1. Introduction
The bone marrow of adult humans is a source of endothelial progenitor cells (EPCs) that circulate in the blood and repair damaged endothelium. The number and function of EPCs is predictive of endothelial function and cardiovascular events. Herein we discuss the impact of individual risk factors on EPC numbers and discuss the potential utility of EPC number as a cardiovascular risk-assessment tool that integrates traditional and emerging cardiovascular risk factors.
2. The systemic basis of cardiovascular disease
Cardiovascular disease the leading cause of mortality in the Western world and manifests as coronary disease, peripheral vascular disease, or ischemic stroke depending on the vascular territory affected. The ageing population and projected increases in prevalence and costs of care have highlighted the need for more effective prevention of cardiovascular disease (Heidenreich, Trogdon et al. 2011). These manifestations of cardiovascular disease share common risk factors of age, hypertension, diabetes, hypercholesterolemia and smoking (Roger, Go et al. 2011). Endothelial dysfunction is the precursor lesion to atherosclerosis and reflects depressed nitric oxide (NO) release from the endothelium (Furchgott 1996; Valgimigli, Merli et al. 2003). Basal release of NO from the endothelium regulates vascular tone and antagonizes the actions of vasoconstrictor substances. Further, NO possesses anti-platelet actions and down-regulates adhesion molecules that attract inflammatory cells to the endothelium( Deanfield, Halcox et al. 2007 ). The degree of endothelial dysfunction shows a graded response to the number of cardiac risk factors present (Bonetti, Lerman et al. 2003; Davignon and Ganz 2004) and is predictive of clinical events(Bonetti, Lerman et al. 2003; Davignon and Ganz 2004; Deanfield, Halcox et al. 2007 ). Since endothelial dysfunction occurs systemically, the atherosclerotic process involves a large portion of the arterial tree before it becomes clinically manifest ( Deanfield, Halcox et al. 2007 ). Patient presentations to a cardiologist, cardiac surgeon, vascular surgeon or stroke neurologist with clinically manifest atherosclerosis are typically preceded by decades of endothelial dysfunction and depressed vascular repair throughout the entire arterial bed (Ross 1993). The systemic nature of atherosclerosis is highlighted by the fact that >50% of patients with stroke or peripheral vascular disease have co-morbid atherosclerotic coronary disease (Hirsch, Haskal et al. 2006; Brott, Halperin et al. 2011) and patients with manifest disease in multiple arterial beds are at an increased risk of cardiovascular death and recurrent events (Steg, Bhatt et al. 2007). Since the description of circulating marrow cells that repair the endogenous arterial bed, “endothelial progenitor cells” (EPCs), an increasing research interest has been focused on how risk factors impact on the numbers of these cells and their ability to repair the vasculature and maintain endothelial function.
3. Endothelial progenitor cells and atherosclerosis
The modern concept that circulating marrow cells, EPCs, circulate in adult animals and repair the vasculature originates stems from the observation in the late 90s that marrow-derived mononuclear cells circulate in adult animals and directly contribute to neovascularization in animal models of hindlimb ischemia, myocardial infarct remodeling and post-stroke neovascularization (Asahara, Murohara et al. 1997; Asahara, Masuda et al. 1999; Zhang, Zhang et al. 2002; Metharom and Caplice 2007). The clinical relevance of EPC numbers was brought to the forefront cardiovascular risk prognostication when EPC numbers were shown to correlate positively with flow mediated brachial artery reactivity (a measure of endothelial function) and inversely with the Framingham risk score (Hill, Zalos et al. 2003; Ghani, Shuaib et al. 2005; Chironi, Walch et al. 2007). Endothelial dysfunction observed in patients with cardiovascular disease or its risk factors may reflect a depressed ability to “renew” the endothelium from the circulating pool of EPCs which act to restore endothelial function. Indeed, patients with coronary artery disease (CAD) and stroke were shown to have EPC numbers that are reduced when compared to
In addition to absolute EPC numbers, the functional capacity of EPCs in repairing the vasculature is impaired by cardiac risk factors. EPCs harvested from the marrow of human patients with ischemic cardiomyopathy show an impaired capacity to effect neovascularization and incorporate into the vasculature in a mouse hindlimb ischemia model (Heeschen, Lehmann et al. 2004). In a human trial testing the efficacy of EPCs in repairing the coronary vasculature after a re-perfused myocardial infarction, the migratory capacity of EPCs to chemotaxins was the strongest multivariate predictor of reduction in infarct size (Britten, Abolmaali et al. 2003). Reduced EPC migration to chemotaxins and reduced ability of human EPCs to effect neovascularization in animal hindlimbs has also been related to individual cardiovascular risk factors such as increasing age, hypertension, hypercholesterolemia, family history of CAD, smoking and high Framingham risk scores (Vasa, Fichtlscherer et al. 2001; Hill, Zalos et al. 2003; Heeschen, Lehmann et al. 2004; Schmidt-Lucke, Rossig et al. 2005; Wang, Gao et al. 2007). While EPCs can be harvested from bone marrow to treat myocardial ischemia (Britten, Abolmaali et al. 2003) or threatened limb ischemia (Comerota, Link et al. 2010) on an investigational basis, herein we focus on the impact of cardiovascular risk factors on EPCs and the potential utility of measuring EPC numbers for risk assessment in primary and secondary prevention. We discuss the impact of individual risk factors on EPC number with a focus on studies undertaken in human subjects and describe how risk factor control boosts EPC numbers. Each of the discussed risk factors individually suppresses EPC mobilization from the marrow and decreases peripheral survival making EPC number a universal risk factor (Hoenig, Bianchi et al. 2008).
