REVIEW

Genetic determinants of adverse outcome (restenosis, malapposition and ) after implantation

Despite its unequivocal superiority compared with balloon , coronary stenting did not abolish the restenosis problem and even brought along a completely new type of pathology. Bare-metal still associate with an approximate 20–30% in-stent restenosis rate and the need for repeat revascularization. Drug-eluting stents (which unfortunately did not completely prevent restenosis either) sometimes determine late-acquired stent malapposition in a significant number of patients. This is occasionally followed by a very serious event – stent thrombosis. Patient comorbidities, stent design, procedural characteristics and antiplatelet therapy influence the risk of poststenting complications. Research in the recent years has also revealed that individual genetic profile plays an important role in adverse outcome after stent implantation. This article reviews the evidence of genetic variations associated with stent restenosis, late-acquired stent malapposition and stent thrombosis.

1,2,3 KEYWORDS: coronary disease n genes n malapposition n restenosis n stent Sandrin C Bergheanu , n thrombosis Douwe Pons1,3, Ioannis Karalis1, Orçun Özsoy1,2, The era of percutaneous coronary intervention and stent thrombosis associated with their Jeffrey JW Verschuren1, (PCI) began with the first balloon angioplasty use [9]. The aim of this article is to briefly present Mark M Ewing1,3,4, performed by Andreas Gruentzig in 1977 [1]. incidence and mechanisms of stent restenosis, Paul HA Quax3,4 & Although this technique provided impressive stent malapposition and stent thrombosis, and to J Wouter Jukema1,3,5,6† immediate results, mid- and long-term follow‑up focus on potential genetic factors related to these †Author for correspondence: was characterized by high restenosis rates and the complications. The majority of available data is 1Department of Cardiology need for repeat revascularization [1,2]. Evolving retrieved from candidate gene approach studies, C5-P, Leiden University Medical our techniques, bare-metal prosthetic devices thus limiting the results to specific pretargeted Center, PO Box 9600, 2300 RC, (stents) were designed to act as a barrier against pathophysiologic sequences. Further novel phar- Leiden, The Netherlands intima growth and recoil, assuring long-time macogenomic approaches, such as genome-wide Tel.: +31 715 266 695 patency of the coronary vessel. In 1986, Sigwart association studies (GWAS) may be able to iden- Fax: +31 715 266 885 and Puel implanted the first in tify new genetic factors for a b­etter prediction of [email protected] a human patient [3]. However, even though outcome after coronary stent deployment. 2Department of Clinical superior to balloon angioplasty alone (32–42% Epidemiology, Leiden University restenosis rate), bare-metal stent (BMS) implan­ In-stent restenosis Medical Center, The Netherlands tation remains vulnerable to restenosis (22–32% In-stent restenosis (ISR) is defined angiographi- 3Einthoven Laboratory for of cases) [4–6] and often requires reintervention. cally when neoformation tissue represents more Experimental Vascular Medicine, Drug-eluting stents (DES) were conceived as than 50% of the lumen diameter at the site of Leiden University Medical an answer to this problem. For the majority, the stented vessel (Figure 1). The clinical con- Center, The Netherlands they consist of a metallic platform covered with firmation of ISR is the recurrence of 4Department of Surgery, Leiden a combination of polymer and cellular prolif- pectoris, which requires further intervention: University Medical Center, eration inhibitor. The antiproliferative agent is target lesion revascularization (TLR) or tar- The Netherlands gradually released in the arterial wall at the site get vessel revascularization (TVR). Although 5Durrer Institute for of stent deployment preventing restenosis. The the severity of angiographic correlates Cardiogenetic Research, first successful DES trials were with sirolimus with the need for TLR, half of the patients The Netherlands stents and led to their approval for use in 2002 with angiographically confirmed ISR do not 6Interuniversity Cardiology and 2003 in Europe and the USA, respec- manifest clinical complaints [6,10]. For this rea- Institute The Netherlands tively [7,8]. Currently, other DES based upon son, authors generally prefer to conduct their (ICIN), The Netherlands , everolimus, , biolimus research in relation to angiographically docu- and tacrolimus are available. DES have success- mented ISR when an insight into the mecha- fully achieved their task of preventing restenosis, nism of restenosis can be observed, while stud- but the experience of the last years has revealed ies comparing different stents are in relation to an increased incidence of stent malapposition clinically driven TLR or TVR.

