Association between plasminogen activator inhibitor-1 and cardiovascular events: a systematic review and meta-analysis

Association between plasminogen activator inhibitor-1 and cardiovascular events: a systematic... Background: Small studies have implicated plasminogen activator inhibitor-1 (PAI-1) as a predictor of cardiovascular events; however, these findings have been inconsistent. We sought out to examine the potential role of PAI-1 as a marker for major adverse cardiovascular events (MACE). Methods: We systematically reviewed all indexed studies examining the association between PAI-1 and MACE (defined as death, myocardial infarction, or cerebrovascular accident) or restenosis. EMBASE, Web of Science, Medline, and the Cochrane Library were searched through October 2016 to identify relevant studies, supplemented by letters to authors and review of citations. Studies reporting the results of PAI-1 antigen and/or activity levels in association with MACE in human subjects were included. Results: Of 5961 articles screened, we identified 38 articles published between 1991 to 2016 that reported PAI-1 levels in 11,557 patients. In studies that examined PAI-1 antigen and activity levels, 15.1% and 29.6% of patients experienced MACE, respectively. Patients with MACE had higher PAI-1 antigen levels with a mean difference of 6. 11 ng/mL (95% CI, 3.27-8.96). This finding was similar among patients with and without known coronary artery disease. Comparatively, studies that stratified by PAI-1 activity levels were not associated with MACE. In contrast, studies of coronary restenosis suggest PAI-1 antigen and activity levels are negatively associated with MACE. Conclusions: Elevated plasma PAI-1 antigen levels are associated with MACE. Definitive studies are needed to ascertain if PAI-1 acts simply as a marker of risk or if it is indeed a bona fide therapeutic target. Keywords: Plasminogen activator inhibitor-1, Biomarkers, Mortality, Myocardial infarction, Meta-analysis Background coronary revascularization [1]. However, complications Obstructive coronary artery disease (CAD) is the leading such as in-stent restenosis and stent thrombosis fol- cause of mortality in the western world. The cornerstone lowing PCI limit its efficacy. Thus, in the peri- of therapy for CAD remains revascularization and revascularization period, preventing thrombotic events secondary medical therapy to modify risk factors. The is paramount until the vessel’s endothelial lining and func- fibrinolytic system has implications for both ap- tion are restored. Second, long term therapy with anti- proaches to disease management. First, percutaneous platelet and/or oral anticoagulation is an integral part of coronary intervention (PCI) with implantation of a secondary preventive medical therapy. Thus, dysregulation coronary stent remains the predominant method of of the fibrinolytic pathways may increase the risk of com- plications from revascularization therapy and diminish the efficacy of long term medical therapy to reduce the * Correspondence: bhibbert@ottawaheart.ca Equal contributors risk of recurrent events. CAPITAL Research Group, University of Ottawa Heart Institute, 40 Ruskin The fibrinolytic system is activated by the conversion Street, H-4238, Ottawa, ON K1Y 4W7, Canada of plasminogen to plasmin by serine proteases such as Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada tissue or urokinase-type plasminogen activator (t-PA and Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Jung et al. Thrombosis Journal (2018) 16:12 Page 2 of 12 u-PA, respectively). In contrast, fibrinolysis is inhibited Inclusion and exclusion criteria and quality assessment by plasminogen activator inhibitor-1 (PAI-1), which is a Studies were included if they met the following criteria: member of the serine protease inhibitor (serpin) family. (1) PAI-1 antigen or activity levels were reported; (2) the Ultimately, thrombosis risk is influenced by the balance population studied comprised individuals aged 18 years between PAI-1 and t-PA. Thus, an increase in the PAI-1 or older; (3) components of MACE (death, myocardial levels in plasma can induce a hypercoagulable state [2]. infarction, and cerebrovascular events including stroke PAI-1 is released by vascular endothelial cells, hepato- and transient ischemic attacks) or restenosis were re- cytes, adipocytes, cardiomyocytes, fibroblasts, and ported; (4) articles were published in English. Exclusion platelets [3, 4]. In healthy humans, plasma levels of PAI- criteria included: (1) PAI-1 polymorphism studies exam- 1 exceed t-PA by a ratio of over 4:1 with most of PAI-1 ining the association between 4G/5G and adverse events; being cleared by the liver [5]. In pathologic condi- (2) animal or in vitro studies; and (3) studies reporting tions, PAI-1 production can be upregulated by pro- hazard ratios only. Full text data extraction was con- inflammatory factors such as TNFα,TGFβ, and insulin ducted by two independent evaluators (R.J. and P.M.). [6]. Elevated plasma PAI-1 levels have been associated Each reviewer independently extracted patient popula- with impaired fibrinolytic activity in stroke and coronary tion characteristics, group sizes, PAI-1 antigen and activ- artery disease [7]. Moreover, PAI-1 antigen and activity ity levels, follow-up duration, and MACE and restenosis. levels are elevated in patients with type 2 diabetes [8], All discrepancies were resolved by consensus prior to hyperinsulinemia [9], and those with insulin resistance locking the database for analysis (Tables 1 and 2). In- [10, 11]. Yet, a definitive assessment of the impact of ele- cluded observational studies were evaluated for quality vated PAI-1 as a biomarker or therapeutic target has yet and risk of bias using the Newcastle-Ottawa Quality As- to be evaluated. Accordingly, we performed a systematic sessment Scale [13] by two independent evaluators (R.J. review and meta-analysis of PAI-1 antigen and activity and P.M.) with disagreements resolved by consensus. levels and their relationship with major adverse cardiovas- Visual funnel plot inspection was used to screen for cular events (MACE) in humans. publication bias. Methods Statistical analysis Literature search strategy The primary clinical endpoint for this study was MACE Literature searches were guided by a medical librarian – a composite of death, myocardial infarction, or cere- with expertise in systematic reviews (S.V.) using a com- brovascular events. The secondary endpoint included bination of key terms and index headings related to PAI- components of the primary as well as coronary resten- 1, coronary disease (informed by the Cochrane review osis in patients undergoing coronary revascularization. search strategy for coronary heart disease in exercise- Mean circulating PAI-1 antigen (ng/mL) and activity based cardiac rehabilitation [12]), and the Cochrane (IU/mL) levels and their associated standard deviations Highly Sensitive search strategy to eliminate articles on were used for analyses. Fourteen studies reported me- animal studies in Medline. The search was additionally dian and interquartile ranges, which were converted to peer-reviewed by a second medical librarian (R.S.). Once approximated means and standard deviations using the finalized, the search strategy was