4. Insulin resistance, the metabolic syndrome and diabetes
Diabetes is a risk factor associated with heightened cardiovascular risk and endothelial dysfunction (De Vriese, Verbeuren et al. 2000; III 2002). In some series, diabetes has been associated with the same coronary risk as established coronary disease thereby making it a “coronary artery disease risk-equivalent” (Haffner, Lehto et al. 1998). Diabetics without manifest cardiovascular disease have decreased EPC numbers compared to age-matched controls (Tepper, Galiano et al. 2002) and diabetics with manifest macrovascular disease such as CAD, peripheral vascular disease or stroke have further reduced EPC numbers (Fadini, Miorin et al. 2005; Brunner, Hoellerl et al. 2011). Further, EPCs in diabetics are dysfunctional when compared to EPCs from non-diabetic subjects. The depressed EPC numbers in diabetes are thought to contribute to impaired collateralization of vascular ischemic beds (Waltenberger 2001) and may predispose this group to developing non-healing diabetic ulcers which may be ameliorated by injecting EPCs into ischemic lower limb muscles (Huang, Li et al. 2005). Indeed, among diabetic patients with peripheral vascular disease, EPC numbers correlated negatively with the ankle brachial index and patients with ischemic ulcers had the lowest EPC numbers (Fadini, Miorin et al. 2005). Blood sugar levels are inversely correlated with EPC numbers implying a direct relationship between hyperglycemia and depressed EPC numbers (Fadini, Miorin et al. 2005). In the laboratory, hyperglycemia directly impairs EPC function by impairing the ability of these cells to migrate (Krankel, Adams et al. 2005). Diabetics with good glucose control have higher EPC numbers and more functional EPCs when compared to diabetics with poorly controlled glucose (Churdchomjan, Kheolamai et al. 2010) and treating newly-diagnosed diabetics with secretagogues increases EPC numbers and is associated with a concordant improvement in endothelial function (Kusuyama, Omura et al. 2006; Liao, Chen et al. 2010). Likewise, insulin-sensitizing agents such as pioglitazone or rosiglitazone boost EPC numbers and the increase in EPCs is correlated with the reduction in C-reactive protein and increase in adiponectin (Kusuyama, Omura et al. 2006; Makino, Okada et al. 2008). The inverse relationship between EPC numbers and HbA1c and insulin resistance indices implies that EPC numbers decline in pre-diabetic states such as the metabolic syndrome and insulin resistance (Tepper, Galiano et al. 2002; Penno, Pucci et al. 2011). Indeed, EPC numbers decrease as more metabolic syndrome criteria are met ( Fadini, de Kreutzenberg et al. 2006 ; Jialal, Devaraj et al. 2010) and are also decreased in other pre-diabetic states such as gestational diabetes (Penno, Pucci et al. 2011) or the polycystic ovarian syndrome (Dessapt-Baradez, Reza et al. 2011). Given that EPC numbers repair the vasculature and maintain endothelial dysfunction, this decreased capacity for repair of the vasculature may provide a mechanism for the increased risk of cardiovascular events observed in patients with the metabolic syndrome (Mottillo, Filion et al. 2010).