10.2217/ICA.10.9 © 2010 Future Medicine Ltd Interv. Cardiol. (2010) 2(2), 147–157 ISSN 1755-5302 147 REVIEW Bergheanu, Pons, Karalis et al.

inhibition by IIb/IIIa and P2Y12 antagonists can be seen to reduce acute stent thrombosis but not in-stent restenosis rates [20], formation is probably not a main player in the development of restenosis. This hypothesis is further confirmed by findings demonstrating that especially the strong prothrombotic genetic risk factors for venous thrombosis do not increase the risk for restenosis [21]. Moreover, results from the Genetic Determinants of Restenosis (GENDER) study [21] have shown that the Factor V Leiden polymorphism (a well-known prothrombotic risk factor) was even found to reduce the risk for restenosis Figure 1. In-stent restenosis. (A) Angiographically documented in-stent after PCI. A total of 3104 consecutive patients restenosis. (B) Intravascular ultrasound documented in-stent restenosis. with stable angina pectoris or non-ST segment 1: neointima; 2: stent contour; 3: vessel contour. elevation (non-STEMI), of whom 2309 (74.4%) received stents, were In-stent restenosis is the result of in-stent included [21]. The Factor V (1691 G>A or cellular proliferation and migration along with Factor V Leiden) amino acid substitution was extracellular matrix accumulation [11]. Classic asso­ciated with a decreased risk of TVR (haz- predictors of angiographic ISR (both in BMS ard ratio [HR]: 0.41; 95% CI: 0.19–0.86). and DES) include diabetes, renal failure, lesion The Factor V allele, which is known to lead to length, reference vessel diameter and postinter- increased activation of protein C, might there- vention lumen area [12,13]. Inflammation plays a fore influence restenosis risk by mechanisms pivotal role in ISR and it is triggered by the vas- not involved in coagulation, but in processes cular during the stent deployment and that have a more prominent role in neointimal by the presence of stent struts within the vessel growth, such as inflammation. Even though in wall [14,15]. Together with inflammation, major another study of the same patient sample, asso- contributors are smooth muscle cell migration ciations were found between P2Y12 receptor and proliferation but the process of resteno- haplotypes and restenosis [22], fewer and smaller sis involves many different cell-types, includ- effects were present in the stented subgroup. ing and endothelial cells, and is also The decrease of the effects in this group could characterized by thrombus formation, and to a be due to inhibition of this receptor by clopi- lesser extent by matrix remodeling. dogrel (although several studies [23–26] failed to demonstrate a functional role of the P2Y12 Genetic factors related to receptor polymorphism in patients receiv- in-stent restenosis ing dual antiplatelet therapy). Therefore, the „„ Genetic variations in genetic variation in this receptor, and also in thrombus formation many other genes with a role in the hemostatic In principle, any vascular intervention ini- system, may have been more important at a tiates the formation of a thrombus. Initial time in which not every patient was receiving studies have shown associations of only a few a stent and concomitant inhibition. polymorphisms in the hemostatic system with The 4G/4G genotype of the PAI-1 4G/5G the risk for adverse events following a PCI. polymorphism determines higher plasminogen These early reports showed significant asso- activator inhibitor (PAI)-1 levels in plasma [27–29] ciations of the PLA1/A2 polymorphism with and tissue [30–32]. The PAI-1 4G allele was asso- acute stent thrombosis and coronary restenosis ciated with an increased risk of restenosis after [16,17]. However, other studies in this field could PCI in the GENDER study [21]. When com- not confirm these associations [18,19]. From the pared with 5G/5G homozygotes, heterozygous hypothesis that carriers of the PLA2 allele have patients were at higher risk for clinically driven a more intense binding of fibrinogen and vit- TVR (HR: 1.46; 95% CI: 1.05–2.03), whereas ronectin, and thus a higher risk of platelet-rich patients with the 4G/4G genotype had an even white thrombus formation, the PLA2 allele further increased risk (HR: 1.69; 95% CI: can be expected to lead to an increased risk 1.19–2.41). Although one smaller study could for acute stent thrombosis. However, as platelet not confirm this association [33], many reports

