Journal of Cardiovascular Pharmacology:
Renin-Angiotensin System Intervention to Prevent In-Stent Restenosis: An Unclosed Chapter
Langeveld, Bas MD*; Roks, Anton J. M. PhD*; Tio, Rene A. MD, PhD†; Voors, Adriaan A. MD, PhD†; Zijlstra, Felix MD, PhD†; van Gilst, Wiek H. PhD*
From the Departments of *Clinical Pharmacology and †Cardiology, University Hospital Groningen, Groningen, the Netherlands.
Received for publication April 28, 2004; accepted October 27, 2004.
Reprints: Bas Langeveld, Department of Clinical Pharmacology, University Hospital Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands (e-mail: email@example.com).
The occurrence of in-stent restenosis is a major drawback of percutaneous transluminal coronary angioplasty with stent placement. Target vessel revascularization is necessary in 15% of patients who receive a stent. Recent advances in the development of drug-eluting stents have reduced these numbers tremendously. However refinement of antirestenotic therapies remains obligatory. The emerging interest in more physiological antirestenotic therapies might unchain an interest in the well-known inhibitors of the rennin-angiotensin system (RAS), the angiotensin-converting enzyme inhibitors, and the angiotensin II type I receptor blockers. Contradictory results overshadow the discussion of whether intervention in the RAS could prevent in-stent restenosis. This review discusses the pathophysiology of in-stent restenosis, the role of the RAS in in-stent restenosis, and the possible role of RAS intervention in the prevention of in-stent restenosis.
Since 1977, coronary artery stenoses have been successfully treated by means of percutaneous coronary transluminal angioplasty (PTCA).1 A major drawback of this procedure is the occurrence of restenosis in 20%-50% of the cases. The introduction of the coronary stent has improved the clinical outcome after PTCA considerably. However, the extensive use of stents has revealed a new issue: in-stent restenosis (ISR). This persistent intimal hyperplasia occurs in 20%-30%, and it makes reintervention necessary in approximately 15% of the patients after stent implantation.2,3 Consequently, ISR is a major health problem after PTCA. Recently, impressive results have emerged in the field of ISR prevention. Drug-eluting stents (DES) coated with the strong antiproliferative agents rapamycin or paclitaxel have been demonstrated to be potent antirestenotic strategies.4,5 Notwithstanding this tremendous progression in antirestenotic therapies, with the use of DES in the "real world," target vessel revascularization remains necessary in approximately 4%.6 Moreover, some worries have emerged about the occurrence of late thrombosis and hypersensitivity reactions after DES implantation.7 Consequently, refinement of antirestenotic therapies remains necessary. Recently, there is an increasing interest in physiological antirestenotic therapies by means of restoring the normal biologic function of the vessel wall.8 Considering this emerging interest, a class of drugs that might be of interest are the inhibitors of the rennin-angiotensin system (RAS).
The RAS plays a fundamental role in maintaining vascular function. Dysfunction of the RAS results in cardiovascular disease. Likewise, the RAS could play a role in the pathophysiology of ISR. RAS intervention, by means of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, is an extensively used and rather safe method for the treatment of cardiovascular disease. With this in mind, RAS intervention, systemically or by means of drug-eluting stents, would be an appealing approach to the prevention of ISR. Unfortunately, controversial findings, and hence opinions, still dominate the discussion of whether RAS inhibition can be used to intervene in ISR. In this review we systematically discuss the pathophysiology of ISR, the role of the RAS in ISR, and the alleged role of RAS intervention in the prevention of ISR by means of ACE inhibitors, angiotensin II type 1 (AT1) receptor blockers, and angiotensin(1-7).
PATHOPHYSIOLOGY OF ISR
Restenosis is the arterial healing response as seen after vascular injury inflicted during PTCA.9 Restenosis after balloon angioplasty involves elastic recoil, negative remodeling, and neointimal formation. Intravascular ultrasound studies have revealed that negative remodeling contributes to approximately 70% of the restenosis after balloon angioplasty. The latter 30% is caused by neointimal formation.10,11 Implantation of a stent in the dilated part of the artery prohibits virtually all elastic recoil and negative remodeling and should therefore prevent restenosis after PTCA. However, restenosis still occurs after stenting, now mainly from excessive neointimal formation.12-14
Neointimal formation after stent placement results from deep focal injury caused by the penetration of stent struts and chronic presence of foreign body material. The amount of neointimal area is proportional to the severity of the injury inflicted to the arterial wall by the stent struts.15 The principal vascular responses after stenting are focal thrombus formation, inflammation, smooth muscle cell (SMC) proliferation and migration, and extracellular matrix deposition16 (see Fig. 1). Furthermore, processes such as apoptosis and oxidative stress are also thought to be involved in the pathophysiology of ISR.17-20
Stent placement induces endothelial denudation and substantial damage to deeper layers of the arterial wall. Consequently, platelets adhere to sites of injury, effectuated by adhesion receptors such as glycoprotein IIb/IIIa. Binding of glycoprotein IIb/IIIa to fibrinogen leads to platelet aggregation and activation. Activated platelets induce release and expression of several growth factors, adhesion molecules, cytokines, and chemokines such as platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), serotonin, thromboxane A2, P-selectin, histamine, interleukin (IL)-6, and IL-8. The most important substance released by activated platelets is PDGF, which is a potent stimulus for SMC proliferation and migration21 (see Fig. 1B).
Virtually immediately after stenting a substantial inflammatory response evolves. Leukocytes are recruited at sites where the endothelium is denuded, and consequently platelets and fibrinogen are exposed. At first the inflammatory reaction consists of rolling and adhesion of mononuclear and polymorphonuclear leukocytes. P-selectin, a glycoprotein expressed on activated platelets, is responsible for the rolling of leukocytes. Subsequently, adhesion molecules of the integrin class mediate the firm adhesion and migration of the leukocytes. The β2 integrin molecule Mac-1 (CD11b/CD18) appears to fulfill a central role in this process. The binding of leukocytes to platelets and the arterial wall activates the leukocytes and thus further amplifies the inflammatory response. Subsequent production of chemokines and cytokines like monocyte chemoattractant protein (MCP)-1 and IL-8 contributes to further recruitment of leukocytes.22-24 The number of surface-adherent leukocytes is a strong determinant of neointimal formation.16,25
After initial adhesion and activation of leukocytes, leukocyte infiltration is observed 3 to 7 days after stenting. Macrophages cluster around the stent struts and form giant cells. As for surface-adherent leukocytes, the number of infiltrating inflammatory cells is also strongly associated with the neointimal area.25,26 Activated macrophages are thought to influence vascular repair by producing a variety of mediators such as interleukins, tumor necrosis factor (TNF)-α, MCP-1, and growth factors such as PDGF and basic fibroblast growth factor (bFGF)24,27 (see Fig. 1C).