then translated to other method described by Wan et al. [14]. bibliographic databases (see Additional file 1 for the full All analyses were performed using Review Manager Medline search). The final search was conducted on (RevMan) 5.3 (Cochrane Collection, Copenhagen, October 2016 in Medline (Ovid) (In-Process & Other Denmark). PAI-1 antigen and activity levels were com- Non-Indexed Citations and Ovid MEDLINE(R) 1946-), pared between patients with or without the outcomes of Embase (Ovid) (Embase Classic + Embase 1947-), interest either as absolute values or dichotomized as high Cochrane Library (Ovid) (from inception), and Web of vs. low. Random effects models stratified by study design Science (Thomson Reuters) (all indexes, from inception). and study quality were used to generate pooled mean dif- Search results were exported to EndNote X7 (Thomson ferences with 95% confidence intervals. Post-hoc meta re- Reuters, New York, USA) and duplicates eliminated gression was performed to account for timing of blood using the program’s duplicate identification feature and draw and acute phase reactions in studies of patients pre- manual inspection. A review protocol was produced but senting with acute myocardial infarction or stroke. not registered in a database. Titles and abstracts were screened by two independent Results reviewers (R.J. and P.M.) using Covidence (Melbourne, Included studies Australia). Full articles were retrieved in cases of missing Study selection abstracts. Corresponding authors were contacted for After excluding duplicate articles, 5961 titles and ab- additional information when necessary. stracts were screened, of which 340 underwent full Jung et al. Thrombosis Journal (2018) 16:12 Page 3 of 12 Table 1 Studies reporting PAI-1 antigen levels (ng/mL) and major adverse cardiovascular events and restenosis Event No Event Reference Year Study Design Follow-up (months) Population of interest N PAI-1 (IU/mL) Range Death MI Restenosis CVA N PAI-1 (IU/mL) Range Sane et al. [50] 1991 Cohort 24 Fibrinolytics 24 57 58 24 n/a n/a n/a 315 54 53 Cortellaro et al. [51] 1993 Case-Control 24 Subgroups Combined 58 11.3 0.7 13 17 n/a 20 87 7.3 0 5 Brannstrom et al. [52] 1995 Cohort 46 Anticoagulant 38 21.9 15.1 38 n/a n/a n/a 167 16.7 11.8 Juhan-Vague et al. [53] 1996 Cohort 24 MI 106 18.2 8 2 40 66 n/a n/a 2700 14.8 8.9 Nordt et al. [54] 1998 Cohort 12 Fibrinolytics 5 28.8 14.3 n/a n/a 5 n/a 26 27.1 15.4 Alaigh et al. [55] 1998 Cohort 6 Elective PCI 28 20.75 11.06 n/a n/a 28 n/a 45 24.5 13.85 Moss et al. [56] 1999 Cohort 26 MI 81 25 18 25 56 n/a n/a 964 29 28 Redondo et al. [57] 2001 Cohort 24 MI 37 40.725 22.28 2 5 30 n/a 157 42.65 21.02 Fornitz et al. [58] 2001 Cohort 6 Elective PCI 7 82.6 26.6 n/a n/a 7 n/a 12 72.2 27 Bogaty et al. [59] 2001 Case-Control 48 MI 23 23.83 19.04 n/a 8 n/a n/a 77 18.9 16.24 Ganti et al. [60] 2002 Cohort n/a MI 4 80.68 16.38 4 n/a n/a n/a 38 61 21.95 Lip et al. [61] 2002 Cohort 12 Stroke 27 56.5 30.7 27 n/a n/a n/a 59 45.9 23.3 Inoue et al. [62] 2003 Cohort 6 MI 24 28 4 n/a n/a 24 n/a 42 29 4 Christ et al. [20] 2005 Cohort 6 Elective PCI 25 14.8 0.7 n/a n/a 25 n/a 55 16.8 2.1 Robinson et al. [63] 2007 Cohort 5 to 51 Coronary Heart Disease 19 36.3 17.9 2 2 n/a 2 79 45.4 25.6 Katsaros et al. [24] 2008 Cohort 6 to 8 Elective PCI 12 11.69 8.05 n/a n/a 12 n/a 61 22.78 18.76 Thogersen et al. [64] 2009 Case-Control n/a Healthy 50 38.27 16.79 n/a 50 n/a n/a 56 29 15.75 Akkus et al. [65] 2009 Cohort 12 Cardiogenic Shock 33 116.5 97.26 33 n/a n/a n/a 27 71.33 54.79 Pineda et al. [66] 2010 Cohort 36 MI 25 65.13 53.3 4 21 n/a n/a 117 70.1 48.34 Wennberg et al. [67] 2012 Case-Control 168 Healthy 469 57.28 25.83 n/a 469 n/a n/a 895 51.23 25.11 Yano et al. [68] 2013 Cohort 20 Smokers 66 65.73 64.57 n/a 11 n/a 55 744 42.97 36.54 Yano et al. [69] 2014 Cohort 30 Hypertension 42 31.67 16.12 4 13 n/a 16 548 28.33 14.87 Knudsen et al. [70] 2014 Case-Control 12 HIV 54 111 8.5 3 51 n/a n/a 54 92 7 Golukhova et al. [71] 2015 Cohort 28 Elective PCI 23 72.75 29.86 2 9 11 n/a 71 49.75 23.16 CVA cerebrovascular accident Jung et al. Thrombosis Journal (2018) 16:12 Page 4 of 12 Table 2 Studies reporting PAI-1 activity levels (IU/mL) and major adverse cardiovascular events and restenosis Event No Event Reference Year Study Design Follow-up (months) Population of interest N PAI-1 Activity (U/mL) Range Death MI Restenosis N PAI-1 Activity (U/mL) Range Sane et al. [50] 1991 Cohort 24 Fibrinolytics 28 17 16 n/a n/a 28 328 19 21 Shah et al. [72] 1992 Cohort 9 Elective PCI 28 8 7.1 n/a n/a 28 40 12 8 Gray et al. [73] 1993 Cohort 0.1 MI 13 20.6 11 n/a 13 n/a 85 20.1 7.9 Malmberg et al. [74] 1994 Case-Control 90 MI 53 23.75 13.34 20 33 n/a 55 18 10.97 Brack et al. [75] 1994 Cohort 4 Elective PCI 16 4.63 4.71 n/a n/a 16 30 5.77 5.06 Nordt et al. [54] 1998 Cohort 12 Fibrinolytics 5 8.7 8.3 n/a 5 n/a 26 9.9 8.2 Jansson et al. [76] 1998 Cohort 120 MI 54 9.1 5.1 54 n/a n/a 69 10.6 7.1 Wiman et al. [77] 2000 Case-Control 3 MI 61 22.1 17.5 n/a 61 n/a 95 18.2 16.5 Wiman et al. [77] 2000 Case-Control 3 Ml 25 15.4 13.6 n/a 25 n/a 38 17.8 12.4 Prisco et al. [78] 2001 Cohort 18 MI 18 11.27 7.64 n/a n/a 18 36 15.8 27.49 Prisco et al. [78] 2001 Cohort 18 Elective PCI 6 8.33 8.1 n/a n/a 6 42 7.57 9.52 Sargento et al. [79] 2003 Cohort 12 MI 7 6.34 1.56 5 2 n/a 80 4.47 1.84 Marcucci et al. [19] 2006 Case-Control 22 2 MI 109 22 9.09 54 55 n/a 411 24.25 10.63 Schoebel et al. [80] 2008 Cohort 2 MI 18 3.7 1.8 n/a n/a 18 42 5.3 3.2 Wiman et al. [77] is presented twice as data for men and women were reported separately Jung et al. Thrombosis Journal (2018) 16:12 Page 5 of 12 review and 38 were ultimately included (Fig. 1, Tables 1 when the analysis was restricted to three high-quality and 2). Study populations were heterogeneous, including studies with a mean difference of 1.14 IU/mL (95% patients presenting with stable angina, acute coronary CI, − 3.37-5.65, P = 0.62; Additional file 1:Figure S5). syndrome, and non-cardiac diseases. Study sample sizes ranged from 19 to 2806. Most studies were of moderate Major adverse cardiovascular events: Pre-existing versus quality (see Additional file 1: Tables S1 and S2 for details no known coronary artery disease of study quality assessments). Funnel plots are shown in Overall, among patients without prior coronary artery Additional file 1: Figures S1 and S2. In pooled analyses disease, 12.2% had an event. PAI-1 antigen levels in of all studies reporting PAI-1 antigen levels (n = 8999), those without previously known coronary artery disease 1362 events were reported, including 234 deaths, 795 were on average 6.44 ng/mL higher in those with MACE myocardial infarctions, 101 cerebrovascular events, and relative to those without (95% CI, 2.64-10.25, P < 0.001; 142 restenoses (Table 1). In all studies that examined Fig. 4a). In studies that included patients with known PAI-1 activity levels (n = 1490), 441 events were re- CAD, 19.3% had MACE. PAI-1 antigen levels in those ported, including 133 deaths, 194 myocardial infarctions, with known CAD were on average 5.49 ng/mL higher in and 114 cases of restenosis (Table 2). those with MACE than those without (95% CI, 0.36- 10.63, P = 0.04; Fig. 4b). No difference in PAI-1 activity PAI-1 and clinical outcomes levels between event and control groups was observed