogenesis.
M. Horlitz et al. / International Journal of Cardiology 83 (2002) 199 – 205
Nitric oxide (NO) has been shown to inhibit monocyte adherence and chemotaxis, platelet adherence and aggregation, and vascular smooth muscle proliferation. The activity of NO is reduced in hypercholesterolemia and after vascular injury [22]. Both simvastatin and lovastatin induce transcriptional activation of the NO synthase gene in human cells in vitro [23]. Therefore, the effects of statins on cholesterol lowering and enhancement of NO activity may result in significant improvement in endothelial function and could be valuable for the prevention and management of restenosis. Moreover, several studies demonstrate that statins may have additional antithrombotic actions by affecting thrombus formation, erythrocyte deformability and levels of fibrinogen. Although the precise mechanism is unclear, one mechanism may involve decreased platelet thromboxane A2 production [15]. The finding that the membrane cholesterol content of both erythrocytes and platelets is reduced in patients treated with pravastatin suggests that statins reverse the thrombotic–fibrinolytic imbalance that accompanies hypercholesterolemia [23]. Effects on inflammation have been observed in a sub-analysis of the CARE trial. Results of this study suggest that pravastatin reduces the higher risk of cardiovascular events associated with an lowering effect on the levels of C-reactive protein as an inflammatory marker [24]. Statins also reduced the incidence of organ rejection and the cytotoxicity of natural killer cells in recipients of heart and kidney transplantation [24]. In conclusion, different pharmacological effects may emphasize the tremendous impact of statins on the development of restenosis. Proposed mechanisms include not only cholesterol-lowering but additional independent effects on endothelial function, plaque stability, thrombosis and inflammation.
4. Clinical trials Three large, randomised, placebo-controlled clinical trials using statins have clearly demonstrated the efficacy of cholesterol lowering as a risk-reduction strategy for prevention of coronary artery disease. These include one primary-prevention trial (the West of Scotland Coronary Prevention Study (WOS-
201
COPS)) and two secondary-prevention trials (the Scandinavian Simvastatin Survival Study (4S) and the Cholesterol and Recurrent Events (CARE) Trial) [25–28]. The 4S was a landmark trial that changed the treatment paradigm in coronary artery disease (CAD) by showing that lowering cholesterol levels can significantly decrease the incidence of death from CAD. A total of 4444 patients with either angina pectoris or prior myocardial infarction (MI), and serum cholesterol levels of 213–310 mg / dl were enrolled in this double-blind study. Over the 5.4 years median follow-up period, Simvastatin treatment lowered total cholesterol and LDL cholesterol levels by 25 and 35%, respectively, changes that were paralleled by a 42% reduction in the incidence of death from CAD. Other benefits of treatment included a 37% reduction in the risk of undergoing myocardial revascularisation procedures [26,27]. The CARE trial demonstrated similar benefits in 4159 post-infarction patients with coronary disease who had total plasma cholesterol values ,240 mg / dl, and LDL cholesterol values of 115–174 mg / dl. Throughout the 5 years of study follow-up, cholesterol levels in the pravastatin group were 28% lower than those in placebo-treated patients and demonstrated a significant risk reduction of 24% in the incidence of fatal coronary events and non-fatal MI [25]. The West of Scotland Coronary Prevention Study showed that the incidence of death and non-fatal MI from CAD could be decreased by reducing cholesterol levels with pravastatin. A total of 6595 men with an average age of 45–64 years, no history of MI and only moderate hypercholesterolemia (mean LDL cholesterol 192 mg / dl), were enrolled in this double-blind study. Over a follow-up period of 3–5 years, the risk of death from CAD was 33% lower in the treatment group compared with the control group. There also was a 31% reduction in non-fatal MI [28]. Despite the promising results of experimental studies and the outcome of large prospective placebocontrolled prevention trials the clinical effect of HMG-CoA reductase inhibitors to prevent or delay the process of restenosis after successful conventional PTCA remained unclear. In an initial trial Sahni et al. treated 157 patients with either lovastatin (n579; 20 mg daily if the
202
M. Horlitz et al. / International Journal of Cardiology 83 (2002) 199 – 205