Smooth Muscle Cell Proliferation and Migration
Focal thrombosis and the inflammatory reaction after stenting result in an outburst of potential mediators of SMC proliferation and migration. Some 7 days after stent implantation, SMCs migrate from the media toward the lumen to form the neointima. Under the influence of PDGF and bFGF these SMCs begin to proliferate. Simultaneously, SMCs also start releasing inflammatory and proliferation mediators, stimulating the vascular healing response. Proliferation of cells in the neointima is maximal 7 days after stenting and declines thereafter.16,28 Moreover, apoptosis is present in the neointima as soon as 7 days after stenting.17 Apoptosis density is inversely correlated with the residual stenosis after angioplasty in an atherosclerotic rabbit model.29 As a result of persisting apoptosis and decreasing SMC proliferation, the absolute cell density in the neointima decreases in time (Fig. 1D).
Extracellular Matrix Deposition
After weeks, SMCs start producing large amounts of proteoglycans and collagen under the influence of PDGF and TGF-β. Consequently, the neointima eventually looses cellularity and gains extracellular matrix, thus forming a more or less stable neointima.13,30,31
Role of Bone Marrow-Derived Cells in Neointimal Formation
Traditionally, it is thought that neointimal cells are originated from the media. Recently, evidence has come to light that bone marrow-derived cells also are involved in the pathophysiology of neointimal formation. Two distinct types of bone marrow-derived cells play a role in neointimal formation: endothelial progenitor cells (EPC) and bone marrow cells that contribute to the composition of the neointima. After vascular injury, EPCs fulfill a role in reendothelialization.32,33 Moreover, more EPCs, brought about by a statin, estrogen, or physical exercise, result in accelerated reendothelialization and subsequent inhibition of neointimal formation after vascular injury in mice.32-34 Furthermore, patients with diffuse ISR show reduced numbers of EPCs together with an impaired adhesive function.35
Bone marrow-derived cells also contribute to the formation of the neointima after vascular injury.36-38 It has been shown that bone marrow-derived cells can differentiate into SMCs and that up to 60% of the neointimal cells are bone marrow-derived.36,37 However, these are data from experimental work with different types of injury, and the contribution of bone marrow-derived cells in the neointima was strongly diverse.38 Consequently, the exact significance of bone marrow-derived cells in the pathophysiology of ISR remains largely unresolved.
In summary, the process of ISR starts with thrombus formation, followed by an inflammatory response and eventually neointimal formation. These processes are evoked by release of proinflammatory substances and growth factors. However, release of hormones such as angiotensin II might also take part in the development of ISR.
RAS AND ISR
The RAS plays a major role in maintaining electrolyte balance, volume status, and blood pressure. Angiotensinogen is hydrolyzed to angiotensin I by renin. Subsequently, angiotensin I is converted to angiotensin II by ACE. Alternative enzymes for angiotensin II production such as human chymase and cathepsin exist in humans, other primates, hamsters, and dogs. In most rodents such pathways are absent.39,40 Furthermore, in the RAS, circulating and tissue ACE are distinguished. The circulating and tissue ACE are thought to effectuate the short- and long-term effects of RAS activation, respectively.41,42
Angiotensin II, the most important effector of the RAS, exerts its physiological effects such as vasoconstriction, aldosterone release, and SMC growth through the stimulation of angiotensin II receptors. In the human cardiovascular system the AT1- and angiotensin II type 2 (AT2) receptors are of importance.43,44
Activation of the AT1 receptor by angiotensin II has several deleterious effects on the cardiovascular system, namely cell migration and proliferation,45-47 extracellular matrix deposition,48,49 inflammation,50,51 promotion of thrombosis,52-54 and production of reactive oxygen species55 (Fig. 2).
ACE inhibition and AT1 receptor blockade are 2 widely used methods to prevent the deleterious effects of RAS stimulation. ACE inhibitors presumably reach their goal by decreasing the conversion from angiotensin I to angiotensin II by inhibiting ACE. Additionally, the degradation of bradykinin is decreased by inhibition of ACE. Bradykinin exerts a favorable influence on the cardiovascular system by the release of antiproliferative and anti-inflammatory substances such as nitric oxide, prostaglandins E2 and I2, and endothelial-derived hyperpolarizing factor.56-59
Selective AT1 receptor blockers inhibit stimulation of the AT1 receptor by angiotensin II. Consequently, adverse effects of angiotensin II, such as cell migration and proliferation, extracellular matrix deposition, inflammation, promotion of thrombosis, and production of reactive oxygen species, are blocked. Furthermore, during selective AT1 receptor blockade, the AT2 receptor can still be activated. The AT2 receptor is thought to counteract the mechanisms stimulated by the AT1 receptor. Activation of the AT2 receptor is associated with NO production, inhibition of proliferation, and induction of apoptosis60-63 (Fig. 2).
Apart from angiotensin II, other RAS products might influence cardiovascular disease. Interestingly, during ACE inhibition and AT1 blockade, plasma levels of angiotensin(1-7) are elevated.56,64-67 Angiotensin(1-7) is a heptapeptide normally formed from angiotensin I by endopeptidases (neutral endopeptidase 24.11, prolyl endopeptidase), or indirectly through ACE-2-mediated formation of angiotensin(1-9), which is subsequently metabolized to angiotensin(1-7). Alternatively, angiotensin(1-7) can be formed from angiotensin II by prolyl endopeptidase, carboxypeptidase, or ACE-2. The AT2- and Mas receptors mediate the counterregulatory effects of angiotensin(1-7).68-73 Angiotensin(1-7) has vasodilatory, antiproliferative, and antithrombotic actions. Moreover, angiotensin(1-7) is an ACE inhibitor and AT1 antagonist itself. Considering the contrast in actions with angiotensin II, angiotensin(1-7) is thought to be the natural counterregulator of angiotensin II64,68,74,75 (Fig. 2).