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found a positive correlation between post-PCI „„Genes involved in smooth muscle PAI-1 levels or activity and restenosis [34,35]. cell proliferation Nevertheless, PAI-1 has a diverse role in several Stents specifically aiming to inhibit inflamma- processes involved in restenosis, also in inflam- tion (dexamethasone-eluting stents) were not mation and pr­oliferation [36]. Even if the 4G proven to be as effective as stents inhibiting both allele would increase the risk for restenosis, this inflammation and cell proliferation[44] . Despite could be mediated by a mechansism not related the fact that restenosis is mainly determined by to fibrinolysis inhibition. Taking these findings proliferation and migration of vacular smooth together, we suggest that coagulation is not a muscle cells (VSMCs), relatively few studies main determinant of the long-term process that investigated genes involved in proliferation, such leads to restenosis. as cell-cycle regulatory genes. A recent important finding in this field by Van Tielet al. was an asso- „„Genetic variations in ciation between the -838 G/A polymorphism in inflammatory factors the cyclin-dependent kinase inhibitor p27(kip1) Early studies investigating the role of genetics in (a key regulator of smooth muscle cell prolifera- restenosis demonstrated associations with variants tion) with ISR [45]. Three polymorphisms con- in genes encoding cytokines [37] and selectins [38] cerning the p27(kip1) gene (-838C>A; -79C>T; – important mediators of inflammation – and +326G>T) were determined in a cohort of suggested a role for inflammation in restenosis. 715 patients undergoing coronary angioplasty One of these studies was performed by Kastrati and stent placement. Patients with the p27(kip1) et al., and included 1850 consecutive stented -838AA genotype had a decreased risk of ISR patients [37]. They demonstrated a protective (HR: 0.28; 95% CI: 0.10–0.77). This find- effect of allele 2 of a polymorphism in exon 2 of ing was replicated in another cohort study of the gene encoding the IL-1 receptor antagonist 2309 patients (HR: 0.61; 95% CI: 0.40–0.93). (IL-1ra), an anti-inflammatory interleukin, on The -838 A allele corresponded to enhanced both angiographic and clinical restenosis (OR: promoter activity, which in turn may explain 0.78; 95% CI: 0.63–0.97 and OR: 0.73; 95% CI: decreased smooth muscle cell proliferation. 0.58–0.92, respectively). Monraats et al. have fur- ther established the important role of inflamma- „„Genetic variations in tory genes in the development of restenosis. In the matrix metalloproteinases GENDER study, the rare alleles of the -260 C/T Matrix metalloproteinases (MMPs) are Zn2+- polymorphism in the CD14 gene, the 117 IIe/Thr requiring proteases capable of degrading a vari- p­olymorphism in the colony-stimulating factor ety of extracellular matrix components. Owing 2 gene (also known as granulocyte–macrophage to their significance in vascular remodeling, colony-stimulating factor [GM-CSF]) and the MMPs are suspected to play an important -1328 G/A polymorphism in the eotaxin gene, role in the pathogenesis of and were associated with decreased risk of TVR [39]. restenosis [46]. In particular, MMP2, MMP3 Eotaxin is a chemokine that selectively recruits and MMP9 are potential players in the proc- eosinophils and was previously reported to be ele- ess of restenosis after PCI. MMP2 and MMP9 vated in plasma of patients with advanced athero- (the gelatinases) are produced by VSMCs and sclerosis. After coronary interventions, eotaxin degrade basement membrane components and levels increase and remain high for at least 24 h, other matrix proteins to allow migration and but no longer than 3 months [40]. proliferation of VSMCs [47]. They are upregu- Furthermore, the variant alleles of two pro- lated and activated in VSMCs during intima moter polymorphisms in the TNF-a gene have formation in many different animal models for been shown to protect against the development of restenosis involving balloon angioplasty [47]. restenosis [41]. Stented patients with the -238A/A An increase in MMP2 levels and activity was genotype (HR: 0.44; 95% CI: 0.23–0.83) and demonstrated in human coronary sinus blood patients with the -1031C/C genotype (HR: 0.72; samples 4 and 24 h after elective coronary angi- 95% CI: 0.52–1.00) needed TVR less frequently. oplasty [48]. This small study, in which only 21 Several other inflammatory genes were demon- out of 47 patients were stented, also showed strated to be involved in the process of restenosis an association between MMP2 levels and res- in this cohort, such as IL-10 and caspase-1 (IL-1b- tenosis. MMP3 (stromelysin-1) expression has converting enzyme) [42,43]. All these findings sup- been found to be related to plaque instability port the hypothesis that restenosis is largely (albeit in pathological studies [49]. MMP3 reduces not solely) determined by inflammation. the matrix content of the vascular wall and is