in Major adverse cardiovascular events the five studies reporting PAI-1 activity levels and PAI-1 antigen levels were higher in those with MACE MACE (Additional file 1: Figure S6). with a mean difference of 6.11 ng/mL (95% CI, 3.27-8.96, P <0.001) – a difference that was present irrespective of Death study design (Fig. 2). When restricted to high-quality stud- In thefivestudies that reported mortality data, 126 deaths ies, PAI-1 antigen levels in patients with MACE were were observed (17.2% of patients). PAI-1 antigen levels were 5.22 ng/mL (95% CI, 2.97-7.54, P < 0.001; Additional file 1: higher among patients who died (mean difference: 10.34 ng/ Figure S3). Among seven studies reporting morning blood mL (95% CI, 1.90-18.79, P = 0.02; Additional file 1:FigureS7). draws between 7:00 and 10:00 am, PAI-1 antigen levels were higher in those with MACE with a mean difference of 4.61 ng/mL (95% CI, 1.49-7.74, P =0.004; Additional Restenosis file 1: Figure S4). Meta-regression analysis of timing of the In the six studies that examined restenosis following per- blood draw and acute phase studies was not pre- cutaneous coronary intervention (with and without cor- dictive of the heterogeneity in our selected studies onary stent implantation), 101 events were observed nor did it contribute to a greater understanding of (29.5% of patients). PAI-1 antigen levels were lower in the impact of PAI-1 in its association with MACE those with restenosis with a mean difference of − (Additional file 1:Table S3). 2.43 ng/mL (95% CI, − 4.48-(− 0.37), P = 0.02; Fig. 5a). In contrast to PAI-1 plasma antigen levels, there was An additional six studies provided restenosis rates and no significant difference in PAI-1 activity levels between PAI-1 activity levels. These studies reported restenosis in those with vs. without MACE (mean difference 0.59 IU/ 119 patients (17.9%). PAI-1 activity was lower in those mL (95% CI, − 1.63-2.80, P = 0.60; Fig. 3). No association with restenosis with a mean difference of − 1.73 IU/mL between PAI-1 activity levels and MACE was observed (95% CI: -2.80-(− 0.67), P = 0.001; Fig. 5b). Fig. 1 Flow diagram of the included PAI-1 studies for meta-analysis Jung et al. Thrombosis Journal (2018) 16:12 Page 6 of 12 Fig. 2 Comparison of mean PAI-1 antigen levels (ng/mL) in patients with major adverse cardiac events and control patients. Data is expressed as a mean difference and analyzed using a random effects model High versus low PAI-1 levels Discussion Three studies stratified their data by high versus low Incident and recurrent cardiovascular events remain im- PAI-1 antigen levels. These studies reported a MACE portant adverse outcomes despite major advances in re- rate of 54.4% [15–17]. High PAI-1 antigen levels vascularization and medical therapy. PAI-1 has been were associated with a 58% greater risk of MACE associated with MACE, but whether it is solely a marker compared to low PAI-1 antigen levels (RR 1.58, 95% for these events or a mediator with the potential of CI: 1.42-1.76, P < 0.0001; Fig. 6). representing a unique therapeutic target is uncertain. Fig. 3 Comparison of mean PAI-1 activity levels (IU/mL) in patients with major adverse cardiac events and control patients. Data is expressed as a mean difference and analyzed using a random effects model Jung et al. Thrombosis Journal (2018) 16:12 Page 7 of 12 Fig. 4 Comparison of mean PAI-1 antigen levels (ng/mL) in patients with primary and secondary major adverse cardiac events and control patients. Data is expressed as a mean difference and analyzed using a random effects model. a PAI-1 levels (ng/mL) in patients with primary major adverse cardiac events. b PAI-1 levels (ng/mL) in patients with secondary major adverse cardiac events Fig. 5 Comparison of mean PAI-1 antigen and activity levels in patients with restenosis and control patients. Data is expressed as a mean difference and analyzed using a random effects model. a Comparison of mean PAI-1 antigen levels (ng/mL) in patients with restenosis. b Comparison of mean PAI-1 activity levels (IU/mL) in patients with restenosis Jung et al. Thrombosis Journal (2018) 16:12 Page 8 of 12 Fig. 6 Comparison of risk of major adverse cardiac events in patients stratified by PAI-1 antigen levels (ng/mL). Data is expressed as a risk ratio and analyzed using a random effects model Our analysis set out to evaluate the current state of evi- entire PAI-1 content in the sample in the form of free dence linking PAI-1 antigen and activity levels with and active PAI-1 (which we refer to as PAI-1 activity), these outcomes. Our study suggests that elevated PAI-1 complexed to t-PA or u-PA, and latent PAI-1. Al- PAI-1 antigen levels are associated with major adverse though PAI-1 antigen and activity levels are correlated, cardiac events in both primary and secondary event antigen levels will not necessarily reflect PAI-1 activity populations. In addition, elevated PAI-1 antigen levels levels [25]. Indeed, at time of acute trauma such as were associated with all-cause mortality. While the plaque rupture, t-PA will complex with PAI-1 at a 1:1 ra- populations studied were heterogeneous, the robust- tio reducing detectable PAI-1 activity but not PAI-1 anti- ness of the association suggests that PAI-1 warrants gen levels. In addition, PAI-1 activity is influenced by further study as a marker and potential mediator of experimental techniques during sample isolation such as adverse cardiovascular events. freeze-thaw or sonication [26], low temperature, low pH, Our findings build upon the growing evidence that and high salt concentrations [27]. Factors which influ- PAI-1 is a biomarker for MACE in patients with CAD. ence PAI-1 activity levels which impacted the signifi- Tofler et al. identified elevated PAI-1 antigen levels to be cance of our findings include the method of PAI-1 predictive of cardiovascular disease [18]. In addition, extraction and isolation [26–30], time of blood draw previous studies of elevated PAI-1 antigen and activity [31], intra- and inter-assay variability in PAI-1 activity levels predicted acute coronary syndrome after coronary and antigen levels [32], and baseline risk factors which stenting [15, 19–22]. Furthermore, Song et al. recently influences PAI-1 levels such as smoking [33, 34], high- identified a causal relationship between elevated PAI-1 fat diet [35], and maximal exercise [36]. Finally, in levels and incident CAD [23]. Our study expands on addition to important biological differences, manifest these findings by identifying elevated PAI-1 antigen differences in the quality and power of studies examin- levels as being associated with MACE in both primary ing antigen and activity levels existed which may explain (incident) and secondary event populations thereby sug- the divergent results. gesting a broader relevance of PAI-1 antigen levels. In In-stent restenosis (ISR) is a result of neointimal for- addition, we demonstrate the potential applicability of mation or intimal thickening that narrows the vascular PAI-1 antigen levels in predicting restenosis, consistent lumen following PCI [37]. The detailed molecular mech- with a previous report by Katsaros et al. [24], which anism behind the pathophysiology of ISR has been identified that patients with the lowest PAI-1 antigen reviewed elsewhere [38]. Briefly, studies have revealed tertile had a 9.5-fold increased risk of in-stent restenosis that the initial recruitment of inflammatory cells is sub- in patients managed with modern drug-eluting stents. sequently followed by smooth muscle cells (SMC) and However, our study, as with those mentioned above, are myofibroblasts recruitment, which creates the extracellu- unable to ascertain if PAI-1 is a mediator or simply a lar matrix that narrows the vascular lumen [38]. SMCs marker of these events. Further study is needed to estab- achieve their peak proliferation at 48-96 h post-injury in lish this important distinction. the media and intima and return to their baseline fol- The association of PAI-1 activity with MACE did not lowing re-endothelialization of that artery within 8 weeks meet our pre-specified thresholds for significance. Al- [39]. Conflicting evidence exists in the literature in the though this finding suggests that PAI-1 antigen levels role of PAI-1 in cell migration. PAI-1 binding to low- may be more robust as a biomarker, PAI-1 activity is a density lipoprotein receptor-related protein 1 (LRP1) in functional measure of the entire PAI-1 content in the SMCs promotes cell migration [40]. However, PAI-1 plasma. The measurement of PAI-1 antigen captures the complexed to vitronectin has been demonstrated to Jung et al. Thrombosis Journal (2018) 16:12 Page 9 of 12 inhibit cell migration and adhesion [41]. Thus, biological be of high quality [48]. The small number of studies may plausibility exists to link PAI-1 and restenosis following have limited the detection of small study effects or coronary intervention. publication bias in funnel plots [49]. Finally, the large Clinically, low PAI-1 antigen and activity levels have variation in study dates (1991 to 2016) spans a broad been found to be associated with increased restenosis in range of pharmacologic and revascularization practices, our study; however, several limitations exist in these particularly coronary stent development, the introduc- studies. First, these selected studies range from 1991 to tion of dual antiplatelet therapy, and broadening indica- 2008, during which time the intervention of choice tions for oral anticoagulation therapy. Accordingly, these evolved from balloon angioplasty to bare-metal stents to findings may not be applicable in patients with specific drug-eluting stents, which reduced the rate of ISR ob- risk profiles or those on contemporary medical therapy. served today [1]. Second, anti-proliferative agents that Finally, while our study is provocative in the association coat drug-eluting stents such as paclitaxel promote PAI- demonstrated interventional studies are needed to link 1 transcription and translation, impacting PAI-1 levels at PAI-1 levels mechanistically to MACE. the site of injury [42]. Third, PAI-1 activity cannot detect PAI-1 complexed to LRP1 found on smooth muscle cells Conclusion and endothelial cells as they are no longer in circulation. PAI-1 plasma levels are promising markers for MACE; Finally, since ISR occurs months following intervention, however, high quality studies in well-defined populations it remains unclear if baseline levels alone would be as are still needed to robustly evaluate the performance of predictive as repeated measurements. Repeat measure- PAI-1 as a clinical biomarker. Whether PAI-1 is a bona ments of PAI-1 levels in these patients which would pro- fide therapeutic target remains to be established. vide a comprehensive assessment of temporal PAI-1 levels from baseline to follow-up angiography or re- Additional file intervention. Nonetheless, despite these limitations we were able to link basal PAI-1 levels and restenosis. Fu- Additional file 1: Association between plasminogen activator inhibitor- 1 and cardiovascular events: a systematic review and meta-analysis. ture studies looking at modern revascularization tech- (DOCX 4410 kb) niques and temporal patterns of PAI-1 are warranted. The value of PAI-1 as a biomarker has been ques- Abbreviations tioned. First, PAI-1 expression is influenced by multiple CAD: Coronary artery disease; MACE: Major adverse cardiovascular events; pro-inflammatory conditions and is associated with vari- PAI-1: Plasminogen activator inhibitor-1; PCI: Percutaneous coronary intervention; t-PA: Tissue-type plasminogen activator; u-PA: Urokinase-type ous cardiovascular risk factors [6, 43]. For example, plasminogen activator metabolic syndrome, obesity [44] and hyperinsulinemia [9]/insulin resistance [10] have all been linked with in- Acknowledgements creased PAI-1 levels. In adjusted analysis, the predictive We thank Risa Shorr (R.S.), MLIS (The Ottawa Hospital, General Campus, Ottawa, Ontario, Canada) for peer-review of the MEDLINE literature search strategy. ability of elevated PAI-1 levels has not been independent of other cardiovascular risk factors and its additive bene- Funding fit in risk prediction models has been lacking [45]. For R.J. was funded by the Vanier CIHR Canada Graduate Scholarship for his graduate studies. example, Yarmolinsky et al. [3] reported that patients with diabetes had a significantly higher level of plasma Availability of data and materials PAI-1, which was associated with MACE. However, dia- All data used for the systematic review and meta-analysis is present in the main betics are at increased risk of both index and recurrent manuscript in Tables 1 and 2. events. Accordingly, further studies are needed in more Authors’ contributions homogenous populations to ascertain the performance R.J. and B.H. participated in the design, data extraction and analysis, and drafted of PAI-1 in each individual cohort. the manuscript. P.M. participated in data extraction and analysis, and drafted the manuscript. F.D.R. helped design and drafted the manuscript. T.S., P.S., and Our study is not without limitations. Relevant data Y.J. participated in data extraction. S.V. helped design the search strategy could not be obtained from certain studies and patient utilized for the systematic review. M.A.F. and A.L. was involved in critical level data were not available. In addition, the broad in- revision of the manuscript. Finally, all authors read and approved the final draft of the manuscript. clusion criteria resulted in a heterogeneous study popu- lation with differing PAI-1 measurement techniques. Ethics approval and consent to participate Variations in assays and standardizations as well as nat- Not applicable. ural variations in PAI-1 levels may have influenced our Consent for publication results. For instance, considerable PAI-1 diurnal changes Not applicable. have been observed in previous studies [46, 47]. Most selected studies were of modest sample size and of low Competing interests or moderate quality with only seven studies deemed to The authors declare that they have no competing interests. Jung et al. 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Relevance of hemostasis on restenosis in clinically stable patients undergoing elective PTCA. Thromb Res. 2008;122:229–36. Submit your next manuscript to BioMed Central and we will help you at every step: • We accept pre-submission inquiries � Our selector tool helps you to find the most relevant journal � We provide round the clock customer support � Convenient online submission � Thorough peer review � Inclusion in PubMed and all major indexing services � Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Thrombosis Journal Springer Journals