In conclusion, ACE inhibitors, AT1 receptor blockers, and angiotensin(1-7) prevent the deleterious effects of angiotensin II on the cardiovascular system by inhibition of cell migration and proliferation, extracellular matrix deposition, inflammation, thrombosis, and production of reactive oxygen species. These processes are key players in the origin of ISR. Moreover, angiotensin II seems to play a role in the development of restenosis. Next to the above-mentioned effects of the RAS, several studies allocate a role for the RAS in the recruitment of bone marrow-derived cells. Angiotensin II increases the proliferation of hematopoietic progenitor cells, and this effect is abolished by an AT1 receptor blocker.76 Furthermore, angiotensin(1-7) acts similarly on hematopoietic stem cells.77,78 As mentioned, bone marrow-derived cells might fulfill a role in the pathophysiology of restenosis. Consequently, the RAS could also participate in the pathophysiology or prevention of ISR by influencing the recruitment of these cells. However, the role of the RAS on bone marrow-derived cells and its possible influence on cardiovascular disease remain to be elucidated.
Hypothetically, a role in the prevention of ISR can be allocated for RAS intervention by means of ACE inhibition, AT1 receptor blockade, combination therapy, or angiotensin(1-7), either systemically or locally applied.
ACE INHIBITORS AND ISR
Experimental Effects of ACE Inhibition
ACE inhibitors prevent neointimal formation after vascular injury in the rat.79 This antirestenotic effect of ACE inhibition is probably related to blockade of angiotensin II production because in rats receiving angiotensin II infusion after vascular injury, neointimal formation was not suppressed by treatment with an ACE inhibitor.80 In other rodents, such as guinea pigs and rabbits, ACE inhibitors also block neointimal formation.81 Part of the antirestenotic effects of ACE inhibitors in rats can be explained by the production of kinins. This is illustrated by the attenuation of the protective effects of ACE inhibition after vascular injury by the kinin antagonist Hoe 140.82
Clinical Effects of ACE Inhibition
In regard to the antirestenotic effects of ACE inhibitors in animal models, an important role seemed to be reserved for ACE inhibition in the prevention of restenosis. This initial optimism was tempered by demonstration of the inability to diminish neointimal formation with ACE inhibition after vascular injury in larger animals.83,84 Moreover, the MERCATOR and MARCATOR, two large human trials, showed no effect of the ACE inhibitor cilazapril on restenosis.85,86 Likewise, the PARIS showed no benefit of ACE inhibition after stenting.87
Possible explanations for these discrepancies in studies are alternative pathways of angiotensin II production, lack of tissue ACE inhibition, and inappropriate study design. During ACE inhibition alternative pathways, such as human chymase and cathepsin-dependent angiotensin II production, can become significant. Consequently, ACE inhibition in animal species that possess human chymase will be less effective in attenuating neointimal formation because angiotensin II is still present.88 Moreover, the specific chymase inhibitor Suc-Val-Pro-Phep inhibits neointimal formation in grafted jugular veins in dogs, thereby illustrating the importance of chymase-dependent angiotensin II production during vascular injury.88 Finally, Hojo et al consolidated the role of alternative angiotensin II production in restenosis by revealing that ACE inhibition during PTCA could not prevent the increase in angiotensin II production in the human coronary circulation.89
In addition to alternative angiotensin II conversion, lack of tissue ACE inhibition could play a role. Tissue ACE is induced in SMCs in the neointima after vascular injury in the rat.90 Moreover, at sites of angioplasty injury in humans, obtained during autopsy, ACE is also up-regulated. In the early stages, ACE expression is mainly present in the macrophages. When SMCs appear in the neointima, they also show increased expression of ACE.91 Macrophages and SMCs in the neointima after stenting in dogs also show an up-regulation of ACE.92 Furthermore, to prevent neointimal formation, inhibition of tissue ACE activity is more important than inhibition of plasma ACE activity after vascular injury. Rakugi et al demonstrated that mainly the residual tissue ACE activity during ACE inhibition is strongly associated with neointimal formation after vascular injury.93 The dose of an ACE inhibitor required to achieve blood pressure reduction is lower than the dose required for inhibition of tissue ACE. In the MERCATOR and MARCATOR, the doses of ACE inhibitor used were adequate to elicit an antihypertensive effect but potentially inadequate to inhibit tissue ACE activity.93
Furthermore, appropriate study design is of utmost importance. In clinical trials that failed to show prevention of restenosis, ACE inhibition treatment was initiated after PTCA or stenting. However, administration of the ACE inhibitor before vascular injury is more efficient to attenuate neointimal formation.79
Based on theoretical considerations, ACE inhibitors administered in an adequate dose and before PTCA or stenting, could reduce restenosis. However, chymase-dependent angiotensin II formation,88 the unfeasibility of high-dose ACE inhibitor administration to inhibit tissue ACE,94 and the large number of negative clinical studies after PTCA and stenting85,86,95-97 should unchain some skepticism about ACE inhibitors in the prevention of restenosis. The problem of inadequate dosing of the ACE inhibitor might be resolved by means of drug-eluting stents. This possibility remains underexplored until now. AT1 receptor blockers might provide the solution to escape from alternative angiotensin II formation.
AT1 RECEPTOR BLOCKERS AND ISR
Experimental and Clinical Effects of AT1 Receptor Blockers
In several studies, selective AT1 receptor blockers have demonstrated their efficiency to inhibit neointimal formation in the rat carotid injury model.80,98-104 Furthermore, expression of the AT1 receptor is increased in neointimal cells after balloon angioplasty in rats.105 In a porcine coronary artery organ culture model, losartan demonstrated its potency to decrease neointimal proliferation.106 These findings raised enthusiasm because a discrepancy between small- and large-animal and possibly human studies seemed to be absent. Unfortunately, AT1 receptor blockade after stenting in the porcine coronary artery showed no effect, suggesting that angiotensin II is not a major mediator of restenosis.107 In contrast to these results in the pig, the VAL-PREST trial, the first human study concerning AT1 receptor blockade after stenting, showed a significant decrease in angiographic and clinical in-stent restenosis.108 Additionally, in the VALVACE trial, an AT1 receptor blocker was more effective than ACE inhibitors in preventing ISR after stent implantation for acute coronary syndromes in 700 patients.109 However, the exact role of the angiotensin II receptors and AT1 receptor blockers in ISR remains uncertain.