5. Gender and age
Age and male gender are irreversible cardiovascular risk factors. Healthy middle-aged women have higher EPC numbers than men ( Hoetzer, MacEneaney et al. 2007 ). Young men have similar EPC numbers as post-menopausal women and this may explain why men are prone to cardiovascular disease at a younger age. Women, on average tend to develop cardiovascular disease after menopause with an incidence that equals that of age-matched men 10 years after the menopause. This time in a woman’s life, 10 years after the menopause, is associated with a decrease in EPC numbers and EPC function (Bulut, Albrecht et al. 2007; Rousseau, Ayoubi et al. 2010). This decline in EPC numbers may be due to the lack of estrogen since hyper-estrogenic states (e.g. during ovarian stimulation) have been shown to be associated with an increase in EPC numbers and there is a normal variation with the ovarian cycle (Rousseau, Ayoubi et al. 2010). Hormone replacement therapy can boost EPC numbers in post-menopausal females by 25% (Bulut, Albrecht et al. 2007) and enhance endothelial function (Sanada, Higashi et al. 2003; Kalantaridou, Naka et al. 2006).
Ageing is associated with endothelial dysfunction and dysfunctional EPCs that are more prone to apoptosis and have reduced proliferative capacity (Heiss, Keymel et al. 2005; Kushner, Maceneaney et al. 2011). Further, the elderly are less able to mobilize EPCs in response to ischemic stimuli (Scheubel, Zorn et al. 2003). With ageing, the endothelial progenitor cells have shortened telomeres, which are the repetitive DNA at the ends of chromosomes that protect DNA integrity (Kushner, Van Guilder et al. 2009). Telomere shortening has been described in patients with CAD compared to healthy controls (Ogami, Ikura et al. 2004). Hence, this may provide a mechanism whereby EPCs from elderly individuals are more likely to undergo proliferative senescence and an increased susceptibility to apoptosis which can contribute to decreased EPC numbers. This generally occurs around the age of 55 which is temporally associated with the increased period of cardiovascular risk within a human’s lifetime (Kushner, Van Guilder et al. 2009). Hence, the ability to generate functional EPCs, to rejuvenate the endothelium lining the arteries and maintain endothelial function may be key in the pathogenesis of cardiovascular disease with aging.
6. Hypertension
Hypertension is associated with a doubling in the risk for cardiovascular disease with every 20/10 mmHg increment (Chobanian, Bakris et al. 2003). Hypertension is associated with endothelial dysfunction and decreased EPC numbers and reduced EPC function (Vasa, Fichtlscherer et al. 2001; Umemura, Soga et al. 2008; Schulz, Gori et al. 2011). The treatment of hypertension, specifically with drugs inhibiting the renin-angiotensin system, is associated with increased EPCs whereas the use of other classes of drugs such as calcium antagonists, diuretics, and beta-blockers has not been associated with such effects (Umemura, Soga et al. 2008). Similarly, treatment of diabetics with angiogentinsin receptor blockers boosts EPC numbers (Bahlmann, de Groot et al. 2005). Treating patients with an angiotensin-converting enzyme (ACE) inhibitor such as ramipril has similar effects (Bahlmann, de Groot et al. 2005). Angiotensin II reduces the proliferative capacity of cultured EPCs and induces cell death (Imanishi, Hano et al. 2005). Such observations may explain why drugs such as ACE inhibitors may have beneficial effects that are greater than the observed reduction in blood pressure (Yusuf, Sleight et al. 2000).
7. Dyslipidemia
Hypercholesterolemia is a pivotal cardiovascular risk factor and much there is much focus on treating this risk factor (ATP III 2002). Low density lipoprotein cholesterol (LDL-C) is the primary treatment target in both primary and secondary prevention of cardiovascular disease and there is a log-linear relationship between LDL-C level and CAD risk (ATP III 2002). LDL-C is inversely correlated with EPC number and function in human patients (Chen, Zhang et al. 2004). Statin therapy has been shown to increase EPC numbers and function (Fadini, Albiero et al. 2010; Jaumdally, Goon et al. 2010) and to enhance EPC numbers in response to ischemic stimuli (Spadaccio, Pollari et al. 2010; Hibbert, Ma et al. 2011). The improvement of endothelial function associated with statin use is directly correlated with the increase in EPC numbers and measures of EPC function (Higashi, Matsuoka et al. 2010). Similarly, lipid apheresis for resistant hypercholesterolemia improves EPC function and mobilization (Patschan, Patschan et al. 2009; Ramunni, Brescia et al. 2010). Low high density lipoprotein cholesterol (HDL-C) has been identified as secondary therapeutic target and reconstituted HDL-C infusion improves endothelial function and raises EPC numbers (Nieuwdorp, Vergeer et al. 2008).
