By Paul A. Gurbel, MD; Udaya S. Tantry, PhD; Eli I. Lev, MD

In the past decade a vast amount of research and scientific literature has been devoted to cells termed as endothelial progenitor cells (EPCs). This short review will focus on their relevance and importance to interventional cardiology.

What are EPCs and What are Their Roles?

FIGURE: Typical EPC colonies after 7 days of culture stained with antibodies directed against vascular endothelial growth factor receptor 2 (VEGFR-2), CD31, and Tie-2 to confirm endothelial cell lineage. (Source: Lev EI, et al. Eur Heart J. 2010;31:2625-32)

EPCs are a population of bone marrow—derived stem cells that are mobilized into the circulating blood in response to either tissue or vascular injury. In the circulation, they are characterized by the expression of several surface proteins, such as CD34, CD133 and VEGFR-2. These “immature” stem cells have the capability to “home” and adhere to the sites of tissue or vascular injury, and gradually acquire characteristics of mature endothelial cells (typical colonies of EPCs after a period of “maturation” are shown in the FIGURE). Tissue injury may spontaneously occur following acute coronary syndrome or iatrogenically during percutaneous coronary intervention (PCI). In this setting, the role of EPCs is probably to ensure neovascularization of necrotic tissue.

EPCs have been shown to have an important role in the process of vascular repair and specifically in the enhancement of re-endothelialization following injury of the endothelial lining of an artery (e.g., balloon angioplasty or stenting). In this respect, it is important to note that mature endothelial cells in the surrounding vessel area of an implanted stent have a limited capability to mobilize and proliferate, and, thus it appears that cells that come from a remote location, such as EPCs from the bone marrow, have an important role in facilitating re-endothelialization. The role of EPCs in the process of healing and repair of atherosclerotic or iatrogenic vascular injury may explain their clinical importance.

It has been suggested that there is a substantial reduction in the levels of circulating EPCs in patients with cardiovascular diseases or with cardiovascular risk factors. The most marked reduction appears to be in patients with long-standing diabetes. Reduced blood levels of EPCs, in turn, have been independently associated with an increased risk for long-term adverse cardiovascular events (including mortality) and therefore appear to have prognostic significance.

EPCs and Stent Endothelialization

The exact mechanism of human arterial stent re-endothelialization has not been fully elucidated. However, we know from animal studies that EPCs can mobilize and incorporate into vessel wall at the injured site after balloon injury—a process associated with accelerated endothelial regeneration. In addition, transplantation of isolated EPCs (from a remote source) into balloon-injured arteries of animals leads to rapid re-endothelialization and repair of the vessels. In humans, there is indirect evidence for the participation of EPCs in the process of vascular repair.

After acute vascular insults, such as burn injury or coronary artery bypass graft surgery, there is rapid increase in the levels of circulating EPCs. Surprisingly, after coronary artery stenting, which is a relatively localized and focal type of vascular injury, there is also a significant increase in the levels of circulating EPCs. The latter observation suggests that even a limited focal endothelial injury can trigger mobilization of EPCs into the peripheral circulation.

It should be emphasized that effective healing and re-endothelialization is important for the prevention of stent thrombosis. One of the important factors thought to be related to an increased risk of late stent thrombosis is impaired or delayed re-endothelialization. Our group has shown that patients who experience late stent thrombosis following implantation of drug-eluting stents, have lower levels of EPCs and impaired functional properties of the EPCs, compared with patients who did not experience stent thrombosis. These observations imply that lower levels and/or dysfunctional EPCs after coronary stenting may expose the patient to an enhanced risk of stent thrombosis via impaired re-endothelialization.

Clinical Implications for Interventional Cardiology

There are a number of factors that have been shown to raise the circulating levels of and improve the function of EPCs. Among them are a long-term exercise/physical activity program and control of risk factors (e.g., metabolic control in patients with diabetes). Another therapeutic approach shown to significantly improve EPC levels and function is treatment with statins, especially high-dose statins. It is possible that part of the positive clinical effects of high-dose statins given before elective or urgent PCI in reducing adverse cardiac events are mediated by promoting EPC mobilization into the circulation. These EPCs may, in turn, facilitate re-endothelialization and vascular repair following the PCI and at sites of spontaneous injury beyond the stent site, thus reducing potential ischemic complications.

A novel approach to utilize the positive properties of EPCs in the setting of PCI is the design of coronary stents covered with an anti-CD34 antibody that can “attract” CD34 positive ECPs, the so called “EPC capture stent” (GenousTM, OrbusNeich; Wanchai, Hong Kong). In several animal models (e.g., rabbit iliac artery denudation model) implantation of the EPC capture stent was associated with accelerated re-endothelialization of the stent and reduced thrombogenicity compared with bare-metal stents. In humans, several small studies have shown that implantation of these stents is safe and associated with a relatively low rate of stent thrombosis. However, we await the results of large ongoing randomized studies which examine the long-term clinical outcomes associated with implantation of EPC capture stents in patients with coronary artery disease.

In conclusion, EPCs are bone marrow—derived cells that may have an important role in vascular repair and re-endothelialization. They appear to take part in and facilitate re-endothelialization following coronary stenting. Several approaches have been employed to increase their circulating levels in the post-PCI setting, including treatment with high-dose statins. Implantation of EPC-capture stents enhances local EPC levels at the site of vessel injury. Further research is required to better understand their comprehensive role in injury repair following stenting, and to fully implement their potential as a therapy for general vascular repair.

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References

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Lev EI, Leshem-Lev D, Mager A, et al. Eur Heart J. 2010;31:2625-32.

Padfield GJ, Newby DE, Mills NL. J Am Coll Cardiol. 2010; 55:1553-65.

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Paul A. Gurbel, MD; Udaya S. Tantry, PhD; and Eli I. Lev, MD, are from the Sinai Center for Thrombosis Research in Baltimore, Maryland. Dr. Lev is also from the Rabin Medical Center, in Petah-Tikva, Israel.

Keywords: Coronary Artery Disease, Acute Coronary Syndrome, Drug-Eluting Stents, Stem Cells, Membrane Proteins, Vascular Endothelial Growth Factor Receptor-2, Blood Platelets, Risk Factors, Iliac Artery, Stents, Percutaneous Coronary Intervention, Vascular System Injuries, Bone Marrow, Regeneration, Thrombosis, Motor Activity, Coronary Artery Bypass, Endothelial Cells, Diabetes Mellitus

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