Interaction Between AT Receptors
Recently, some experiments have contributed to the elucidation of the role of AT1 and AT2 receptors and their antagonists in neointimal formation. Vascular injury induces AT1 and AT2 receptor expression.101,105 Harada et al studied the AT1 receptor-mediated signaling during neointimal formation. In AT1a knockout mice, neointimal formation after vascular injury was similar to that in wild-type mice. Angiotensin II administration enhanced neointimal formation only in wild-type mice. Furthermore, neointimal formation was reduced by an AT1 receptor blocker only in wild-type mice. These results suggest that neointimal formation can be modified by AT1 receptor blockade. However, neointimal formation remains abundant without AT1 receptor signaling.110
Wu et al elucidated the function of the AT2 receptor during AT1 receptor antagonism after vascular injury. Neointimal formation was attenuated in wild-type mice by AT1 receptor blockade; this effect was less prominent in AT2 knockout mice. Moreover, the anti-inflammatory effects of AT1 receptor blockade were decreased in AT2 knockout mice. This was shown by higher expression of inflammatory markers such as MCP-1, TNF-α, IL-6, and IL-1β and infiltration of leukocytes and macrophages. In conclusion, stimulation of the AT2 receptor during AT1 receptor antagonism is important in the decrease of neointimal formation after vascular injury.111
Furthermore, it was demonstrated that the increase of neointimal formation in AT2 receptor knockout mice is caused by an increase in DNA synthesis in SMCs and a decrease in apoptosis. This suggests that the AT2 receptor exerts antiproliferative and proapoptotic effects after vascular injury.112
Although angiotensin II is not the sole hormone involved in restenosis, the antirestenotic effects of AT1 receptor blockers in small animal models of vascular injury and the decrement of ISR rate in the VAL-PREST and VALVACE trials propose a role for AT1 receptor blockers in the prevention of restenosis. Moreover, next to the attenuation of the deleterious effects of AT1 receptor stimulation, part of the antirestenotic effects of AT1 receptor blockers are mediated through stimulation of the AT2 receptor. The contribution of AT2 receptor stimulation in restenosis may in fact be one of the reasons why ACE inhibitors do not have antirestenotic properties because absence of angiotensin II during ACE inhibition avoids AT2 receptor stimulation. Nevertheless, AT1 receptor blockade seems to play a role in the attenuation of restenosis.
Most research concerning AT1 receptor blockade has been focused vascular injury after balloon dilatation and systemic AT1 receptor blockade. Future experiments should clarify particularly the exact role and usefulness of local application of AT1 receptor blockers in ISR.
COMBINATION OF ACE INHIBITORS AND AT1 RECEPTOR BLOCKERS AND ISR
Accumulating evidence suggests that combination therapy with an ACE inhibitor and an AT1 receptor blocker is superior to monotherapy of either drug alone in the treatment of cardiovascular disease. An ACE inhibitor and AT1 receptor blocker combined induce greater reductions in blood pressure and heart weight in hypertensive rats, enhance myocardial infarct size in pigs, and show beneficial effects in rats with heart failure.113-116 Additionally, in humans combination therapy shows a larger improvement in cardiac function in heart failure patients, compared with monotherapy. 117,118 Moreover, Kim et al found that the combination of an ACE inhibitor and an AT1 receptor blocker also increases the reduction of intimal hyperplasia after balloon injury as compared with either of these drugs alone.119
Because attenuation of neointimal formation by ACE inhibition is partly mediated by blockade of angiotensin II production, and because chymase-dependent angiotensin II formation plays an important role in neointimal formation, ACE inhibition alone might be insufficient to prevent restenosis.80,88,89 Addition of an AT1 receptor blocker to ACE-inhibition therapy could block the detrimental effects of chymase-dependent angiotensin II production after vascular injury. Moreover, chymase-dependent production of angiotensin II might still enable stimulation of the AT2 receptor for additional antirestenotic effects.
Additionally, bradykinin-mediated NO production contributes to the antirestenotic effect of ACE inhibition.82 Moreover, the beneficial effects of combination therapy on neointimal formation also are at least partly mediated through bradykinin or NO.119 Consequently, combination of blockade of the deleterious effects of chymase-dependent angiotensin II formation by AT1 receptor blockade and the increase of bradykinin- and NO-mediated effects by ACE inhibition might explain the superiority of combination therapy with ACE inhibition and AT1 receptor blockade compared with monotherapy. Possible adverse effects of combination therapy could be prevented by local application of these drugs.119,120
ANGIOTENSIN(1-7) AND ISR
As mentioned, angiotensin(1-7) opposes many actions of angiotensin II: it has antiproliferative and antithrombotic actions.68 The beneficial effect of angiotensin(1-7) on the cardiovascular system is illustrated by the attenuation of heart failure after myocardial infarction in rats and the antihypertensive effects in hypertensive rats.121,122 Furthermore, continuous angiotensin(1-7) infusion reduces DNA synthesis and neointimal formation after vascular injury in a rat carotid artery.123 Recently, we have shown at our laboratory that angiotensin(1-7) infusion also reduces ISR in a rat model.140
Therefore, angiotensin(1-7) might be an interesting drug. However, the pharmacokinetic properties of angiotensin(1-7) limit the use as a systemic, therapeutic drug; the half-life of circulating angiotensin(1-7) is approximately 10 s.124 During treatment with angiotensin(1-7), infusion would be necessary to maintain substantial plasma levels of angiotensin(1-7). Because continuous infusion in humans is unfeasible, systemic treatment in human with angiotensin(1-7) seems pointless. Nevertheless, local therapy with angiotensin(1-7) remains possible. For the prevention of ISR, angiotensin(1-7) could be administered by means of a drug-eluting stent or local gene therapy. A high dose of peptide could be locally applied to the site of vascular injury.
Until now, the role of angiotensin(1-7) in ISR remains mostly unresolved. Several options for prevention of ISR with this endogenous peptide are present. Future studies must further verify its possible contribution in ISR prevention.
As mentioned, RAS intervention to prevent ISR should be primarily aimed at local application of these drugs. However, many uncertainties exist concerning the drug dose and release profile of drug-eluting stents. With regard to the drug dose, it is recommended to estimate the effective and safe dose by a multiple dosing study. Since, the amount of drug coated on the stent is often limited, the maximal possible loading dose and lower doses should be tested.125 As for RAS intervention, little is known about locally needed concentrations. At least for ACE inhibitors, a sufficient dose for tissue ACE inhibition is required for attenuation of neointimal formation.93
Furthermore, local release of drugs does not ensure adequate delivery; this is dependent on several physiological forces and physicochemical properties of the drug. There are computational methods for determination of such local stent pharmacokinetics, which may become of importance for future drug-eluting stent development.126,127
To make a rough estimation of the required dose, though, one could assume that the steady-state concentration of ACE inhibitor or AT1 receptor blocker that is needed in the tissue should be about 10−8 mol/L. It is feasible that this concentration has to be reached in a tissue volume of about 1 mL (assuming a 3.5 × 20 mm stent and a tissue penetration of 5 mm). Thus, at an average molecular weight of 450 g/mol, an amount of 10−11 mol, and an average t1/2 of 6 hours, a release of ∼0.02 μg per day to the tissue is needed. For 120 days of release, a total amount of 24 μg of drug should be available for the tissue. Because the loading capacity for the anti-inflammatory agent rapamycin exceeds 100 μg, it is conceivable that the principle of drug elution is applicable also for RAS inhibitors.128
The release profile of drug-eluting stents is also of importance. An extended period of drug elution is necessary, but the exact duration of this period is a subject of discussion. The active healing process of neointimal formation appears to last approximately 4 weeks in animal models, and longer periods are seen in human autopsy material.129,130 Subsequently, effective drug elution should be at least 4 weeks. However, for rapamycin-eluting stents it is known that complete elution of the drug over 15 days is effective in preventing ISR.131 Concerning RAS intervention, ACE activity was seen as long as 6 months after stent implantation in a case report.132 However, it was shown that ACE and AT1 receptor-positive macrophages are mainly present early after stenting and decrease thereafter.133 The latter suggest that only a limited period of RAS blockade is necessary. However, because AT1 receptors are present for a long period on SMCs of human in-stent restenotic lesions, a longer duration of AT1 receptor blockade to prevent ISR might be needed.133 Consequently, systemic AT1 receptor blockade to prevent ISR should be applied in clinically used doses for a prolonged period of time. As for locally applied AT1 receptor blockade, the limitation in eluting periods of stents might prevent the possibility of long-term treatment. However, short drug-eluting periods might also be sufficient to prevent ISR, as seen with the rapamycin-eluting stent.