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therefore expected to protect against resteno- vessel wall and/or of plaque volume decrease sis [49]. Functional studies have shown that the behind the stent (including clot lysis or plaque MMP3 -1612 5A/6A promoter polymorphism regression) [58–62]. The main repercussion of late is associated with altered MMP3 expression. SM (persistent or acquired) is stent thrombo- Carriers of the 6A/6A genotype were found to sis (ST) [9]. Independent predictors of LASM have a reduced MMP3 expression [50–53] and include lesion length, unstable angina, absence were at increased risk of developing restenosis of diabetes and primary stenting in acute myo- in a subset of the Regression Growth Evaluation cardial infarction (MI) [63,59]. The risk of LASM Statin Study (REGRESS) in which stents were in patients with DES is approximately four-times not yet frequently used [54], and in two other higher compared with those with BMS [9]. This studies with luminal narrowing after plain bal- is due to the fact that in BMS, hypersensitivity to loon angioplasty [55,56]. However, an asso­ciation the metallic stent is mostly associated with rest- between the MMP3 5A/6A polymorphism enosis, whereas in DES, hypersensitivity to the could not be confirmed in a study that included metallic stent, the polymer or to the drug is asso- 217 stented patients. In addition, unpublished ciated with positive remodeling and e­xcessive results from the GENDER study demonstrated inflammation in the vessel wall[64] . no association between this polymorphism and clinical restenosis in stented patients. Therefore, Genetic factors related to even though matrix formation is an important stent malapposition process in the development of restenosis, vari- We have previously investigated seven poly- ations in genes involved in matrix remodeling morphisms involved in inflammatory processes were infrequently investigated or studies yielded and related to restenosis on the risk of LASM negative results and were not published. in sirolimus-eluting stent (SES) patients [65]. In total, 104 STEMI patients from the MISSION Stent malapposition intervention study [62] were genotyped for the Stent malapposition (SM), commonly detected caspase-1 5352 G/A, eotaxin 1382 A/G, CD14 by intravascular ultrasonography (IVUS), rep- 260 A/G, colony-stimulating factor 2 1943 resents a separation of the stent struts from C/T, IL10 -1117 C/T , IL10 4251 C/T and the intimal surface of the arterial wall (in the the TNF-a 1211 C/T polymorphisms. LASM absence of a side branch) with evidence of occurred in 26 out of 104 (25%) patients. We blood speckles behind the struts (Figure 2A) [57]. found a significantly higher risk for LASM in SM may be acute (present immediately after patients carrying the caspase-1 (CASP1) 5352 A implantation), persistent (present both imme- allele (RR: 2.32; 95% CI: 1.22–4.42). In addi- diately after implantation and at follow-up) or tion, mean neointimal growth was significantly late-acquired (present only at follow-up). Acute lower in patients carrying this LASM risk allele and persistent SM are mainly procedure driven (1.6 vs 4.1%; p = 0.014). The other six poly- while late-acquired stent malapposition (LASM) morphisms related to inflammation were not is a consequence of positive remodeling of the significantly related to the risk of LASM. Given the limited number of patients included in the study, similar reports are needed to confirm our findings. Moreover, a direct relation between the CASP1 5352 A allele and the risk of ST was not investigated. To our knowledge, no other studies have yet scrutinized the role of genetic variations in LASM.

Stent thrombosis Stent thrombosis (Figure 2B) is a complication that occurs in 0.8–2% of patients undergoing PCI and is associated with large MI and death [66]. ST is categorized into acute ST (within 24 h from stent implantation), subacute ST (within Figure 2. Stent malapposition and thrombosis. (A) Intravascular ultrasound 1–30 days from stent implantation), late ST documented stent malapposition. (B) Angiographically documented (within 30 days – 1 year) and very late ST stent thrombosis. 1: lumen contour behind stent struts; 2: vessel contour; (>1 year after stent implantation). Subacute 3: stent thrombosis. and acute ST are classically related to procedure