serum cholesterol level was ,300 mg / dl and 40 mg daily if the serum cholesterol was higher) in addition to conventional therapy or conventional therapy alone (n578; aspirin, dipyridamole, calcium channel blocker) [14]. The serum cholesterol level in the lovastatin group significantly decreased from 212649 to 175641 mg / dl, whereas the serum cholesterol level in the control group decreased from 207649 to 196648 mg / dl. Restenosis was reported in 12% of treated and 45% of non-treated patients. However, follow-up was incomplete with only 63% of treated patients and 37% of non-treated patients undergoing follow-up angiography at an interval of 2–10 months. The study was not blinded and only 157 patients were included. These factors limit the validity of this trial. The Lovastatin Restenosis Trial (LRT) was a well designed, large multicenter, prospective, doubleblind, placebo-controlled randomised study. Treatment was commenced between 7 and 10 days before successful angioplasty and the dose of lovastatin used was 40 mg orally twice daily [29]. Of 404 patients randomly assigned to study groups, 354 patients with total cholesterol between 180 and 300 mg / dl underwent successful elective angioplasty, 321 underwent angiographic assessment at 6 months. The purpose of the study was to determine whether aggressive lipid lowering therapy would reduce the rate of restenosis through reduction of cholesterol or possibly by direct effects on endothelial healing, resulting in a decreased smooth muscle cell proliferative response to angioplasty injury. Despite a 42% lipid-lowering effect in the treatment group at 1 month, no prevention or reduction of restenosis could be demonstrated in the first 6 months. The patients in the lovastatin group and the placebo group were similar with respect to clinical, angiographic and laboratory characteristics. The mean luminal diameter reduction was 64611% in the lovastatin group, as compared with 63611% in the placebo group [30,31]. The Angioplasty Plus Probucol / Lovastatin Evaluation (APPLE) using lovastatin to lower LDL levels in combination with probucol to prevent LDL oxidation showed that this combined strategy was also ineffective in preventing restenosis or subsequent cardiac events throughout the first 6 months after PTCA [32]. A total of 239 patients were enrolled, 68% were randomised to active therapy and 32% to placebo. Patients with total cholesterol values between 150
and 300 mg / dl were started on active or placebo therapy between 48 h before and 24 h after successful elective PTCA. The combination of lovastatin and probucol was highly effective at reducing total cholesterol (227%) and LDL (230%), although HDL levels were also proportionately reduced (227%). At follow-up angiography there were no significant differences between the active and placebo groups with respect to restenosis. A total of 51% of patients in the active group were noted to have a minimal luminal diameter of .50% compared with 46% of the placebo-treated patients. In a multicenter, double-blind study termed ‘Prevention des Restenoses par Elisor apres Dilatation Coronaire Transluminale’ (Prevention of Restenosis by Elisor (trade name for Pravastatin) After Transluminal Coronary Angioplasty) (PREDICT) 695 patients were randomised to receive pravastatin (n5 347; 40 mg / day) or placebo (n5348) for 6 months after successful PTCA. The primary angiographic end point was minimal lumen diameter (MLD) at followup, assessed by quantitative coronary angiography [33]. A total of 556 patients were available for re-angiography and despite a significant reduction in total and low density lipoprotein cholesterol and triglyceride levels and a significant increase in HDL cholesterol levels, there was no effect on angiographic outcome at the target site. At follow-up the MLD was 1.4760.62 mm in the placebo group and 1.5460.66 mm in the pravastatin group. The restenosis rate was 43.8% in the placebo group and 39.2% in the pravastatin group. Clinical restenosis did not differ between both groups. Subsequently, a small randomized pravastatin study in a Japanese population showed no effect on angiographic restenosis either [34]. Although all HMG-CoA reductase inhibitors were found to have a direct effect on smooth muscle cell proliferation in experimental investigations fluvastatins appeared to inhibit neointimal formation to the greatest extent [35]. Whereas previous studies investigated effective lipid lowering as the antirestenosis mechanism, the multicenter Fluvastatin Angioplasty Restenosis (FLARE) trial was conceived to evaluate the direct inhibitory effect of fluvastatin 40 mg twice daily on the coronary vascular myocyte, independent of any influence on serum lipid concentrations. To ensure adaequate tissue distribution, fluvastatin was
M. Horlitz et al. / International Journal of Cardiology 83 (2002) 199 – 205
administered 2–4 weeks before angioplasty. There were 1054 patients randomised to receive either fluvastatin or placebo; 834 patients underwent successful angioplasty and angiographic follow-up at 2662 weeks was performed in 93%. The primary endpoint was angiographic restenosis. No difference in the primary endpoint (fluvastatin 0.2360.49 mm, placebo-group 0.2360.53 mm), in angiographic restenosis rate (fluvastatin 28%, placebo 31%) or in the incidence of clinical events could be detected between both treatment groups. In short, treatment with fluvastatin did not affect the process of restenosis [2,35].