Many polymers, such as polyurethanes, have been used as stent coatings. Biocompatibility of these polymers is of the utmost importance. Currently, biodegradable polymers and biodegradable stent matrices are coming into use. Newly developed biodegradable polymers and drug-delivery systems enable more desirable release profiles, independent of hydrophilicity and the molecular weight of the drug.134,135 These new drug-delivery systems could also provide a means for prolonged eluting periods for AT1 receptor blockers. However, in the development of drug-eluting stents, extensive pharmacokinetic studies are still essential to establish efficacy and safety.
RAS INTERVENTION IN THE ERA OF DRUG-ELUTING STENTS
Currently, ISR is opposed by the use of drug-eluting stents coated with strongly antiproliferative agents.4,5 However, with these antirestenotic strategies some drawbacks have emerged. Late thrombosis and hypersensitivity reactions are of major concern.7 Furthermore, paclitaxel and rapamycin are known to have unfavorable effects on the endothelium.136-138 In light of the recent interest in more physiological endothelium and arterial-recovering antirestenotic therapies, these finding are worrisome.8 RAS intervention has endothelium-protective properties, even in the setting of vascular injury.121,139 Therefore, the potential antirestenotic effects of RAS intervention, together with the endothelium and arterial protective properties makes RAS intervention a promising strategy for the prevention of ISR, especially in the era of strongly antiproliferative drug-eluting stents.
RAS intervention is already extensively used in cardiovascular disease. Moreover, it is a safe method for the treatment of manifestations of cardiovascular disease. Consequently, RAS intervention would be an attractive way to prevent ISR in a more physiological manner.
The RAS is not the sole factor for restenosis; however, it surely plays a part in the pathophysiology. The effects of RAS intervention on restenosis have been elaborately studied. The usefulness of ACE inhibitors for ISR prevention is disputable. Their inefficiency is probably a result of alternative angiotensin II-forming pathways and unfeasibility of high-dose therapy. The use of local application of an ACE inhibitor by means of drug-eluting stents remains unresolved.
AT1 receptor blockers have been proven effective in reducing restenosis in animal models and in humans. Systemically administered AT1 receptor blockade has reduced ISR in two clinical studies. AT1 receptor blocker-eluting stents could be another possible antirestenotic therapy. Consequently, the use of AT1 receptor blockers should be further studied to reveal its applicability. Moreover, a combination of an AT1 receptor blocker and an ACE inhibitor might be a more potent antirestenotic strategy.
The role of angiotensin(1-7) in ISR is largely unknown. Because of the antirestenotic actions of this endogenous peptide after vascular injury and stent implantation in the rat, local administration might be a possible solution for ISR.
Restenosis and the RAS have been extensively studied. However, most studies concerning RAS intervention focused on restenosis after balloon dilatation and not ISR. Moreover, the use of local application of RAS intervention has remained unresolved. In the era of drug-eluting stents, RAS intervention remains a promising antirestenotic strategy because of the endothelium and arterial-healing properties. In conclusion, future studies should aim at local RAS intervention with AT1 receptor blockers, combination therapy, or angiotensin(1-7) to attenuate ISR. Many additional experiments have to be performed before the chapter of ISR and RAS intervention can be closed.
1. Gruntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med.
2. 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. Benestent Study Group. N Engl J Med.
3. 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. Stent Restenosis Study Investigators. N Engl J Med.
4. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med.
5. Park SJ, Shim WH, Ho DS, et al. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med.
6. Lemos PA, Serruys PW, van Domburg RT, et al. Unrestricted utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the "real world": the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry. Circulation.
7. Virmani R, Guagliumi G, Farb A, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation.
8. Losordo DW, Isner JM, Diaz-Sandoval LJ. Endothelial recovery: the next target in restenosis prevention. Circulation.
9. Topol E. Textbook of Interventional Cardiology.
Philadelphia: W.B. Saunders, 1994.
10. Sangiorgi G, Taylor AJ, Farb A, et al. Histopathology of postpercutaneous transluminal coronary angioplasty remodeling in human coronary arteries. Am Heart J.
11. Mintz GS, Popma JJ, Pichard AD, et al. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation.
12. Moreno PR, Palacios IF, Leon MN, et al. Histopathologic comparison of human coronary in-stent and post-balloon angioplasty restenotic tissue. Am J Cardiol.
13. Grewe PH, Deneke T, Machraoui A, et al. Acute and chronic tissue response to coronary stent implantation: pathologic findings in human specimen. J Am Coll Cardiol.
14. Hoffmann R, Mintz GS, Dussaillant GR, et al. Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation.
15. Schwartz RS, Huber KC, Murphy JG, et al. Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol.
16. Edelman ER, Rogers C. Pathobiologic responses to stenting. Am J Cardiol.
17. Kollum M, Kaiser S, Kinscherf R, et al. Apoptosis after stent implantation compared with balloon angioplasty in rabbits. Role of macrophages. Arterioscler Thromb Vasc Biol.
18. Brasen JH, Kivela A, Roser K, et al. Angiogenesis, vascular endothelial growth factor and platelet-derived growth factor-BB expression, iron deposition, and oxidation-specific epitopes in stented human coronary arteries. Arterioscler Thromb Vasc Biol.