Association between plasminogen activator inhibitor-1 and cardiovascular events: a systematic review and meta-analysis

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Medicine & Public Health; Angiology; Cardiology; Hematology
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Abstract

Background: Small studies have implicated plasminogen activator inhibitor-1 (PAI-1) as a predictor of cardiovascular events; however, these findings have been inconsistent. We sought out to examine the potential role of PAI-1 as a marker for major adverse cardiovascular events (MACE). Methods: We systematically reviewed all indexed studies examining the association between PAI-1 and MACE (defined as death, myocardial infarction, or cerebrovascular accident) or restenosis. EMBASE, Web of Science, Medline, and the Cochrane Library were searched through October 2016 to identify relevant studies, supplemented by letters to authors and review of citations. Studies reporting the results of PAI-1 antigen and/or activity levels in association with MACE in human subjects were included. Results: Of 5961 articles screened, we identified 38 articles published between 1991 to 2016 that reported PAI-1 levels in 11,557 patients. In studies that examined PAI-1 antigen and activity levels, 15.1% and 29.6% of patients experienced MACE, respectively. Patients with MACE had higher PAI-1 antigen levels with a mean difference of 6. 11 ng/mL (95% CI, 3.27-8.96). This finding was similar among patients with and without known coronary artery disease. Comparatively, studies that stratified by PAI-1 activity levels were not associated with MACE. In contrast, studies of coronary restenosis suggest PAI-1 antigen and activity levels are negatively associated with MACE. Conclusions: Elevated plasma PAI-1 antigen levels are associated with MACE. Definitive studies are needed to ascertain if PAI-1 acts simply as a marker of risk or if it is indeed a bona fide therapeutic target. Keywords: Plasminogen activator inhibitor-1, Biomarkers, Mortality, Myocardial infarction, Meta-analysis Background coronary revascularization [1]. However, complications Obstructive coronary artery disease (CAD) is the leading such as in-stent restenosis and stent thrombosis fol- cause of mortality in the western world. The cornerstone lowing PCI limit its efficacy. Thus, in the peri- of therapy for CAD remains revascularization and revascularization period, preventing thrombotic events secondary medical therapy to modify risk factors. The is paramount until the vessel’s endothelial lining and func- fibrinolytic system has implications for both ap- tion are restored. Second, long term therapy with anti- proaches to disease management. First, percutaneous platelet and/or oral anticoagulation is an integral part of coronary intervention (PCI) with implantation of a secondary preventive medical therapy. Thus, dysregulation coronary stent remains the predominant method of of the fibrinolytic pathways may increase the risk of com- plications from revascularization therapy and diminish the efficacy of long term medical therapy to reduce the * Correspondence: bhibbert@ottawaheart.ca Equal contributors risk of recurrent events. CAPITAL Research Group, University of Ottawa Heart Institute, 40 Ruskin The fibrinolytic system is activated by the conversion Street, H-4238, Ottawa, ON K1Y 4W7, Canada of plasminogen to plasmin by serine proteases such as Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada tissue or urokinase-type plasminogen activator (t-PA and Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Jung et al. Thrombosis Journal (2018) 16:12 Page 2 of 12 u-PA, respectively). In contrast, fibrinolysis is inhibited Inclusion and exclusion criteria and quality assessment by plasminogen activator inhibitor-1 (PAI-1), which is a Studies were included if they met the following criteria: member of the serine protease inhibitor (serpin) family. (1) PAI-1 antigen or activity levels were reported; (2) the Ultimately, thrombosis risk is influenced by the balance population studied comprised individuals aged 18 years between PAI-1 and t-PA. Thus, an increase in the PAI-1 or older; (3) components of MACE (death, myocardial levels in plasma can induce a hypercoagulable state [2]. infarction, and cerebrovascular events including stroke PAI-1 is released by vascular endothelial cells, hepato- and transient ischemic attacks) or restenosis were re- cytes, adipocytes, cardiomyocytes, fibroblasts, and ported; (4) articles were published in English. Exclusion platelets [3, 4]. In healthy humans, plasma levels of PAI- criteria included: (1) PAI-1 polymorphism studies exam- 1 exceed t-PA by a ratio of over 4:1 with most of PAI-1 ining the association between 4G/5G and adverse events; being cleared by the liver [5]. In pathologic condi- (2) animal or in vitro studies; and (3) studies reporting tions, PAI-1 production can be upregulated by pro- hazard ratios only. Full text data extraction was con- inflammatory factors such as TNFα,TGFβ, and insulin ducted by two independent evaluators (R.J. and P.M.). [6]. Elevated plasma PAI-1 levels have been associated Each reviewer independently extracted patient popula- with impaired fibrinolytic activity in stroke and coronary tion characteristics, group sizes, PAI-1 antigen and activ- artery disease [7]. Moreover, PAI-1 antigen and activity ity levels, follow-up duration, and MACE and restenosis. levels are elevated in patients with type 2 diabetes [8], All discrepancies were resolved by consensus prior to hyperinsulinemia [9], and those with insulin resistance locking the database for analysis (Tables 1 and 2). In- [10, 11]. Yet, a definitive assessment of the impact of ele- cluded observational studies were evaluated for quality vated PAI-1 as a biomarker or therapeutic target has yet and risk of bias using the Newcastle-Ottawa Quality As- to be evaluated. Accordingly, we performed a systematic sessment Scale [13] by two independent evaluators (R.J. review and meta-analysis of PAI-1 antigen and activity and P.M.) with disagreements resolved by consensus. levels and their relationship with major adverse cardiovas- Visual funnel plot inspection was used to screen for cular events (MACE) in humans. publication bias. Methods Statistical analysis Literature search strategy The primary clinical endpoint for this study was MACE Literature searches were guided by a medical librarian – a composite of death, myocardial infarction, or cere- with expertise in systematic reviews (S.V.) using a com- brovascular events. The secondary endpoint included bination of key terms and index headings related to PAI- components of the primary as well as coronary resten- 1, coronary disease (informed by the Cochrane review osis in patients undergoing coronary revascularization. search strategy for coronary heart disease in exercise- Mean circulating PAI-1 antigen (ng/mL) and activity based cardiac rehabilitation [12]), and the Cochrane (IU/mL) levels and their associated standard deviations Highly Sensitive search strategy to eliminate articles on were used for analyses. Fourteen studies reported