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parameters such as stent underdeployment stent implantation and healthy control subjects. (acute SM) [67,68] or procedure-related compli- Carriers of the aforementioned prothrombotic cations such as coronary dissections [69,70]. By versions did not appear to be at any increased contrast, (very) late ST appears to be an active risk for stent thrombosis. Selection of patients phenomenon associated with late SM (persistent (differences in number of elective and acute stent or acquired) [9,71], stent type [9], duration of dual implantations) and the treatment of more com- antiplatelet therapy [66] and inflammation [58]. plex coronary lesions in the latter study or the lim- Gene variations in the platelet aggregation ited power might explain these discrepancies [76]. pathway, responsiveness to clopidogrel or pres- Angiolillo et al. have investigated the differential ence of inherited thrombophilic disorders were platelet sensitivity between PLA1 homo­zygotes a­ssociated with both acute and late ST. and PLA2 carriers in 38 patients undergoing coro- nary stent implantation and receiving a clopidog- Genetic factors related to rel 300 mg loading dose [77]. They demon­strated stent thrombosis that PLA2 carriers have a lower inhibition of „„ Platelet receptor platelet reactivity following the standard clopi- gene polymorphism dogrel loading dose, which might finally lead to Platelet aggregation involves the binding of fibrin- stent thrombosis. ogen to the glycoprotein (GP) IIb/IIIa receptor on the platelet surface. One polymorphism of the GP „„Genetic variations in response IIIa gene (PLA1/A2 or HPA1a/1b) has been related to clopidogrel to the inherited risk of coronary thrombosis [72]. In current practice, patients undergoing PCI Of importance, the same polymorphism had no and stent deployment are prescribed clopidogrel influence on the degree of myocardial salvage 300–600 mg as a loading dose followed by 1 year achieved in 133 acute MI patients undergoing dual antiplatelet therapy (aspirin 80–325 mg and coronary stenting and abciximab administra- clopidogrel 75 mg daily) and continued with tion [73]. The PLA2 polymorphism is a substitu- life-long aspirin intake. A good responsiveness to tion of cytosine for thymidine at position 1565 clopidogrel is therefore crucial in order to prevent in exon 2. Walter et al. investigated the associa- thrombotic events following stent deployment. tion of the PLA2 allele with acute and subacute Clopidogrel is an inactive prodrug that stent thrombosis in 318 consecutive BMS patients requires two-step oxidation by the hepatic stented for coronary dissection, acute occlusion or cytocrome P450 (CYP) enzymes to transform high residual restenosis after percutaneous trans- into an active metabolite that further inhibits luminal coronary angioplasty, lesions in bypass the ADP P2Y12 receptor producing the anti- grafts and restenotic lesions [74]. They found that aggregation effect. The genes encoding the CYP patients with the PLA2 allele had an increased enzymes are polymorphic and several variants risk of stent thrombosis compared with patients were related to a decreased catalytic activity and homozygous for PLA1 (OR: 5.26; 95% CI: subsequent attenuated effect of the drug. 1.55–17.85). Kastrati et al. partially confirmed The CYP3A5 gene has a functional poly- these findings in their prospective study includ- morphism that includes the expressor (*1) and ing 1759 patients with stable and unstable angina nonexpressor (*3) alleles [78,79]. Suh et al. com- pectoris [75]. No difference was observed at 30 days pared clinical outcome in 348 patients (with after stent placement in terms of ST or a composite stable angina, unstable angina or non-STEMI) end point of death, MI or urgent revasculariza- who had PCI with BMS implantation [79]. tion between PLA1/A1 and PLA1/A2 carriers. Antiplatelet therapy consisted of aspirin (100– However, the incidence of ST and the composite 300 mg daily, prescribed indefinitely) and clopi- end point were higher in the PLA2 homozygotes dogrel (75 mg daily after 300 mg loading dose) versus PLA1 homozygotes (8.7 vs 1.7%; p = 0.002 administered for at least 4 weeks after the pro- and 13.0 vs 5.4%; p = 0.06, respectively). cedure. Atherothrombotic events (a composite of More recently, Sucker et al. assessed the rel- cardiac death, MI and nonhemorrhagic stroke) evance of prothrombotic platelet-receptor poly­ occurred more frequently within 6 months after morphisms for the onset of coronary stent stent implantation among the patients with thrombosis in 316 patients [76]. They compared the nonexpressor genotype than among those the prevalence of GP Iba, GP IIb, GP IIIa with the expressor genotype (14/193 vs 3/155; (including PLA1/A2) and GP Ia prothrombotic p = 0.023). Moreover, the CYP3A5 polymor- poly­morphisms in patients with coronary stent phism was a predictor of athrothrombotic events thrombosis occurring in the first 6 month after in clopidogrel users.