19. Azevedo LC, Pedro MA, Souza LC, et al. Oxidative stress as a signaling mechanism of the vascular response to injury: the redox hypothesis of restenosis. Cardiovasc Res.
20. Tardif JC, Cote G, Lesperance J, et al. Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. Multivitamins and Probucol Study Group. N Engl J Med.
21. Chandrasekar B, Tanguay JF. Platelets and restenosis. J Am Coll Cardiol.
22. Yeo EL, Sheppard JA, Feuerstein IA. Role of P-selectin and leukocyte activation in polymorphonuclear cell adhesion to surface adherent activated platelets under physiologic shear conditions (an injury vessel wall model). Blood.
23. Diacovo TG, Roth SJ, Buccola JM, et al. Neutrophil rolling, arrest, and transmigration across activated, surface-adherent platelets via sequential action of P-selectin and the beta 2-integrin CD11b/CD18. Blood.
24. Welt FG, Rogers C. Inflammation and restenosis in the stent era. Arterioscler Thromb Vasc Biol.
25. Rogers C, Welt FG, Karnovsky MJ, et al. Monocyte recruitment and neointimal hyperplasia in rabbits. Coupled inhibitory effects of heparin. Arterioscler Thromb Vasc Biol.
26. Kornowski R, Hong MK, Tio FO, et al. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol.
27. Libby P, Schwartz D, Brogi E, et al. A cascade model for restenosis. A special case of atherosclerosis progression. Circulation.
28. Carter AJ, Laird JR, Farb A, et al. Morphologic characteristics of lesion formation and time course of smooth muscle cell proliferation in a porcine proliferative restenosis model. J Am Coll Cardiol.
29. Durand E, Mallat Z, Addad F, et al. Time courses of apoptosis and cell proliferation and their relationship to arterial remodeling and restenosis after angioplasty in an atherosclerotic rabbit model. J Am Coll Cardiol.
30. Glover C, Ma X, Chen YX, et al. Human in-stent restenosis tissue obtained by means of coronary atherectomy consists of an abundant proteoglycan matrix with a paucity of cell proliferation. Am Heart J.
31. Chung IM, Gold HK, Schwartz SM, et al. Enhanced extracellular matrix accumulation in restenosis of coronary arteries after stent deployment. J Am Coll Cardiol.
32. Walter DH, Rittig K, Bahlmann FH, et al. Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation.
33. Strehlow K, Werner N, Berweiler J, et al. Estrogen increases bone marrow-derived endothelial progenitor cell production and diminishes neointima formation. Circulation.
34. Laufs U, Werner N, Link A, et al. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation.
35. George J, Herz I, Goldstein E, et al. Number and adhesive properties of circulating endothelial progenitor cells in patients with in-stent restenosis. Arterioscler Thromb Vasc Biol.
36. Sata M, Saiura A, Kunisato A, et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med.
37. Xu Y, Arai H, Zhuge X, et al. Role of bone marrow-derived progenitor cells in cuff-induced vascular injury in mice. Arterioscler Thromb Vasc Biol.
38. Tanaka K, Sata M, Hirata Y, et al. Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries. Circ Res.
39. Urata H, Kinoshita A, Misono KS, et al. Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem.
40. Dzau VJ, Sasamura H, Hein L. Heterogeneity of angiotensin synthetic pathways and receptor subtypes: physiological and pharmacological implications. J Hypertens Suppl.
41. Dzau VJ. Short- and long-term determinants of cardiovascular function and therapy: contributions of circulating and tissue renin-angiotensin systems. J Cardiovasc Pharmacol.
42. Dzau VJ. Vascular renin-angiotensin system and vascular protection. J Cardiovasc Pharmacol.
43. Chiu AT, Herblin WF, McCall DE, et al. Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun.
44. Bumpus FM, Catt KJ, Chiu AT, et al. Nomenclature for angiotensin receptors. A report of the Nomenclature Committee of the Council for High Blood Pressure Research. Hypertension.
45. Bell L, Madri JA. Influence of the angiotensin system on endothelial and smooth muscle cell migration. Am J Pathol.
46. Daemen MJ, Lombardi DM, Bosman FT, et al. Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Circ Res.
47. Kohno M, Ohmori K, Nozaki S, et al. Effects of valsartan on angiotensin II-induced migration of human coronary artery smooth muscle cells. Hypertens Res.
48. Scott-Burden T, Hahn AW, Resink TJ, et al. Modulation of extracellular matrix by angiotensin II: stimulated glycoconjugate synthesis and growth in vascular smooth muscle cells. J Cardiovasc Pharmacol.
49. Tharaux PL, Chatziantoniou C, Fakhouri F, et al. Angiotensin II activates collagen I gene through a mechanism involving the MAP/ER kinase pathway. Hypertension.
50. Ruiz-Ortega M, Lorenzo O, Suzuki Y, et al. Proinflammatory actions of angiotensins. Curr Opin Nephrol Hypertens.
51. Prasad A, Koh KK, Schenke WH, et al. Role of angiotensin II type 1 receptor in the regulation of cellular adhesion molecules in atherosclerosis. Am Heart J.
52. Ridker PM, Gaboury CL, Conlin PR, et al. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function. Circulation.
53. Kerins DM, Hao Q, Vaughan DE. Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV. J Clin Invest.
54. Vaughan DE. The renin-angiotensin system and fibrinolysis. Am J Cardiol.
55. Wolf G. Free radical production and angiotensin. Curr Hypertens Rep.
56. Campbell DJ, Kladis A, Duncan AM. Effects of converting enzyme inhibitors on angiotensin and bradykinin peptides. Hypertension.
57. Gavras H, Gavras I. Endothelial Function in Cardiovascular Disease: The Role of Bradykinin.
London: Science Press, 1996.
58. Miura H, Liu Y, Gutterman DD. Human coronary arteriolar dilation to bradykinin depends on membrane hyperpolarization: contribution of nitric oxide and Ca2+
59. Nakashima M, Mombouli JV, Taylor AA, et al. Endothelium-dependent hyperpolarization caused by bradykinin in human coronary arteries. J Clin Invest.
60. Kurisu S, Ozono R, Oshima T, et al. Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis. Hypertension.
61. Meffert S, Stoll M, Steckelings UM, et al. The angiotensin II AT2
receptor inhibits proliferation and promotes differentiation in PC12W cells. Mol Cell Endocrinol.
62. Nakajima M, Hutchinson HG, Fujinaga M, et al. The angiotensin II type 2 (AT2
) receptor antagonizes the growth effects of the AT1 receptor: gain-of-function study using gene transfer. Proc Natl Acad Sci USA.
