Dipyridamole and vascular healing following stent implantation.

Introduction: Patients undergoing coronary stent implantation incur a 2% annual rate of adverse events, largely driven by in-stent restenosis (ISR) due to neointimal (NI) tissue proliferation, a process in which smooth muscle cell (SMC) biology may play a central role. Dipyridamole (DP) is an approved therapeutic agent with data supporting improved vascular patency rates. Pre-clinical data supports that DP may enact its vasculoprotective effects via adenosine receptor-A2B (ADOR-A2B). We sought to evaluate the efficacy of DP to mitigate ISR in a pre-clinical rabbit stent model. Methods & Results: 24 New Zealand White Rabbits were divided into two cohorts-non-atherosclerosis and atherosclerosis (n = 12/cohort, 6 male and 6 female). Following stent implantation, rabbits were randomized 1:1 to control or oral dipyridamole therapy for 6 weeks followed by optical coherence tomography (OCT) and histology assessment of NI burden and stent strut healing. Compared to control, DP demonstrated a 16.6% relative reduction in NI volume (14.7 ± 0.8% vs. 12.5 ± 0.4%, p = 0.03) and a 36.2% relative increase in optimally healed stent struts (37.8 ± 2.8% vs. 54.6 ± 2.5%, p < 0.0001). Atherosclerosis demonstrated attenuated effect with no difference in NI burden (15.2 ± 1.0% vs. 16.9 ± 0.8%, p = 0.22) and only a 14.2% relative increase in strut healing (68.3 ± 4.1% vs. 78.7 ± 2.5%, p = 0.02). DP treated rabbits had a 44.6% (p = 0.045) relative reduction in NI SMC content. In vitro assessment of DP and coronary artery SMCs yielded dose-dependent reduction in SMC migration and proliferation. Selective small molecule antagonism of ADOR-A2B abrogated the effects of DP on SMC proliferation. DP modulated SMC phenotypic switching with ADOR-A2B siRNA knockdown supporting its role in the observed effects. Conclusion: Dipyridamole reduces NI proliferation and improves stent healing in a preclinical model of stent implantation with conventional antiplatelets. Atherosclerosis attenuates the observed effect. Clinical trials of DP as an adjunctive agent may be warranted to evaluate for clinical efficacy in stent outcomes.

Evaluation of a Rabbit Model of Vascular Stent Healing: Application of Optical Coherence Tomography.

Percutaneous coronary intervention (PCI) is a management strategy for symptomatic obstructive coronary artery disease (CAD). Despite advancements, in-stent restenosis (ISR) still imparts a 1-2% annual rate of repeat revascularization-a focus of ongoing translational research. Optical coherence tomography (OCT) provides high resolution virtual histology of stents. Our study evaluates the use of OCT for virtual histological assessment of stent healing in a rabbit aorta model, enabling complete assessment of intraluminal healing throughout the stent. ISR varies based on intra-stent location, stent length, and stent type in a rabbit model-important considerations for translational experimental design. Atherosclerosis leads to more prominent ISR proliferation independent of stent-related factors. The rabbit stent model mirrors clinical observations, while OCT-based virtual histology demonstrates utility for pre-clinical stent assessment. Pre-clinical models should incorporate clinical and stent factors as feasible to maximize translation to clinical practice.

Plasminogen Activator Inhibitor-1-Positive Platelet-Derived Extracellular Vesicles Predicts MACE and the Proinflammatory SMC Phenotype.

Patients with established coronary artery disease remain at elevated risk of major adverse cardiac events. The goal of this study was to evaluate the utility of plasminogen activator inhibitor-1-positive platelet-derived extracellular vesicles as a biomarker for major adverse cardiac events and to explore potential underlying mechanisms. Our study suggests these extracellular vesicles as a potential biomarker to identify and a therapeutic target to ameliorate neointimal formation of high-risk patients.

Modifiable Risk Factors and Residual Risk Following Coronary Revascularization: Insights From a Regionalized Dedicated Follow-Up Clinic.