me- animal studies in Medline. The search was additionally dian and interquartile ranges, which were converted to peer-reviewed by a second medical librarian (R.S.). Once approximated means and standard deviations using the finalized, the search strategy was then translated to other method described by Wan et al. [14]. bibliographic databases (see Additional file 1 for the full All analyses were performed using Review Manager Medline search). The final search was conducted on (RevMan) 5.3 (Cochrane Collection, Copenhagen, October 2016 in Medline (Ovid) (In-Process & Other Denmark). PAI-1 antigen and activity levels were com- Non-Indexed Citations and Ovid MEDLINE(R) 1946-), pared between patients with or without the outcomes of Embase (Ovid) (Embase Classic + Embase 1947-), interest either as absolute values or dichotomized as high Cochrane Library (Ovid) (from inception), and Web of vs. low. Random effects models stratified by study design Science (Thomson Reuters) (all indexes, from inception). and study quality were used to generate pooled mean dif- Search results were exported to EndNote X7 (Thomson ferences with 95% confidence intervals. Post-hoc meta re- Reuters, New York, USA) and duplicates eliminated gression was performed to account for timing of blood using the program’s duplicate identification feature and draw and acute phase reactions in studies of patients pre- manual inspection. A review protocol was produced but senting with acute myocardial infarction or stroke. not registered in a database. Titles and abstracts were screened by two independent Results reviewers (R.J. and P.M.) using Covidence (Melbourne, Included studies Australia). Full articles were retrieved in cases of missing Study selection abstracts. Corresponding authors were contacted for After excluding duplicate articles, 5961 titles and ab- additional information when necessary. stracts were screened, of which 340 underwent full Jung et al. Thrombosis Journal (2018) 16:12 Page 3 of 12 Table 1 Studies reporting PAI-1 antigen levels (ng/mL) and major adverse cardiovascular events and restenosis Event No Event Reference Year Study Design Follow-up (months) Population of interest N PAI-1 (IU/mL) Range Death MI Restenosis CVA N PAI-1 (IU/mL) Range Sane et al. [50] 1991 Cohort 24 Fibrinolytics 24 57 58 24 n/a n/a n/a 315 54 53 Cortellaro et al. [51] 1993 Case-Control 24 Subgroups Combined 58 11.3 0.7 13 17 n/a 20 87 7.3 0 5 Brannstrom et al. [52] 1995 Cohort 46 Anticoagulant 38 21.9 15.1 38 n/a n/a n/a 167 16.7 11.8 Juhan-Vague et al. [53] 1996 Cohort 24 MI 106 18.2 8 2 40 66 n/a n/a 2700 14.8 8.9 Nordt et al. [54] 1998 Cohort 12 Fibrinolytics 5 28.8 14.3 n/a n/a 5 n/a 26 27.1 15.4 Alaigh et al. [55] 1998 Cohort 6 Elective PCI 28 20.75 11.06 n/a n/a 28 n/a 45 24.5 13.85 Moss et al. [56] 1999 Cohort 26 MI 81 25 18 25 56 n/a n/a 964 29 28 Redondo et al. [57] 2001 Cohort 24 MI 37 40.725 22.28 2 5 30 n/a 157 42.65 21.02 Fornitz et al. [58] 2001 Cohort 6 Elective PCI 7 82.6 26.6 n/a n/a 7 n/a 12 72.2 27 Bogaty et al. [59] 2001 Case-Control 48 MI 23 23.83 19.04 n/a 8 n/a n/a 77 18.9 16.24 Ganti et al. [60] 2002 Cohort n/a MI 4 80.68 16.38 4 n/a n/a n/a 38 61 21.95 Lip et al. [61] 2002 Cohort 12 Stroke 27 56.5 30.7 27 n/a n/a n/a 59 45.9 23.3 Inoue et al. [62] 2003 Cohort 6 MI 24 28 4 n/a n/a 24 n/a 42 29 4 Christ et al. [20] 2005 Cohort 6 Elective PCI 25 14.8 0.7 n/a n/a 25 n/a 55 16.8 2.1 Robinson et al. [63] 2007 Cohort 5 to 51 Coronary Heart Disease 19 36.3 17.9 2 2 n/a 2 79 45.4 25.6 Katsaros et al. [24] 2008 Cohort 6 to 8 Elective PCI 12 11.69 8.05 n/a n/a 12 n/a 61 22.78 18.76 Thogersen et al. [64] 2009 Case-Control n/a Healthy 50 38.27 16.79 n/a 50 n/a n/a 56 29 15.75 Akkus et al. [65] 2009 Cohort 12 Cardiogenic Shock 33 116.5 97.26 33 n/a n/a n/a 27 71.33 54.79 Pineda et al. [66] 2010 Cohort 36 MI 25 65.13 53.3 4 21 n/a n/a 117 70.1 48.34 Wennberg et al. [67] 2012 Case-Control 168 Healthy 469 57.28 25.83 n/a 469 n/a n/a 895 51.23 25.11 Yano et al. [68] 2013 Cohort 20 Smokers 66 65.73 64.57 n/a 11 n/a 55 744 42.97 36.54 Yano et al. [69] 2014 Cohort 30 Hypertension 42 31.67 16.12 4 13 n/a 16 548 28.33 14.87 Knudsen et al. [70] 2014 Case-Control 12 HIV 54 111 8.5 3 51 n/a n/a 54 92 7 Golukhova et al. [71] 2015 Cohort 28 Elective PCI 23 72.75 29.86 2 9 11 n/a 71 49.75 23.16 CVA cerebrovascular accident Jung et al. Thrombosis Journal (2018) 16:12 Page 4 of 12 Table 2 Studies reporting PAI-1 activity levels (IU/mL) and major adverse cardiovascular events and restenosis Event No Event Reference Year Study Design Follow-up (months) Population of interest N PAI-1 Activity (U/mL) Range Death MI Restenosis N PAI-1 Activity (U/mL) Range Sane et al. [50] 1991 Cohort 24 Fibrinolytics 28 17 16 n/a n/a 28 328 19 21 Shah et al. [72] 1992 Cohort 9 Elective PCI 28 8 7.1 n/a n/a 28 40 12 8 Gray et al. [73] 1993 Cohort 0.1 MI 13 20.6 11 n/a 13 n/a 85 20.1 7.9 Malmberg et al. [74] 1994 Case-Control 90 MI 53 23.75 13.34 20 33 n/a 55 18 10.97 Brack et al. [75] 1994 Cohort 4 Elective PCI 16 4.63 4.71 n/a n/a 16 30 5.77 5.06 Nordt et al. [54] 1998 Cohort 12 Fibrinolytics 5 8.7 8.3 n/a 5 n/a 26 9.9 8.2 Jansson et al. [76] 1998 Cohort 120 MI 54 9.1 5.1 54 n/a n/a 69 10.6 7.1 Wiman et al. [77] 2000 Case-Control 3 MI 61 22.1 17.5 n/a 61 n/a 95 18.2 16.5 Wiman et al. [77] 2000 Case-Control 3 Ml 25 15.4 13.6 n/a 25 n/a 38 17.8 12.4 Prisco et al. [78] 2001 Cohort 18 MI 18 11.27 7.64 n/a n/a 18 36 15.8 27.49 Prisco et al. [78] 2001 Cohort 18 Elective PCI 6 8.33 8.1 n/a n/a 6 42 7.57 9.52 Sargento et al. [79] 2003 Cohort 12 MI 7 6.34 1.56 5 2 n/a 80 4.47 1.84 Marcucci et al. [19] 2006 Case-Control 22 2 MI 109 22 9.09 54 55 n/a 411 24.25 10.63 Schoebel et al. [80] 2008 Cohort 2 MI 18 3.7 1.8 n/a n/a 18 42 5.3 3.2 Wiman et al. [77] is presented twice as data for men and women were reported separately Jung et al. Thrombosis Journal (2018) 16:12 Page 5 of 12 review and 38 were ultimately included (Fig. 1, Tables 1 when the analysis was restricted to three high-quality and 2). Study populations were heterogeneous, including studies with a mean difference of 1.14 IU/mL (95% patients presenting with stable angina, acute coronary CI, − 3.37-5.65, P = 0.62; Additional file 1:Figure S5). syndrome, and non-cardiac diseases. Study sample sizes ranged from 19 to 2806. Most studies were of moderate Major adverse cardiovascular events: Pre-existing versus quality (see Additional file 1: Tables S1 and S2 for details no known coronary artery disease of study quality assessments). Funnel plots are shown in Overall, among patients without prior coronary artery Additional file 1: Figures S1 and S2. In pooled analyses disease, 12.2% had an event. PAI-1 antigen levels in of all studies reporting PAI-1 antigen levels (n = 8999), those without previously known coronary artery disease 1362 events were reported, including 234 deaths, 795 were on average 6.44 ng/mL higher in those with MACE myocardial infarctions, 101 cerebrovascular events, and relative to those without (95% CI, 2.64-10.25, P < 0.001; 142 restenoses (Table 1). In all studies that examined Fig. 4a). In studies that included patients with known PAI-1 activity levels (n = 1490), 441 events were re- CAD, 19.3% had MACE. PAI-1 antigen levels in those ported, including 133 deaths, 194 myocardial infarctions, with known CAD were