63. Horiuchi M, Hayashida W, Kambe T, et al. Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and induces apoptosis. J Biol Chem.
64. Kohara K, Brosnihan KB, Chappell MC, et al. Angiotensin (1-7). A member of circulating angiotensin peptides. Hypertension.
65. Luque M, Martin P, Martell N, et al. Effects of captopril related to increased levels of prostacyclin and angiotensin(1-7) in essential hypertension. J Hypertens.
66. Yamada K, Iyer SN, Chappell MC, et al. Differential response of angiotensin peptides in the urine of hypertensive animals. Regul Pept.
67. Iyer SN, Chappell MC, Averill DB, et al. Vasodepressor actions of angiotensin(1-7) unmasked during combined treatment with lisinopril and losartan. Hypertension.
68. Ferrario CM, Chappell MC, Tallant EA, et al. Counterregulatory actions of angiotensin(1-7). Hypertension.
69. Zisman LS, Keller RS, Weaver B, et al. Increased angiotensin(1-7)-forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme homologue ACE2. Circulation.
70. Zisman LS, Meixell GE, Bristow MR, et al. Angiotensin (1-7) formation in the intact human heart: in vivo dependence on angiotensin II as substrate. Circulation.
71. Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res.
72. Tipnis SR, Hooper NM, Hyde R, et al. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem.
73. Santos RA, Simoes e Silva AC, Maric C, et al. Angiotensin(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA.
74. Kucharewicz I, Pawlak R, Matys T, et al. Antithrombotic effect of captopril and losartan is mediated by angiotensin(1-7). Hypertension.
75. Roks AJ, van Geel PP, Pinto YM, et al. Angiotensin (1-7) is a modulator of the human renin-angiotensin system. Hypertension.
76. Rodgers KE, Xiong S, Steer R, et al. Effect of angiotensin II on hematopoietic progenitor cell proliferation. Stem Cells.
77. Rodgers K, Xiong S, diZerega GS. Effect of angiotensin II and angiotensin(1-7) on hematopoietic recovery after intravenous chemotherapy. Cancer Chemother Pharmacol.
78. Ellefson DD, diZerega GS, Espinoza T, et al. Synergistic effects of co-administration of angiotensin 1-7 and Neupogen on hematopoietic recovery in mice. Cancer Chemother Pharmacol.
79. Powell JS, Clozel JP, Muller RK, et al. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science.
80. Osterrieder W, Muller RK, Powell JS, et al. Role of angiotensin II in injury-induced neointima formation in rats. Hypertension.
81. Clozel JP, Hess P, Michael C, et al. Inhibition of converting enzyme and neointima formation after vascular injury in rabbits and guinea pigs. Hypertension.
82. Farhy RD, Carretero OA, Ho KL, et al. Role of kinins and nitric oxide in the effects of angiotensin converting enzyme inhibitors on neointima formation. Circ Res.
83. Huber KC, Schwartz RS, Edwards WD, et al. Effects of angiotensin converting enzyme inhibition on neointimal proliferation in a porcine coronary injury model. Am Heart J.
84. Hanson SR, Powell JS, Dodson T, et al. Effects of angiotensin converting enzyme inhibition with cilazapril on intimal hyperplasia in injured arteries and vascular grafts in the baboon. Hypertension.
85. Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: a multicenter, randomized, double-blind placebo-controlled trial. Multicenter European Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MERCATOR) Study Group. Circulation.
86. Faxon DP. Effect of high dose angiotensin-converting enzyme inhibition on restenosis: final results of the MARCATOR Study, a multicenter, double-blind, placebo-controlled trial of cilazapril. The Multicenter American Research Trial With Cilazapril After Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MARCATOR) Study Group. J Am Coll Cardiol.
87. Meurice T, Bauters C, Hermant X, et al. Effect of ACE inhibitors on angiographic restenosis after coronary stenting (PARIS): a randomised, double-blind, placebo-controlled trial. Lancet.
88. Nishimoto M, Takai S, Kim S, et al. Significance of chymase-dependent angiotensin II-forming pathway in the development of vascular proliferation. Circulation.
89. Hojo Y, Ikeda U, Katsuki T, et al. Inhibition of angiotensin converting enzyme cannot prevent increases in angiotensin II production in coronary circulation. Heart.
90. Rakugi H, Kim DK, Krieger JE, et al. Induction of angiotensin converting enzyme in the neointima after vascular injury. Possible role in restenosis. J Clin Invest.
91. Ohishi M, Ueda M, Rakugi H, et al. Upregulation of angiotensin-converting enzyme during the healing process after injury at the site of percutaneous transluminal coronary angioplasty in humans. Circulation.
92. Nishibe T, Miyazaki K, Kudo F, et al. Induction of angiotensin converting enzyme in neointima after intravascular stent placement. Int Angiol.
93. Rakugi H, Wang DS, Dzau VJ, et al. Potential importance of tissue angiotensin-converting enzyme inhibition in preventing neointima formation. Circulation.
94. Pratt RE, Dzau VJ. Pharmacological strategies to prevent restenosis: lessons learned from blockade of the renin-angiotensin system. Circulation.
95. Meurice T, Bauters C, Hermant X, et al. Effect of ACE inhibitors on angiographic restenosis after coronary stenting (PARIS): a randomised, double-blind, placebo-controlled trial. Lancet.
96. Ribichini F, Wijns W, Ferrero V, et al. Effect of angiotensin-converting enzyme inhibition on restenosis after coronary stenting. Am J Cardiol.
97. Koch W, Mehilli J, von Beckerath N, et al. Angiotensin I-converting enzyme (ACE) inhibitors and restenosis after coronary artery stenting in patients with the DD genotype of the ACE gene. J Am Coll Cardiol.
98. Prescott MF, Webb RL, Reidy MA. Angiotensin-converting enzyme inhibitor versus angiotensin II, AT1 receptor antagonist. Effects on smooth muscle cell migration and proliferation after balloon catheter injury. Am J Pathol.
99. Taguchi J, Abe J, Okazaki H, et al. Angiotensin converting enzyme inhibitors or DuP753 prevent neointimal formation following balloon injury with single topical or multiple systemic application. Biochem Biophys Res Commun.
100. Kauffman RF, Bean JS, Zimmerman KM, et al. Losartan, a nonpeptide angiotensin II (Ang II) receptor antagonist, inhibits neointima formation following balloon injury to rat carotid arteries. Life Sci.
101. Janiak P, Pillon A, Prost JF, et al. Role of angiotensin subtype 2 receptor in neointima formation after vascular injury. Hypertension.