OBJECTIVE: To ensure compliance with optimal secondary prevention strategies and document the residual risk of patients following revascularization, we established a postrevascularization clinic for risk-factor optimization at 1 year, with outcomes recorded in a web-based registry. Although coronary revascularization can reduce ischemia, medical treatment of coronary artery disease (CAD) remains the cornerstone of ongoing risk reduction. While standardized referral pathways and protocols for revascularization are prevalent and well studied, post-revascularization care is often less formalized. PATIENTS AND METHODS: The University of Ottawa Heart Institute is a tertiary-care center providing coronary revascularization services. From 2015 to 2019, data were prospectively recorded in the CAPITAL revascularization registry, and patient-level procedural, clinical, and outcome data are collected in the year following revascularization. Major adverse cardiovascular event (MACE) was defined as death, myocardial infarction, unplanned revascularization, or cerebrovascular accident. Kaplan-Meier curves were generated to evaluate time-to-event data for clinical outcomes by risk-factor management, and comparisons were performed using log-rank tests and reported by hazard ratio (HR) and 95% confidence intervals (CIs). RESULTS: A cohort of 4147 patients completed 1-year follow-up after revascularization procedure that included 3462 undergoing percutaneous coronary intervention (PCI), 589 undergoing coronary artery bypass graft (CABG), and 96 undergoing both PCI and CABG. In the year following revascularization (median follow-up 13.3 months-interquartile range [IQR]: 11.9-16.5) 11% of patients experienced MACE, with female patients being disproportionately at risk. Moreover, 47.7% of patients had ≥2 risk factors (diabetes, dyslipidemia, overweight, active smoker) at the time of follow-up, with 45.0% of patients with diabetes failing to achieve target hemoglobin (Hb) A1c, 54.8% of smokers continuing to smoke, and 27.1% of patients failing to achieve guideline-directed lipid targets. CONCLUSION: Patients who have undergone revascularization procedures remain at elevated risk for MACE, and inadequately controlled risk factors are prevalent in follow-up. This highlights the need for aggressive secondary prevention strategies and implementation of programs to optimize postrevascularization care.

Revisiting the Evidence for Dipyridamole in Reducing Restenosis: A Systematic Review and Meta-analysis.

ABSTRACT: Atherosclerosis remains a leading cause of morbidity and mortality, with revascularization remaining a cornerstone of management. Conventional revascularization modalities remain challenged by target vessel reocclusion-an event driven by mechanical, thrombotic, and proliferative processes. Despite considerable advancements, restenosis remains the focus of ongoing research. Adjunctive agents, including dipyridamole, offer a multitude of effects that may improve vascular homeostasis. We sought to quantify the potential therapeutic impact of dipyridamole on vascular occlusion. We performed a literature search (EMBASE and MEDLINE) examining studies that encompassed 3 areas: (1) one of the designated medical therapies applied in (2) the setting of a vascular intervention with (3) an outcome including vascular occlusion rates and/or quantification of neointimal proliferation/restenosis. The primary outcome was vascular occlusion rates. The secondary outcome was the degree of restenosis by neointimal quantification. Both human and animal studies were included in this translational analysis. There were 6,839 articles screened, from which 73 studies were included, encompassing 16,146 vessels followed up for a mean of 327.3 days (range 7-3650 days). Preclinical studies demonstrate that dipyridamole results in reduced vascular occlusion rates {24.9% vs. 48.8%, risk ratio 0.53 [95% confidence interval (CI) 0.40-0.70], I2 = 39%, P < 0.00001}, owing to diminished neointimal proliferation [standardized mean differences -1.13 (95% CI -1.74 to -0.53), I2 = 91%, P = 0.0002]. Clinical studies similarly demonstrated reduced occlusion rates with dipyridamole therapy [23.5% vs. 31.0%, risk ratio 0.77 (95% CI 0.67-0.88), I2 = 84%, P < 0.0001]. Dipyridamole may improve post-intervention vascular patency and mitigate restenosis. Dedicated studies are warranted to delineate its role as an adjunctive agent after revascularization.

Performance of Plasma Adenosine as a Biomarker for Predicting Cardiovascular Risk.