on average 5.49 ng/mL higher in and 114 cases of restenosis (Table 2). those with MACE than those without (95% CI, 0.36- 10.63, P = 0.04; Fig. 4b). No difference in PAI-1 activity PAI-1 and clinical outcomes levels between event and control groups was observed in Major adverse cardiovascular events the five studies reporting PAI-1 activity levels and PAI-1 antigen levels were higher in those with MACE MACE (Additional file 1: Figure S6). with a mean difference of 6.11 ng/mL (95% CI, 3.27-8.96, P <0.001) – a difference that was present irrespective of Death study design (Fig. 2). When restricted to high-quality stud- In thefivestudies that reported mortality data, 126 deaths ies, PAI-1 antigen levels in patients with MACE were were observed (17.2% of patients). PAI-1 antigen levels were 5.22 ng/mL (95% CI, 2.97-7.54, P < 0.001; Additional file 1: higher among patients who died (mean difference: 10.34 ng/ Figure S3). Among seven studies reporting morning blood mL (95% CI, 1.90-18.79, P = 0.02; Additional file 1:FigureS7). draws between 7:00 and 10:00 am, PAI-1 antigen levels were higher in those with MACE with a mean difference of 4.61 ng/mL (95% CI, 1.49-7.74, P =0.004; Additional Restenosis file 1: Figure S4). Meta-regression analysis of timing of the In the six studies that examined restenosis following per- blood draw and acute phase studies was not pre- cutaneous coronary intervention (with and without cor- dictive of the heterogeneity in our selected studies onary stent implantation), 101 events were observed nor did it contribute to a greater understanding of (29.5% of patients). PAI-1 antigen levels were lower in the impact of PAI-1 in its association with MACE those with restenosis with a mean difference of − (Additional file 1:Table S3). 2.43 ng/mL (95% CI, − 4.48-(− 0.37), P = 0.02; Fig. 5a). In contrast to PAI-1 plasma antigen levels, there was An additional six studies provided restenosis rates and no significant difference in PAI-1 activity levels between PAI-1 activity levels. These studies reported restenosis in those with vs. without MACE (mean difference 0.59 IU/ 119 patients (17.9%). PAI-1 activity was lower in those mL (95% CI, − 1.63-2.80, P = 0.60; Fig. 3). No association with restenosis with a mean difference of − 1.73 IU/mL between PAI-1 activity levels and MACE was observed (95% CI: -2.80-(− 0.67), P = 0.001; Fig. 5b). Fig. 1 Flow diagram of the included PAI-1 studies for meta-analysis Jung et al. Thrombosis Journal (2018) 16:12 Page 6 of 12 Fig. 2 Comparison of mean PAI-1 antigen levels (ng/mL) in patients with major adverse cardiac events and control patients. Data is expressed as a mean difference and analyzed using a random effects model High versus low PAI-1 levels Discussion Three studies stratified their data by high versus low Incident and recurrent cardiovascular events remain im- PAI-1 antigen levels. These studies reported a MACE portant adverse outcomes despite major advances in re- rate of 54.4% [15–17]. High PAI-1 antigen levels vascularization and medical therapy. PAI-1 has been were associated with a 58% greater risk of MACE associated with MACE, but whether it is solely a marker compared to low PAI-1 antigen levels (RR 1.58, 95% for these events or a mediator with the potential of CI: 1.42-1.76, P < 0.0001; Fig. 6). representing a unique therapeutic target is uncertain. Fig. 3 Comparison of mean PAI-1 activity levels (IU/mL) in patients with major adverse cardiac events and control patients. Data is expressed as a mean difference and analyzed using a random effects model Jung et al. Thrombosis Journal (2018) 16:12 Page 7 of 12 Fig. 4 Comparison of mean PAI-1 antigen levels (ng/mL) in patients with primary and secondary major adverse cardiac events and control patients. Data is expressed as a mean difference and analyzed using a random effects model. a PAI-1 levels (ng/mL) in patients with primary major adverse cardiac events. b PAI-1 levels (ng/mL) in patients with secondary major adverse cardiac events Fig. 5 Comparison of mean PAI-1 antigen and activity levels in patients with restenosis and control patients. Data is expressed as a mean difference and analyzed using a random effects model. a Comparison of mean PAI-1 antigen levels (ng/mL) in patients with restenosis. b Comparison of mean PAI-1 activity levels (IU/mL) in patients with restenosis Jung et al. Thrombosis Journal (2018) 16:12 Page 8 of 12 Fig. 6 Comparison of risk of major adverse cardiac events in patients stratified by PAI-1 antigen levels (ng/mL). Data is expressed as a risk ratio and analyzed using a random effects model Our analysis set out to evaluate the current state of evi- entire PAI-1 content in the sample in the form of free dence linking PAI-1 antigen and activity levels with and active PAI-1 (which we refer to as PAI-1 activity), these outcomes. Our study suggests that elevated PAI-1 complexed to t-PA or u-PA, and latent PAI-1. Al- PAI-1 antigen levels are associated with major adverse though PAI-1 antigen and activity levels are correlated, cardiac events in both primary and secondary event antigen levels will not necessarily reflect PAI-1 activity populations. In addition, elevated PAI-1 antigen levels levels [25]. Indeed, at time of acute trauma such as were associated with all-cause mortality. While the plaque rupture, t-PA will complex with PAI-1 at a 1:1 ra- populations studied were heterogeneous, the robust- tio reducing detectable PAI-1 activity but not PAI-1 anti- ness of the association suggests that PAI-1 warrants gen levels. In addition, PAI-1 activity is influenced by further study as a marker and potential mediator of experimental techniques during sample isolation such as adverse cardiovascular events. freeze-thaw or sonication [26], low temperature, low pH, Our findings build upon the growing evidence that and high salt concentrations [27]. Factors which influ- PAI-1 is a biomarker for MACE in patients with CAD. ence PAI-1 activity levels which impacted the signifi- Tofler et al. identified elevated PAI-1 antigen levels to be cance of our findings include the method of PAI-1 predictive of cardiovascular disease [18]. In addition, extraction and isolation [26–30], time of blood draw previous studies of elevated PAI-1 antigen and activity [31], intra- and inter-assay variability in PAI-1 activity levels predicted acute coronary syndrome after coronary and antigen levels [32], and baseline risk factors which stenting [15, 19–22]. Furthermore, Song et al. recently influences PAI-1 levels such as smoking [33, 34], high- identified a causal relationship between elevated PAI-1 fat diet [35], and maximal exercise [36]. Finally, in levels and incident CAD [23]. Our study expands on addition to important biological differences, manifest these findings by identifying elevated PAI-1 antigen differences in the quality and power of studies examin- levels as being associated with MACE in both primary ing antigen and activity levels existed which may explain (incident) and secondary event populations thereby sug- the divergent results. gesting a broader relevance of PAI-1 antigen levels. In In-stent restenosis (ISR) is a result of neointimal for- addition, we demonstrate the potential applicability of mation or intimal thickening that narrows the vascular PAI-1 antigen levels in predicting