102. Azuma H, Niimi Y, Hamasaki H. Prevention of intimal thickening after endothelial removal by a nonpeptide angiotensin II receptor antagonist, losartan. Br J Pharmacol.
103. Kawamura M, Terashita Z, Okuda H, et al. TCV-116, a novel angiotensin II receptor antagonist, prevents intimal thickening and impairment of vascular function after carotid injury in rats. J Pharmacol Exp Ther.
104. Nozawa Y, Matsuura N, Miyake H, et al. Effects of TH-142177 on angiotensin II-induced proliferation, migration and intracellular signaling in vascular smooth muscle cells and on neointimal thickening after balloon injury. Life Sci.
105. Viswanathan M, Stromberg C, Seltzer A, et al. Balloon angioplasty enhances the expression of angiotensin II AT1 receptors in neointima of rat aorta. J Clin Invest.
106. Wilson DP, Saward L, Zahradka P, et al. Angiotensin II receptor antagonists prevent neointimal proliferation in a porcine coronary artery organ culture model. Cardiovasc Res.
107. Huckle WR, Drag MD, Acker WR, et al. Effects of subtype-selective and balanced angiotensin II receptor antagonists in a porcine coronary artery model of vascular restenosis. Circulation.
108. Peters S, Gotting B, Trummel M, et al. Valsartan for prevention of restenosis after stenting of type B2/C lesions: the VAL-PREST trial. J Invasive Cardiol.
109. Peters S, Trummel M, Meyners W. Valsartan versus angiotensin-converting enzyme-inhibition in acute coronary syndrome after successful stent implantation of the culprit lesion-results from the VALVACE trial. Eur Heart J.
110. Harada K, Komuro I, Sugaya T, et al. Vascular injury causes neointimal formation in angiotensin II type 1a receptor knockout mice. Circ Res.
111. Wu L, Iwai M, Nakagami H, et al. Roles of angiotensin II type 2 receptor stimulation associated with selective angiotensin II type 1 receptor blockade with valsartan in the improvement of inflammation-induced vascular injury. Circulation.
112. Suzuki J, Iwai M, Nakagami H, et al. Role of angiotensin II-regulated apoptosis through distinct AT1
receptors in neointimal formation. Circulation.
113. Menard J, Campbell DJ, Azizi M, et al. Synergistic effects of ACE inhibition and Ang II antagonism on blood pressure, cardiac weight, and renin in spontaneously hypertensive rats. Circulation.
114. Kim S, Zhan Y, Izumi Y, et al. Cardiovascular effects of combination of perindopril, candesartan, and amlodipine in hypertensive rats. Hypertension.
115. Weidenbach R, Schulz R, Gres P, et al. Enhanced reduction of myocardial infarct size by combined ACE inhibition and AT(1)-receptor antagonism. Br J Pharmacol.
116. Kim S, Yoshiyama M, Izumi Y, et al. Effects of combination of ACE inhibitor and angiotensin receptor blocker on cardiac remodeling, cardiac function, and survival in rat heart failure. Circulation.
117. Hamroff G, Katz SD, Mancini D, et al. Addition of angiotensin II receptor blockade to maximal angiotensin-converting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure. Circulation.
118. McKelvie RS, Yusuf S, Pericak D, et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation.
119. Kim S, Izumi Y, Izumiya Y, et al. Beneficial effects of combined blockade of ACE and AT1 receptor on intimal hyperplasia in balloon-injured rat artery. Arterioscler Thromb Vasc Biol.
120. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med.
121. Loot AE, Roks AJ, Henning RH, et al. Angiotensin (1-7) attenuates the development of heart failure after myocardial infarction in rats. Circulation.
122. Iyer SN, Ferrario CM, Chappell MC. Angiotensin(1-7) contributes to the antihypertensive effects of blockade of the renin-angiotensin system. Hypertension.
123. Strawn WB, Ferrario CM, Tallant EA. Angiotensin(1-7) reduces smooth muscle growth after vascular injury. Hypertension.
124. Yamada K, Iyer SN, Chappell MC, et al. Converting enzyme determines plasma clearance of angiotensin(1-7). Hypertension.
125. Schwartz RS, Edelman ER, Carter A, et al. Drug-eluting stents in preclinical studies: recommended evaluation from a consensus group. Circulation.
126. Hwang CW, Wu D, Edelman ER. Physiological transport forces govern drug distribution for stent-based delivery. Circulation.
127. Hwang CW, Wu D, Edelman ER. Impact of transport and drug properties on the local pharmacology of drug-eluting stents. Int J Cardiovasc Intervent.
128. Klugherz BD, Llanos G, Lieuallen W, et al. Twenty-eight-day efficacy and phamacokinetics of the sirolimus-eluting stent. Coron Artery Dis.
129. Farb A, Sangiorgi G, Carter AJ, et al. Pathology of acute and chronic coronary stenting in humans. Circulation.
130. Komatsu R, Ueda M, Naruko T, et al. Neointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analyses. Circulation.
131. Sousa JE, Costa MA, Abizaid AC, et al. Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up. Circulation.
132. Ribichini F, Pugno F, Ferrero V, et al. Angiotensin-converting enzyme tissue activity in the diffuse in-stent restenotic plaque. Circulation.
133. Wagenaar LJ, van Boven AJ, van der Wal AC, et al. Differential localisation of the renin-angiotensin system in de-novo lesions and in-stent restenotic lesions in in-vivo human coronary arteries. Cardiovasc Res.
134. al Lamee K. Surface modification of stents for improving biocompatibility. Med Device Technol.
135. Alexis F, Venkatraman SS, Rath SK, et al. In vitro study of release mechanisms of paclitaxel and rapamycin from drug-incorporated biodegradable stent matrices. J Control Release.
136. Farb A, Heller PF, Shroff S, et al. Pathological analysis of local delivery of paclitaxel via a polymer-coated stent. Circulation.
137. Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med.
138. Jeanmart H, Malo O, Carrier M, et al. Comparative study of cyclosporine and tacrolimus vs newer immunosuppressants mycophenolate mofetil and rapamycin on coronary endothelial function. J Heart Lung Transplant.
139. Van Belle E, Meurice T, Tio FO, et al. ACE inhibition accelerates endothelial regrowth in vivo: a possible explanation for the benefit observed with ACE inhibitors following arterial injury. Biochem Biophys Res Commun.
140. Langeveld B, van Gilst WH, Tio RA, et al. Angiotensin(1-7) attenuates neointimal formation after stent implantation in the rat. Hypertension.
2004 November 15 (ePub ahead of print).
rennin-angiotensin system; stent; restenosis
© 2005 Lippincott Williams & Wilkins, Inc.
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