Adenosine boasts promising preclinical and clinical data supporting a vital role in modulating vascular homeostasis. Its widespread use as a diagnostic and therapeutic agent have been limited by its short half-life and complex biology, though adenosine-modulators have shown promise in improving vascular healing. Moreover, circulating adenosine has shown promise in predicting cardiovascular (CV) events. We sought to delineate whether circulating plasma adenosine levels predict CV events in patients undergoing invasive assessment for coronary artery disease. Patients undergoing invasive angiography had clinical data prospectively recorded in the Cardiovascular and Percutaneous ClInical TriALs (CAPITAL) revascularization registry and blood samples collected in the CAPITAL Biobank from which adenosine levels were quantified. Tertile-based analysis was used to assess prediction of major adverse cardiovascular events (MACE; composite of death, myocardial infarction, unplanned revascularization, and cerebrovascular accident). Secondary analyses included MACE subgroups, clinical subgroups and adenosine levels. There were 1,815 patients undergoing angiography who had blood collected with adenosine quantified in 1,323. Of those quantified, 51.0% were revascularized and 7.3% experienced MACE in 12 months of follow-up. Tertile-based analysis failed to demonstrate any stratification of MACE rates (log rank, P = 0.83), when comparing low-to-middle (hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.68-1.78, P = 0.70) or low-to-high adenosine tertiles (HR 0.95, 95% CI 0.56-1.57, P = 0.84). In adjusted analysis, adenosine similarly failed to predict MACE. Finally, adenosine did not predict outcomes in patients with acute coronary syndrome nor in those revascularized or treated medically. Plasma adenosine levels do not predict subsequent CV outcomes or aid in patient risk stratification.

Contrast-free optical coherence tomography:Systematic evaluation of non-contrast media for intravascular assessment.

BACKGROUND: Coronary revascularization using imaging guidance is rapidly becoming the standard of care. Intravascular optical coherence tomography uses near-infrared light to obtain high resolution intravascular images. Standard optical coherence tomography imaging technique employs iodinated contrast dye to achieve the required blood clearance during acquisition. We sought to systematically evaluate the technical performance of saline as an alternative to iodinated contrast for intravascular optical coherence tomography assessment. METHODS AND RESULTS: We performed bench top optical coherence tomography analysis on nylon tubing with sequential contrast/saline dilutions to empirically derive adjustment coefficients. We then applied these coefficients in vivo in an established rabbit abdominal stenting model with both saline and contrast optical coherence tomography imaging. In this model, we assessed the impact of saline on both quantitative and qualitative vessel assessment. Nylon tubing assessment demonstrated a linear relationship between saline and contrast for both area and diameter. We then derived adjustment coefficients, allowing for accurate calculation of area and diameter when converting saline into both contrast and reference dimensions. In vivo studies confirmed reduced area with saline versus contrast [7.43 (5.67-8.36) mm2 versus 8.2 (6.34-9.39) mm2, p = 0.001] and diameter [3.08 mm versus 3.23 mm, p = 0.001]. Following correction, a strong relationship was achieved in vivo between saline and contrast in both area and diameter without compromising image quality, artefact, or strut assessment. CONCLUSION: Saline generates reduced dimensions compared to contrast during intravascular optical coherence tomography imaging. The relationship across physiologic coronary diameters is linear and can be corrected with high fidelity. Saline does not adversely impact image quality, artefact, or strut assessment.

The balloon impasse sign in percutaneous transvenous mitral valvuloplasty.

Percutaneous transvenous mitral valvuloplasty (PTMV) is an established therapy for rheumatic mitral stenosis (MS). While the Wilkins score standardizes the description of valve anatomy and predicts successful PTMV, echocardiographic assessment has some limitations. The 'balloon impasse' sign is the inability to cross a stenotic valve with a deflated Inoue balloon. This sign was described in the 1990s as an indicator of severe subvalvular thickening (regardless of the echocardiographic findings), portending an increased risk of severe mitral regurgitation (MR) post-PTMV. Despite its implications for management, it has been seldom reported. A 57-year-old woman with symptomatic, severe MS and a Wilkins score of 7 underwent PTMV. The 'balloon impasse' sign was observed when attempting to cross the stenotic valve. When the balloon was fully inflated, severe MR was noted, and the patient required mitral valve replacement. This case demonstrates the continued importance of the 'balloon impasse' sign and its implications for the therapeutic efficacy of PTMV.