203
factors, which mediate neointimal lesions characterized by abnormal migration and proliferation of vascular smooth muscle cells in the intima. Moreover, balloon injury results in the loss of endothelium-derived NO, which plays an important role as an endogenous inhibitor of vascular lesion formation because of its function in maintaining vascular homeostasis [22]. The clinical results should not be interpreted as an incentive to adopt a nihilistic attitude in patients undergoing angioplasty. Although statins do not have an effect on restenosis, their effect on the progression of atherosclerosis and on the clinical events associated with such progression is undoubted.
5. Discussion 6. Statins after coronary stenting Even though the benefits of treatment with HMGCoA reductase inhibitors in primary and secondary prevention of coronary artery disease are undisputed, no effect has been shown on clinical or angiographic medium-term (less than 1 year) restenosis after conventional PTCA. Experimentally demonstrated effects of statins on arterial smooth muscle cells failed to translate into a clinical effect. No benefit has been shown, either via an effect on lipid level, or via an effect on human monocyte proliferation. Different explanations have been provided for this shortcoming. Initially, cells in culture may not represent an appropriate model for the hypertrophic, hyperplastic myocyte changes triggered by angioplasty. Secondly, in the clinical situation, characterized by fluctuations in the drug plasma level, a steady state cannot be reached. Moreover, it seems unlikely that restenosis after conventional angioplasty and the progression of atherosclerosis have a similar pathophysiological basis. Therefore, restenosis can not be viewed simply as an acceleration of atherosclerosis in response to a severe mechanical injury. It is a much more complex process than simple cell proliferation. The cellular biological mechanisms following balloon angioplasty are only partially understood. Recent progress in molecular biology has provided a number of interactive processes like cell adhesion, coagulation, cell migration, cell proliferation and synthesis of extracellular matrix [11]. Experimental studies have demonstrated that vascular damage after dilatation may induce local expression of mitogens and chemotactic
Restenosis after coronary stenting occurs due to neointimal proliferation and it was postulated that statins might have a beneficial influence on the restenosis rate due to their known antiproliferative effect. Unfortunately, there is only little information available about the effect of statins on restenosis after stenting. Nevertheless, results of first clinical trials are promising. Walter et al. have demonstrated that HMG-CoA reductase inhibitors are associated with lower restenosis and improved clinical results in patients undergoing stent implantations [36]. In a placebo-controlled study, 525 patients were randomised to receive statins (most patients (176, 68.2%) received simvastatin, 36% (14.3%) received lovastatin, 26 (10.1%) atorvastatin, 16 (5.8%) fluvastatin and 4 (1.6%) pravastatin) or placebo (n5267) for 6 months after successful stenting. At follow-up the angiographic restenosis rate (restenosis $50%) was 38% in the placebo group and only 25% in the treated group. Larger trials are already designed to verify the promising results and to confirm the ability of statins to influence the incidence of restenosis after successful stent deployment.
7. Vascular gene therapy Our review demonstrates clearly that statins do not prevent restenosis in clinical trials. Therefore, restenosis after PTCA remains a burning issue and is
204
M. Horlitz et al. / International Journal of Cardiology 83 (2002) 199 – 205
still the major limitation of short-to-medium term success of this procedure. A large number of alternative approaches have been already conducted but only few interventions have appeared to be effective. In this context, the vessel wall as a target for gene therapy may yield more promising results in future [37]. Vascular gene therapy is a new area where only a few preliminary results from human trials are available. Most of the experimental studies have been targeted to affect endothelial regeneration and angiogenesis including transfection of vascular smooth muscle cells with plasmid constructs encoding ‘vasoprotective’ genes to enhance endothelial regeneration and vascular generation of nitric oxide (NO) to inhibit myointimal hyperplasia and migration after balloon injury [38,39]. Niebauer et al. could demonstrate that human endothelial cells generate more NO when transfected with a plasmid construct encoding nitric oxide synthase. The increase of NO was associated with a reduction of endothelial adhesiveness for monocytes and an enhanced resistance to cytokine induced adhesiveness [37]. The underlying mechanism may be multifactorial. NO inhibits monocyte adhesion to the endothelium, mediated by cGMP modulation of adhesion signaling. Moreover, NO down-regulates the endothelial expression of monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) [22]. Therefore, NO exerts massive protective effect on human endothelial cells by playing a critical role in monocyte-vessel wall interaction. These data suggest the possibility of NOS transfection as a potential therapeutic approach to treat restenosis and in-stent restenosis following angioplasty. Supplementation of L-arginine as the substrate for the enzyme nitric oxide synthase chronically enhances vascular NO generation, resulting in inhibition of neointimal lesion formation, attenuation of macrophage infiltration, and improved vasomotion in hypercholesteolemic rabbits [40]. Intramural delivery of L-arginine (the precursor of NO) following angioplasty causes a sustained increase in NO elaboration, associated with an attenuation of endothelial monocyte adherence and an enhanced apoptosis of vascular cells [41]. Moreover, it could be demonstrated for the first time that intramural delivery of L-arginine induces apoptosis of resident macrophages in vivo as a
underlying mechanism of reduced rate of restenosis in the L-arginine treated vessels [22]. Even though gene therapy has demonstrated promising results for the treatment of restenosis and the application of therapeutic angiogenesis, further developments in gene transfer vectors, gene delivery techniques and identification of effective treatment genes will be required before the full value of gene therapy can be assessed.