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These findings are especially interesting since treated with clopidogrel who underwent PCI a number of studies (which were not aimed and stenting, a number were followed-up for at clinical end points) found no association 15 months. Patients were initially admitted between the CYP3A5 variants and clopidogrel with non-STEMI (71%) and STEMI (29%). response and/or residual platelet aggregation They received a clopidogrel 300 mg loading (RPA) [80–82] nor did a number of studies with dose, followed by 75 mg daily maintenance clinical end points [83,84]. dose for up to 15 months. For CYP2C19, the Trenk et al. investigated whether the CYP2C19 presence of at least one copy of the *2 allele 681G>A *2 polymorphism was associated with was associated with a higher rate of compos- high (>14%) RPA on clopidogrel and whether ite death from cardiovascular causes, non-fatal high on-clopidogrel RPA affects clinical out- MI, non-fatal stroke (HR: 1.42; 95% CI: 0.98– come after elective coronary stent placement [85]. 2.05) and of definite/probable ST (HR: 3.33; RPA was assessed in 797 consecutive patients 95% CI: 1.28–8.62) than did non-carriers. after a 600-mg loading dose and after the first Sibbing et al. assessed the role of the mutant 75 mg maintenance dose of clopidogrel before *2 allele of the CYP2C19 polymorphism on the discharge. Patients were followed-up for 1 year. 30‑day incidence of definite ST in 2485 consec- Between the *2 carriers and *1/*1 carriers (wild- utive patients undergoing coronary stent place- type) the authors found significant (p < 0.001) ment [87]. There are a number of differences differences in the proportion of patients with with regard to the previous study [83]: STEMI RPA>14%, both after loading (62.4 vs 43.4%, patients were excluded; the end point was acute respectively) and at predischarge (41.3 vs 22.5%, and subacute definite ST; and, patients received respectively). RPA over 14% at discharge was clopidogrel 600 mg loading dose. associated with a threefold increase (95% CI: Drug-eluting stents were used in 25% and 1.4–6.8; p = 0.004) in the 1‑year incidence BMS in 75% of the patients. Of the patients of death and MI. However, the authors could studied, 73% were CYP2C19 wild-type homo­ not demonstrate a direct relation between the zygotes (*1/*1) and 27% carried at least one of CYP2C19*2 allele and clinical outcome. the *2 allele. The cumulative 30‑day incidence This relationship was demonstrated by of ST was significantly higher in CYP2C19*2 Giusti et al. in a subana­lysis of the The Low allele carriers versus wild-type homozygotes Responsiveness to Clopidogrel and Sirolimus- or (1.5 vs 0.4%; HR: 3.81; 95% CI: 1.45–10.02; Paclitaxel-Eluting Stent Thrombosis (RECLOSE) p = 0.006). The risk of ST was highest (2.1%) in trial [86]. The role of the CYP2C19*2 polymor- patients carrying the CYP2C19 *2/*2 genotype phism in the occurrence of DES ST (definite or (p = 0.002). probable) or the composite end point of ST (def- Recently, Collet et al. demonstrated the inite or probable) and cardiac mortality within role of the CYP2C19*2 allele in 259 young 6‑month follow-up was assessed in 772 patients patients (aged <45 years) who survived a first undergoing PCI and receiving either sirolimus MI and received clopidogrel treatment for at or paclitaxel DES. Patients with acute coronary least 1 month [88]. The primary end point was syndrome (ACS) and STEMI were included as a composite of death, MI and urgent coronary well as patients with left main disease, chronic revascularization occurring during exposure total occlusions, bifurcation lesions or diffuse to clopidogrel. The secondary end point was disease. All patients received aspirin (325 mg) angio­graphy-documented ST. Median clopi- and a loading dose of clopidogrel 600 mg before dogrel treatment duration was approximately the pro­cedure, followed by a maintenance dose 1 year. The primary end point occurred more of clopidogrel 75 mg and aspirin 325 mg daily. frequently in carriers than in noncarriers (15 Patients with ST or ST and cardiac mortality end vs 11 events; HR: 3.69; 95% CI: 1.69–8.05; point had a higher prevalence of the *2 allele (54.1 p = 0.0005), as did ST (eight vs four events; vs 31.3%; p = 0.025 and 51.7 vs 31.2%; p = 0.020, HR: 6.02; 95% CI: 1.81–20.04; p = 0.0009). respectively). At multivariate logistic regression The effect of the CYP2C19*2 genetic vari- ana­lysis, the CYP2C19*2 allele was an independ- ant persisted from 6 months after clopidogrel ent risk factor for ST (OR: 3.43; 95% CI: 1.01– initiation up to the end of follow-up (HR: 12.78; p = 0.047) and ST and cardiac mortality 3.00; 95% CI: 1.27–7.10; p = 0.009). The (OR: 2.7; 95% CI: 1.00–8.42; p = 0.049). CYP2C19*2 genetic variant appeared to be Mega et al. reconfirmed these findings the only independent predictor of cardiovas- on long-term assessment of patients from cular events (HR: 4.04; 95% CI: 1.81–9.02; TRITON-TIMI 38 study [83]. Of 1389 patients p = 0.0006).