restenosis, consistent lumen following PCI [37]. The detailed molecular mech- with a previous report by Katsaros et al. [24], which anism behind the pathophysiology of ISR has been identified that patients with the lowest PAI-1 antigen reviewed elsewhere [38]. Briefly, studies have revealed tertile had a 9.5-fold increased risk of in-stent restenosis that the initial recruitment of inflammatory cells is sub- in patients managed with modern drug-eluting stents. sequently followed by smooth muscle cells (SMC) and However, our study, as with those mentioned above, are myofibroblasts recruitment, which creates the extracellu- unable to ascertain if PAI-1 is a mediator or simply a lar matrix that narrows the vascular lumen [38]. SMCs marker of these events. Further study is needed to estab- achieve their peak proliferation at 48-96 h post-injury in lish this important distinction. the media and intima and return to their baseline fol- The association of PAI-1 activity with MACE did not lowing re-endothelialization of that artery within 8 weeks meet our pre-specified thresholds for significance. Al- [39]. Conflicting evidence exists in the literature in the though this finding suggests that PAI-1 antigen levels role of PAI-1 in cell migration. PAI-1 binding to low- may be more robust as a biomarker, PAI-1 activity is a density lipoprotein receptor-related protein 1 (LRP1) in functional measure of the entire PAI-1 content in the SMCs promotes cell migration [40]. However, PAI-1 plasma. The measurement of PAI-1 antigen captures the complexed to vitronectin has been demonstrated to Jung et al. Thrombosis Journal (2018) 16:12 Page 9 of 12 inhibit cell migration and adhesion [41]. Thus, biological be of high quality [48]. The small number of studies may plausibility exists to link PAI-1 and restenosis following have limited the detection of small study effects or coronary intervention. publication bias in funnel plots [49]. Finally, the large Clinically, low PAI-1 antigen and activity levels have variation in study dates (1991 to 2016) spans a broad been found to be associated with increased restenosis in range of pharmacologic and revascularization practices, our study; however, several limitations exist in these particularly coronary stent development, the introduc- studies. First, these selected studies range from 1991 to tion of dual antiplatelet therapy, and broadening indica- 2008, during which time the intervention of choice tions for oral anticoagulation therapy. Accordingly, these evolved from balloon angioplasty to bare-metal stents to findings may not be applicable in patients with specific drug-eluting stents, which reduced the rate of ISR ob- risk profiles or those on contemporary medical therapy. served today [1]. Second, anti-proliferative agents that Finally, while our study is provocative in the association coat drug-eluting stents such as paclitaxel promote PAI- demonstrated interventional studies are needed to link 1 transcription and translation, impacting PAI-1 levels at PAI-1 levels mechanistically to MACE. the site of injury [42]. Third, PAI-1 activity cannot detect PAI-1 complexed to LRP1 found on smooth muscle cells Conclusion and endothelial cells as they are no longer in circulation. PAI-1 plasma levels are promising markers for MACE; Finally, since ISR occurs months following intervention, however, high quality studies in well-defined populations it remains unclear if baseline levels alone would be as are still needed to robustly evaluate the performance of predictive as repeated measurements. Repeat measure- PAI-1 as a clinical biomarker. Whether PAI-1 is a bona ments of PAI-1 levels in these patients which would pro- fide therapeutic target remains to be established. vide a comprehensive assessment of temporal PAI-1 levels from baseline to follow-up angiography or re- Additional file intervention. Nonetheless, despite these limitations we were able to link basal PAI-1 levels and restenosis. Fu- Additional file 1: Association between plasminogen activator inhibitor- 1 and cardiovascular events: a systematic review and meta-analysis. ture studies looking at modern revascularization tech- (DOCX 4410 kb) niques and temporal patterns of PAI-1 are warranted. The value of PAI-1 as a biomarker has been ques- Abbreviations tioned. First, PAI-1 expression is influenced by multiple CAD: Coronary artery disease; MACE: Major adverse cardiovascular events; pro-inflammatory conditions and is associated with vari- PAI-1: Plasminogen activator inhibitor-1; PCI: Percutaneous coronary intervention; t-PA: Tissue-type plasminogen activator; u-PA: Urokinase-type ous cardiovascular risk factors [6, 43]. For example, plasminogen activator metabolic syndrome, obesity [44] and hyperinsulinemia [9]/insulin resistance [10] have all been linked with in- Acknowledgements creased PAI-1 levels. In adjusted analysis, the predictive We thank Risa Shorr (R.S.), MLIS (The Ottawa Hospital, General Campus, Ottawa, Ontario, Canada) for peer-review of the MEDLINE literature search strategy. ability of elevated PAI-1 levels has not been independent of other cardiovascular risk factors and its additive bene- Funding fit in risk prediction models has been lacking [45]. For R.J. was funded by the Vanier CIHR Canada Graduate Scholarship for his graduate studies. example, Yarmolinsky et al. [3] reported that patients with diabetes had a significantly higher level of plasma Availability of data and materials PAI-1, which was associated with MACE. However, dia- All data used for the systematic review and meta-analysis is present in the main betics are at increased risk of both index and recurrent manuscript in Tables 1 and 2. events. Accordingly, further studies are needed in more Authors’ contributions homogenous populations to ascertain the performance R.J. and B.H. participated in the design, data extraction and analysis, and drafted of PAI-1 in each individual cohort. the manuscript. P.M. participated in data extraction and analysis, and drafted the manuscript. F.D.R. helped design and drafted the manuscript. T.S., P.S., and Our study is not without limitations. Relevant data Y.J. participated in data extraction. S.V. helped design the search strategy could not be obtained from certain studies and patient utilized for the systematic review. M.A.F. and A.L. was involved in critical level data were not available. In addition, the broad in- revision of the manuscript. Finally, all authors read and approved the final draft of the manuscript. clusion criteria resulted in a heterogeneous study popu- lation with differing PAI-1 measurement techniques. Ethics approval and consent to participate Variations in assays and standardizations as well as nat- Not applicable. ural variations in PAI-1 levels may have influenced our Consent for publication results. For instance, considerable PAI-1 diurnal changes Not applicable. have been observed in previous studies [46, 47]. Most selected studies were of modest sample size and of low Competing interests or moderate quality with only seven studies deemed to The authors declare that they have no competing interests. Jung et al. 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Thrombosis JournalSpringer Journals

Published: Jun 5, 2018

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