8. Inflammatory conditions
Inflammatory conditions such as rheumatoid arthritis (RA) have, relative to traditional risk factors, been only recently associated with an increased cardiovascular risk. Like other cardiovascular risk factors, RA is associated with endothelial dysfunction (Herbrig, Haensel et al. 2006). Patients with RA have a life expectancy that is reduced by 5-10 years and the excess mortality is from cardiovascular disease which is increased roughly 4-fold (Wrigley, Lip et al. 2010). RA is particularly associated with a virulent form of coronary atherosclerosis characterized by high coronary artery calcium scores. However, the patients with RA that are at particular cardiovascular risk are those with active disease and high disease activity scores (Grisar, Aletaha et al. 2005). EPC numbers and EPC proliferative capacity show an inverse correlation with disease activity scores (Grisar, Aletaha et al. 2005; Herbrig, Haensel et al. 2006; Egan, Caporali et al. 2008). The increased risk of cardiovascular events is not limited to RA and has been described in other inflammatory states such as systemic lupus erythematosus (SLE) (Urowitz, Bookman et al. 1976; Roman, Shanker et al. 2003), human immunodeficiency virus (HIV) infection (van Leuven, Sankatsing et al. 2007), inflammatory bowel disease (Danese and Fiocchi 2003) or periodontitis (Mattila, Nieminen et al. 1989). Pre-menopausal women with SLE have a risk of myocardial infarction that is increased a staggering 50-fold compared to healthy controls (Manzi, Meilahn et al. 1997). SLE is associated with impaired EPC function and hence a decreased capacity to repair the endothelium (Deng, Li et al. 2010; Ablin, Boguslavski et al. 2011). Inflammatory conditions are almost universally associated with increased inflammatory markers such as C-reactive protein (CRP) and cytokines such as tumor necrosis factor alpha (TNF-α) which is primarily made by macrophages and inhibits proliferation of repair cells in the body. CRP and TNF-α are directly toxic to EPCs; reducing survival and impairing function (Verma, Kuliszewski et al. 2004; Chen, Zhong et al. 2011). The number of EPCs in patients with inflammatory diseases such as Kawasaki’s disease is inversely correlated with plasma CRP and TNF-α (Xu, Men et al. 2010). Treating inflammatory disease such as RA with steroids or anti-TNF-α therapies boosts EPC numbers and may thus have salutary effects on cardiovascular health (Ablin, Boguslavski et al. 2006; Grisar, Aletaha et al. 2007).
9. Physical activity
A recent meta-analysis has shown that individuals exercising ~150 minutes at moderate intensity have a 14% lower risk of CAD compared to sedentary individuals (Sattelmair, Pertman et al. 2011). There was a dose-response relationship with higher grades of physical activityassociated with proportional reductions in incident CAD. In patients with CAD,exercise-based rehabilitation is associated with a 20% reduction in mortality and a 26% reduction in cardiac mortality (Taylor, Brown et al. 2004). Exercise enhances endothelial function and increases NO bioavailability(Hambrecht, Adams et al. 2003; Green, Maiorana et al. 2004; Higashi and Yoshizumi 2004). Since EPC number is a fundamental determinant of endothelial function, it would be expected that exercise mobilizes EPCs. Indeed, a three month exercise prescription in humans increases EPC numbers and this independent of the effects of exercise on body mass, adiposity, blood pressure or lipids ( Hoetzer, Van Guilder et al. 2007 ). Importantly, the improvement in endothelial function correlated with the increase in the number of circulating EPCs (r=0.81, p<0.001) and the increase in NO synthesis (Steiner, Niessner et al. 2005). This suggests that exercise-induced EPC mobilization enhances vascular repair. Exercise may also halt atherosclerotic disease progression as ascertained in both the coronary and carotid beds(Belardinelli, Paolini et al. 2001; Hambrecht, Walther et al. 2004; Rauramaa, Halonen et al. 2004). While multiple studies have shown exercise to mobilize EPCs,the total amount of physical activity has been associated directly with EPC numbers which is consistent with a dose-response (Adams, Lenk et al. 2004; Sandri, Adams et al. 2005; Luk, Dai et al. 2009). Of great interest is the intensity of exercise required to mobilize EPCs. Most protocols have described symptom-limited exercise testing that is of a vigorous nature (Adams, Lenk et al. 2004; Rehman, Li et al. 2004; Sandri, Adams et al. 2005). While 10 minutes of moderate (~70% of VO2 max) exercise did not increased circulating EPC numbers, 30 minutes of moderate or intense (~80% VO2 max) exercise increased EPC numbers (Laufs, Urhausen et al. 2005).This level of intensity is approximately consistent with guideline recommendations for the secondary prevention of CAD(Smith, Allen et al. 2006).