Evaluation of plasminogen activator inhibitor-1 as a biomarker of unplanned revascularization and major adverse cardiac events in coronary angiography and percutaneous coronary intervention.

BACKGROUND: The stented coronary artery remains at high-risk of complications, particularly in the form of stent thrombosis and in-stent restenosis. Improving our ability to identify patients at high-risk for these complications may provide opportunities for intervention. PAI-1 has been implicated in the pathophysiology of stent complications in preclinical studies, suggesting it may be a clinically valuable biomarker to predict adverse events following percutaneous coronary intervention. METHODS: Plasma PAI-1 levels were measured in 910 subjects immediately after coronary angiography between 2015 and 2019. The primary outcome was the incidence of unplanned revascularization (UR) at 12 months. The secondary outcome was the incidence of major adverse cardiac events (MACE). RESULTS: UR and MACE occurred in 49 and 103 patients in 12 months. Reduced plasma PAI-1 levels were associated with UR (4386.1 pg/mL [IQR, 2778.7-6664.6], n = 49, vs. 5247.6 pg/mL [IQR, 3414.1-7836.1], n = 861; p = 0.04). Tertile PAI-1 levels were predictive of UR after adjustment for known clinical risk factors associated with adverse outcomes. In post-hoc landmark analysis, UR was enhanced with low plasma PAI-1 levels for late complications (beyond 30 days). Finally, an updated systematic review and meta-analysis did not reveal an association between plasma PAI-1 and MACE. CONCLUSION: PAI-1 levels are not independently associated with UR nor MACE in patients undergoing angiography but associated with UR following adjustment with known clinical factors. In our landmark analysis, low PAI-1 levels were associated with UR for late stent complications. As such, future studies should focus on the mediatory role of PAI-1 in the pathogenesis of stent complications.

Evaluation of an in vitro coronary stent thrombosis model for preclinical assessment.

Stent thrombosis remains an infrequent but significant complication following percutaneous coronary intervention. Preclinical models to rapidly screen and validate therapeutic compounds for efficacy are lacking. Herein, we describe a reproducible, high throughput and cost-effective method to evaluate candidate therapeutics and devices for either treatment or propensity to develop stent thrombosis in an in vitro bench-top model. Increasing degree of stent malapposition (0.00 mm, 0.10 mm, 0.25 mm and 0.50 mm) was associated with increasing thrombosis and luminal area occlusion (4.1 ± 0.5%, 6.3 ± 0.5%, 19.7 ± 4.5%, and 92.6 ± 7.4%, p < 0.0001, respectively). Differences in stent design in the form of bare-metal, drug-eluting, and bioresorbable vascular scaffolds demonstrated differences in stent thrombus burden (14.7 ± 3.8% vs. 20.5 ± 3.1% vs. 86.8 ± 5.3%, p < 0.01, respectively). Finally, thrombus burden was significantly reduced when healthy blood samples were incubated with Heparin, ASA/Ticagrelor (DAPT), and Heparin+DAPT compared to control (DMSO) at 4.1 ± 0.6%, 6.9 ± 1.7%, 4.5 ± 1.2%, and 12.1 ± 1.8%, respectively (p < 0.01). The reported model produces high throughput reproducible thrombosis results across a spectrum of antithrombotic agents, stent design, and degrees of apposition. Importantly, performance recapitulates clinical observations of antiplatelet/antithrombotic regimens as well as device and deployment characteristics. Accordingly, this model may serve as a screening tool for candidate therapies in preclinical evaluation.

Journal Initiatives to Enhance Preclinical Research: Analyses of Stroke, Nature Medicine, Science Translational Medicine.