8. Conclusion The results of the present clinical studies suggest that HMG-CoA reductase inhibitors have no short-tomedium term effects on angiographic restenosis or clinical events after successful conventional PTCA despite their proven benefits in primary and secondary prevention of atherosclerosis and their significant effect on reduction in lipids. Statins may affect restenosis after coronary stenting although there is still no evidence for this at the moment. A better understanding of the pathophysiology of restenosis, improved experimental models and alternative approaches, such as targeting expression and activities of specific cell molecules, are required to facilitate the development of therapeutic agents which are effective in preventing restenosis. Innovative approaches including gene therapy and local drug delivery appear to be effective in future and may yield more promising results. The endothelium may be genetically engineered to have local effects on the vessel wall or to secrete substances to have systemic effects. Accordingly, new clinical trials with the intention to affect the process of restenosis are already underway.
References [1] Landau C, Lange RA, Hillis DL. Percutaneous transluminal coronary angioplasty. New Engl J Med 1994;330:981–93. [2] Foley DP, Bonnier H, Jackson G et al. Prevention of restenosis after coronary balloon angioplasty: rationale and design of the Fluvastatin Angioplasty Restenosis (FLARE) Trial. Am J Cardiol 1994;73:50D–61D. [3] Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. New Engl J Med 1987;316:701–6.
M. Horlitz et al. / International Journal of Cardiology 83 (2002) 199 – 205 [4] Fischman DL, Leon MB, Baim DS et al. A randomized comparison of coronary stent placement and balloon angioplasty in the treatment of coronary artery disease. (The STRESS trial). New Engl J Med 1994;331:496–501. [5] Serruys PW, de Jaegere P, Kiemeneij F et al. A comparison of balloon expandable stent implantation with balloon angioplasty in patients with coronary artery disease. (The Benestent study). New Engl J Med 1994;331:489–95. [6] Serruys PW, Macaya C, de Jaegere P et al. Interim analysis of the Benestent trial (abstract). Circulation 1993;88:I594. [7] Haude M, Erbel R, Hafner G et al. Multizentrische Ergebnisse der koronaren Implantation von Ballon expandierbaren Palmaz-Schatz¨ ¨ Gefaß-Stutzen. Z Kardiol 1993;82:77–86. [8] Chesebro KST, Lam JYT, Badimon L, Fuster V. Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia. Circulation 1987;60:10B–6B. [9] Guiteras VP, Bourassa MG, David PR et al. Restenosis after successful percutaneous transluminal coronary angioplasty: The Montreal Heart Institute experience. Am J Cardiol 1987;60:50B–5B. [10] Liu MW, Roubin GS, King III SB. Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia. Circulation 1989;79:1374–87. ¨ [11] Luescher TF, Oemar BS, Yang Z, Noll G. Molekulare und zellulare ¨ Mechanismen der Arteriosklerose und Restenose: M.oglichkeiten der Gentherpie. Z Kardiol 1996;85:495–508. [12] Califf RM, Fortin DF, Frid DJ et al. Restenosis after coronary angioplasty: an overview. J Am Cardiol 1991;17:2B–13B. [13] Hermans WRM, Rensing BJ, Strauss BH, Serruys PW. Prevention of restenosis after percutaneous transluminal coronary angioplasty: the search for a ‘magic bullet’. Am Heart J 1991;122:171–87. [14] Sahni R, Maniet AR, Voci G, Banka VS. Prevention of restenosis by lovastatin after successful coronary angioplasty. Am Heart J 1991;121:1600–8. [15] Vaughan CJ, Gotto AM, Basson CTB. The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol 2000;35:1– 10. [16] Eckardt H, Voelker W, Bruenning T, Buddecke E. Lovastatin reduces myointimal proliferation after vascular injury (abstract). Eur Heart J 1991;12(Suppl. 9). [17] Gellman J, Ezekowitz MD, Sarembock IJ et al. Effect of lovastatin on intimal hyperplasia after balloon angioplasty: a study in an atherosclerotic hypercholesterolemic rabbit. J Am Coll Cardiol 1991;17:251–9. [18] Soma MR, Donetti E, Parolini C, Mazzini G, Ferrari C, Fumagalli R. HMG-CoA reductase inhibitors: In vivo effects on carotid intimal thickening in normocholesterolaemic rabbits. Arterioscler Thromb 1993;13:71–8. [19] Endo A, Kuroda M, Tsujita Y. ML-236A, ML-236B, ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinum. J Antibiot 1976;29:1346–8. [20] Farnier M, Davignon J. Current and future treatment of hyperlipidemia: The role of statins. Am J Cardiol 1998;82:3J–10J. [21] Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. Lancet 1996;348:1079–82. [22] Niebauer J, Schwarzacher SP, Hayase M et al. Local L-arginine delivery after balloon angioplasty reduces monocyte binding and induces apoptosis. Circulation 1999;100:1830–5. [23] Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000;101:207–13. [24] Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999;100:230–5.