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In a study of 2208 patients presenting with relation between a Factor V Leiden heterozygous acute MI (among which 1535 underwent PCI), patient and stent thrombosis (simultaneous occlu- patients carrying any two CYP2C19 loss-of- sion of two stents, one in the left anterior descend- function alleles (*2, *3, *4 or *5), had a higher ing and one in the right coronary artery at rate of death from any cause, nonfatal stroke 4 days after implantation in a patient receiving or MI during 1 year of follow-up than patients standard dual antiplatelet therapy) [90]. Further with none (21.5 vs 13.3%; adjusted HR: 1.98; larger studies are therefore needed before Factor 95% CI: 1.10–3.58) [84]. Among the patients V Leiden may be linked to ST. who underwent PCI during hospitalization, the rate of cardiovascular events among carriers of Limitations CYP2C19 loss-of-function alleles was 3.58-times Many studies have managed to identify genes higher (95% CI: 1.71–7.51) than among those and polymorphisms involved in the post-stent- with none. ing outcome after scrutinizing various plausible In order to develop a risk score with better pathophysiologic mechanisms. However, to pre- prediction of RPA, Geisler et al. analyzed the dict an accurate scale of adverse effects, an inter- CYP2C19*2 genotype and previously identified action assessment between genetic, nongenetic nongenetic risk factors (age >65 years, Type 2 (traditional risk factors) as well as epigenetic fac- diabetes mellitus, decreased left ventricular tors is of extreme importance. This information function, renal failure and ACS) [81]. They remains momentarily scarce. demonstrated a significant correlation of the Also of importance, findings from certain nongenetic factors (c² = 5.32; p = 0.021) and studies sometimes cannot be confirmed by other CYP2C19*2 (c²= 21.31; p < 0.0001) with high studies. This is largely explained by variation RPA, and the highest association for the com- in study settings and therefore the replication bination of both (c²= 25.85; p < 0.0001). This of findings in independent studies needs to be was the first study to demonstrate that predic- further emphasized. tion of clopidogrel responsiveness may be sub- The candidate gene approach used to date in stantially improved by adding the CYP2C19*2 the majority of investigations narrows the results genotype to nongenetic risk factors. The impor- to specific areas of interest. tant influence of theCYP2C19*2 g­enotype over platelet function and cardiovascular outcomes Conclusion was recently confirmed by Shuldiner et al. in In-stent restenosis and stent thrombosis remain the first GWAS paper identifying CYP2C19 as important limitations of the current PCI prac- a candidate gene. In the Pharmacogenomics of tice. Besides the procedure-related risk factors and Antiplatelet Intervention (PAPI) Study, clopi- medication, solid evidence demonstrated that a dogrel was administered for 7 days to 429 healthy patient’s own response to stent implantation influ- individuals and the response was measured by ences the outcome. Individual genetic responses ex vivo platelet aggregometry [89]. A GWAS was involve inflammation, cellular proliferation, plate- performed followed by geno­typing the loss-of- let receptors and drug metabolism pathways. A function cytochrome CYP2C19*2 variant. The better understanding of stent pathology has led relation between CYP2C19*2 g­enotype and plate- to the identification of new important genes and let aggregation was replicated in 227 clopidog- genetic polymorphisms. These discoveries may rel-treated patients undergoing PCI (p = 0.02). help us better identify the vulnerable patients Patients with the CYP2C19*2 variant were more who need extraordinary therapeutic measures. likely (20.9 vs 10.0%) to have a cardio­vascular Conversely, genetic–epidemiologic studies have ischemic event or death during 1 year of follow-up identified genes that have subsequently revealed (HR: 2.42; 95% CI: 1.18–4.99; p = 0.02). important pathophysiologic mechanisms.