Background and Purpose- Preclinical research using animals often informs clinical trials. However, its value is dependent on its scientific validity and reproducibility, which are, in turn, dependent on rigorous study design and reporting. In 2011, Stroke introduced a Basic Science Checklist to enhance the reporting and methodology of its preclinical studies. Except for Nature and Science journals, few others have implemented similar initiatives. We sought to estimate the impact of these journal interventions on the quality of their published reports. Methods- All articles published in Stroke, Nature Medicine, and Science Translational Medicine over 9 to 18 years and in 2 control journals without analogous interventions over a corresponding 11.5 years were reviewed to identify reports of experiments in nonhuman mammals with proposed clinical relevance. The effect of journal interventions on the reporting and use of key study design elements was estimated via interrupted time-series analyses. Results- Of 33 009 articles screened, 4162 studies met inclusion criteria. In the 3.5 to 12 years preceding each journal's intervention, the proportions of studies reporting and using key study design elements were stable except for blinding in Stroke and randomization in Science Translational Medicine, which were both increasing. Post-intervention, abrupt and often marked increases were seen in the reporting of randomization status (level change: +17% to +44%, P≤0.005), blinding (level change: +20% to +40%, P≤0.008), and sample size estimation (level change: 0% to +40%, P≤0.002 in 2 journals). Significant but more modest improvements in the use of these study design elements were also observed. These improvements were not seen in control journals. Conclusions- Journal interventions such as Stroke's author submission checklist can meaningfully improve the quality of published preclinical research and should be considered to enhance study transparency and design. However, such interventions are alone insufficient to fully address widespread shortcomings in preclinical research practices.

Evaluation of Plasma Adenosine as a Marker of Cardiovascular Risk: Analytical and Biological Considerations.

Background Adenosine is a ubiquitous regulatory molecule known to modulate signaling in many cells and processes vital to vascular homeostasis. While studies of adenosine receptors have dominated research in the field, quantification of adenosine systemically and locally remains limited owing largely to technical restrictions. Given the potential clinical implications of adenosine biology, there is a need for adequately powered studies examining the role of plasma adenosine in vascular health. We sought to describe the analytical and biological factors that affect quantification of adenosine in humans in a large, real-world cohort of patients undergoing evaluation for coronary artery disease. Methods and Results Between November 2016 and April 2018, we assessed 1141 patients undergoing angiography for evaluation of coronary artery disease. High-performance liquid chromatography was used for quantification of plasma adenosine concentration, yielding an analytical coefficient of variance (CVa) of 3.2%, intra-subject variance (CVi) 35.8% and inter-subject variance (CVg) 56.7%. Traditional cardiovascular risk factors, medications, and clinical presentation had no significant impact on adenosine levels. Conversely, increasing age (P=0.027) and the presence of obstructive coronary artery disease (P=0.026) were associated with lower adenosine levels. Adjusted multivariable analysis supported only age being inversely associated with adenosine levels (P=0.039). Conclusions Plasma adenosine is not significantly impacted by traditional cardiovascular risk factors; however, advancing age and presence of obstructive coronary artery disease may be associated with lower adenosine levels. The degree of intra- and inter-subject variance of adenosine has important implications for biomarker use as a prognosticator of cardiovascular outcomes and as an end point in clinical studies.

Female Authorship in Preclinical Cardiovascular Research: Temporal Trends and Influence on Experimental Design.

In this analysis of 3,396 preclinical cardiovascular studies, women were first, senior, and both first and senior authors in 41.3%, 20.7%, and 11.0% of the studies, respectively. Female authorship increased over a 10-year period. However, the proportion of studies with first and senior authors of differing sex was low and stable, suggesting that segregation by sex in mentorship relationships exists and persists. Female authors were more likely to consider sex as a biological variable, but author sex was not associated with other measures of experimental rigor or research impact, indicating that women's underrepresentation was not due to differences in research capacity or impact.

Performance of plasminogen activator inhibitor-1 as a biomarker in patients undergoing coronary angiography: Analytical and biological considerations.