205
[25] Sacks FM, Pfeffer MA, Moye LA et al. For the cholersterol and recurrent events trial investigators. New Engl J Med 1996;335:1001–9. [26] Scandinavian Simvastatin Survival Study Group. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S). Lancet 1995;345:1274–5. [27] Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Study (4S). Lancet 1994;344:1383–9. [28] West of Scotland Coronary Prevention Study Group, Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. New Engl J Med 995;1333:1301–7. [29] the Lovastatin Restenosis Trial Study Group, Weintraub WS, Boccuzzi SJ, Brown CL et al. Background and methods for the Lovastatin restenosis trial after percutaneous transluminal coronary angioplasty. Am J Cardiol 1992;70:293–9. [30] Lovastatin restenosis trial study group. Lovastatin Restenosis trial: final results (abstract). Circulation 1993;88:I–506. [31] the Lovastatin Restenosis Trial Study Group, Weintraub WS, Boccuzzi SJ, Klein JL et al. Lack of effect of lovastatin on restenosis after coronary angioplasty. New Engl J Med 1994;331:1331–7. [32] O’Keefe JH, Stone GW, McCallister BD et al. Lovastatin plus probucol for prevention of restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol 1996;77:649–52. [33] for the PREDICT Trial Investigators, Bertrand ME, McFadden EP, Fruchart J-C et al. Effect of pravastatin on angiographic restenosis after coronary balloon angioplasty. J Am Coll Cardiol 1997;30:863– 9. [34] Onaka H, Hirota Y, Kita Y. The effect of pravastatin on prevention of restenosis after successful percutaneous coronary angioplasty. Jpn Circ J 1994;58:100–6. [35] Serruys PW, Foley DP, Jackson G et al. A randomized placebocontrolled trial of fluvastatin for prevention of restenosis after successful coronary balloon angioplasty. Final results of the fluvastatin angiographic restenosis (FLARE) trial. Eur Heart J 1999;20:58–69. ¨ [36] Walter DH, Schachinger M, Elsner M et al. Effect of statin therapy on restenosis after coronary stent implantation. Am J Cardiol 2000;85:962–8. [37] Niebauer J, Dulak J, Chan JR, Tsao PS, Cooke JP. Gene transfer of nitric oxide synthase. Effects on endothelial biology. J Am Coll Cardiol 1999;34:1201–7. [38] Von der Leyen HE, Braun-Dullaeus R, Mann MJ, Zhang L, Niebauer J, Dzau VJ. A pressure-mediated non-viral method for efficient arterial gene and oligonucleotide transfer. Hum Gene Ther 1999;10:2355–64. [39] Von der Leyen HE, Gibbons GH, Morishita R et al. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Natl Acad Sci USA 1995;92:1137–41. [40] Wang BY, Candipan RC, Arjomandi M, Hsiun PT, Tsao PS, Cooke JP. Arginine restores nitric oxide activity and inhibits monocyte accumulation after vascular injury in hypercholesterolemic rabbits. J Am Coll Cardiol 1996;28:1573–9. [41] Schwarzacher SP, Lim TT, Wang BY et al. Local intramural delivery of L-arginine enhances nitric oxide generation and inhibits lesion formation after balloon angioplasty. Circulation 1997;95:1863–9.