„„Factor V Leiden mutation Future perspective Factor V Leiden is the most common inherited The speed by which new genes are being thrombophilic disorder, resulting from a sin- related to stent pathology is matched by the gle mutation (1691 G>A) in the Factor V gene. speed of new developments in stent technol- Individuals heterozygous for this mutation are ogy and m­edication. Novel pharmacogenomic at increased risk for venous thrombosis, and approaches (e.g., GWAS and the 1000 genome in homozygous individuals the risk becomes project) may help to identify unknown genetic extremely high. Although conceivable, there factors for a ­better prediction of outcome after is only one case report to document a possible stent implantation [91].

future science group www.futuremedicine.com 153 REVIEW Bergheanu, Pons, Karalis et al.

It is, however, difficult to predict whether learned from genetic and pathophysiologic stud- screening for established polymorphisms will ies, the newly available resources (e.g., stents, prove, in the future, a cost-effective method for antiplatelet drugs and imaging) and refined improved stent-type selection or medication in implantation techniques will definitely improve the daily routine. PCI performances and extend its use. The classic stents appear to be rapidly being replaced by new and complex body–polymer– Financial & competing interests disclosure drug constructs that address most, if not all, of the Professor Dr J Wouter Jukema is an established clinical current problems. The new generation of stents investigator of the Netherlands Heart Foundation may appear capable of modulating local inflam- (2001D032) and project leader of the HP 7 – mation to permit a good re-endothelization, to Pharmacogenetic EU project HEALTH-F2–2007 223004 prevent stent thrombosis, to reduce the duration PHASE. The authors have no other relevant affiliations or of antiplatelet medication and, if necessary, even financial involvement with any organization or entity with to degrade after local healing is achieved. a financial interest in or financial conflict with the subject New drugs such as prasugrel, ticagrelor and matter or materials d­iscussed in the manuscript apart from cangrelor seem to effectively inhibit platelet those disclosed. aggregation with little or no interindividual No writing assistance was utilized in the production of response variability. The combination of lessons this manuscript.

Executive summary Genetic variants associated with an increased or decreased risk of in-stent restenosis ƒƒ Genetic variations in thrombus formation. -- Associated with increased risk – 4G allele of the PAI-1 4G/5G polymorphism. -- Associated with decreased risk – Factor V 1691G>A (Factor V Leiden) amino acid substitution. ƒƒ Genetic variations in inflammatory factors. -- Associated with increased risk – A/A genotype of the IL-10 -2849 G/A polymorphism; A/A genotype of the IL-10 -1082 G/A polymorphism; G/G genotype of the IL-10 +4259 A/G polymorphism; A/A genotype of the caspase-1 5352 G/A polymorphism. -- Associated with decreased risk – *2 allele of the IL-1RA gene; T/T genoype of the CD14–260 C/T polymorphism; Thr allele of the CSF2–117 Ile/Thr polymorphism; A allele of the CCL 11 (eotaxin) 1328 G/A polymorphism; A/A genotype of the TNF -238 G/A polymorphism; C/C genotype of the TNF -1031 T/C polymorphism. ƒƒ Genes involved in smooth muscle cell proliferation. -- Associated with decreased risk – A/A genotype of the p27(kip1)-838G/A polymorphism. Genetic variants associated with an increased risk of stent thrombosis ƒƒ Platelet receptor gene polymorphism. -- PLA2 allele of the GPIIIa PLA1/A2. ƒƒ Genetic variations in response to clopidogrel. -- *3 allele of the CYP3A5 gene (encodes hepatic cytocrome P450 CYP enzymes); *2 allele of the CYP2C19 gene (encodes hepatic cytocrome P450 CYP enzymes).

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