INTRODUCTION AND OBJECTIVE: Target lesion failure continues to limit the efficacy of percutaneous coronary intervention despite advancements in stent design and medical therapy. Identification of biomarkers to risk stratify patients after percutaneous coronary intervention has the potential to focus therapies on cohorts with increased benefits. Plasminogen activator inhibitor-1 has been identified as a candidate biomarker. Herein, we evaluate biological variables which impact plasminogen activator inhibitor-1 levels and analytical characteristics which impact its utility as a biomarker in humans. METHODS: Plasma plasminogen activator inhibitor-1 was measured in 689 patients undergoing coronary angiography. Plasminogen activator inhibitor-1 levels were measured. Clinical and procedural characteristics were collected in a prospective registry. RESULTS: Plasma plasminogen activator inhibitor-1 analytical (CVa = 4.1%), intra-individual (CVi = 44.0%) and inter-individual (CVg = 118.6%) variations with reference change value of 122.3% were calculated. Plasminogen activator inhibitor-1 levels were elevated in patients with cardiovascular risk factors, including type 2 diabetes, pre-diabetes, smokers, obesity, hypertension, and daytime variation in procedure and blood draw. CONCLUSION: Variation in plasma plasminogen activator inhibitor-1 levels is influenced by multiple biological and procedural characteristics. The performance of plasma plasminogen activator inhibitor-1 is consistent with biomarkers in clinical use (N-terminal pro-B-type natriuretic peptide and C-reactive protein) and its applicability is promising.

Adenosine as a Marker and Mediator of Cardiovascular Homeostasis: A Translational Perspective.

Adenosine, a purine nucleoside, is produced broadly and implicated in the homeostasis of many cells and tissues. It signals predominantly via 4 purinergic adenosine receptors (ADORs) - ADORA1, ADORA2A, ADORA2B and ADOosine signaling, both through design as specific ADOR agonists and antagonists and as offtarget effects of existing anti-platelet medications. Despite this, adenosine has yet to be firmly established as either a therapeutic or a prognostic tool in clinical medicine to date. Herein, we provide a bench-to-bedside review of adenosine biology, highlighting the key considerations for further translational development of this proRA3 in addition to non-ADOR mediated effects. Through these signaling mechanisms, adenosine exerts effects on numerous cell types crucial to maintaining vascular homeostasis, especially following vascular injury. Both in vitro and in vivo models have provided considerable insights into adenosine signaling and identified targets for therapeutic intervention. Numerous pharmacologic agents have been developed that modulate adenmising molecule.

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

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.

Role of plasminogen activator inhibitor-1 in coronary pathophysiology.

The standard of care for obstructive atherosclerotic coronary disease is revascularization, predominantly achieved via percutaneous placement of a stent with concurrent medical therapy. Advancements in percutaneous coronary intervention (PCI) have dramatically improved outcomes. However, major complications from PCI due to target lesion failure continue to occur at rates between 5 and 10% in the first twelve months following intervention limiting its therapeutic efficacy. Plasminogen activator inhibitor-1 (PAI-1) is a protein of interest for both arterial remodeling and thrombotic risk as it regulates cell migration and vascular thrombosis. Elevated PAI-1 antigen levels have been identified as a potential biomarker for coronary artery disease and metabolic syndrome while being modulated by a number of atherosclerotic risk factors. Although linked by some studies as a marker of disease severity and prognosis, it remains to be understood whether it is also a mediator and/or therapeutic target of vascular disease. In this review, we discuss the current understanding of PAI-1 in vascular disease and its potential role in in-stent restenosis and stent thrombosis.

Progenitor Cells for Arterial Repair: Incremental Advancements towards Therapeutic Reality.

Coronary revascularization remains the standard treatment for obstructive coronary artery disease and can be accomplished by either percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery. Considerable advances have rendered PCI the most common form of revascularization and improved clinical outcomes. However, numerous challenges to modern PCI remain, namely, in-stent restenosis and stent thrombosis, underscoring the importance of understanding the vessel wall response to injury to identify targets for intervention. Among recent promising discoveries, endothelial progenitor cells (EPCs) have garnered considerable interest given an increasing appreciation of their role in vascular homeostasis and their ability to promote vascular repair after stent placement. Circulating EPC numbers have been inversely correlated with cardiovascular risk, while administration of EPCs in humans has demonstrated improved clinical outcomes. Despite these encouraging results, however, advancing EPCs as a therapeutic modality has been hampered by a fundamental roadblock: what constitutes an EPC? We review current definitions and sources of EPCs as well as the proposed mechanisms of EPC-mediated vascular repair. Additionally, we discuss the current state of EPCs as therapeutic agents, focusing on endogenous augmentation and transplantation.