10. Conclusion: A paradigm for cardiovascular risk assessment
From the above discussion, it is clear that cardiovascular risk factors individually and collectively decrease EPC number and function. This includes traditional risk factors such as age, gender, lipids, hypertension and smoking as well as emerging risk factors such as inflammatory diseases and risk factors that are difficult to quantify such as a family history of vascular disease. Moreover, EPC numbers respond to risk factor modification and thus may provide a dynamic assessment of cardiovascular risk. EPC numbers correlate directly with endothelial function and inversely with Framingham risk score in asymptomatic individuals (Hill, Zalos et al. 2003; Ghani, Shuaib et al. 2005; Chironi, Walch et al. 2007). EPC numbers correlate inversely with the number of vascular beds with subclinical disease in asymptomatic patients (Chironi, Walch et al. 2007) and with cardiovascular disease surrogates such as carotid intima-media thickness after correction for the Framingham risk score and CRP ( Fadini, Coracina et al. 2006 ). We believe that the measurement of EPCs represents a unique opportunity for cardiovascular risk assessment in the primary prevention setting. While patients in the low risk category by traditional risk factors are unlikely to have their risk category altered by EPC measurement, EPC measurement could be of great utility in the asymptomatic patient at intermediate risk of cardiovascular disease. Such a patient could be re-categorized into a low risk category if their EPC count is high or could be deemed suitable for the commencement of medications for risk factor control if the EPC count is low and categorizes the patient at higher risk. Patients who are at high risk by traditional risk-assessment tools or who have established cardiovascular disease would need treatment and would be unlikely to have high EPC counts. This proposed paradigm is illustrated in Figure 1.
The measurement of EPC utilizes flow cytometry which is available in many metropolitan hospitals. The cost of a single EPC count is relatively low costing ~35AUD (30€ or $40USD) if EPCs are defined as CD34+KDR+ cells. However, there are several barriers to the implementation of EPC number as a cardiovascular risk prognosticator. Firstly, there is lack of universal agreement on the surface markers that define EPCs. While most studies define EPCs as CD34+KDR+ cells, others also utilize the AC133 surface marker. We propose that the CD34+KDR+definition should be utilized since EPCnumber measured in this way have predicted cardiovascular events (Schmidt-Lucke, Rossig et al. 2005; Werner, Kosiol et al. 2005; Kunz, Liang et al. 2006; Wang, Gao et al. 2007). The second major barrier to the implementation of EPC number in routine cardiovascular risk assessment is the lack of established “normal” and “at risk” levels. These need to be established from primary prevention cohorts and can be measured retrospectively in one cohort and then validated in another. Thirdly, a set of standards for the measurement of EPC numbers will be required. This would include studies on the normal biological variability of EPC numbers and accepted standards for acceptable intra-measurement and inter-measurement coefficients of variation. However, this marker of cardiovascular risk has many advantages which include integrating cardiovascular risk in a single measurement and followed serially to assess the impact of risk factor modification on cardiovascular risk.
References
- 1.
Ablin J. N. Boguslavski V. et al. 2006 "Effect of anti-TNFalpha treatment on circulating endothelial progenitor cells (EPCs) in rheumatoid arthritis. "79 25 2364 2369 . - 2.
Ablin J. N. Boguslavski V. et al. 2011 "Enhanced adhesive properties of endothelial progenitor cells (EPCs) in patients with SLE ."31 6 773 778 . - 3.
Adams V. Lenk K. et al. 2004 "Increase of Circulating Endothelial Progenitor Cells in Patients with Coronary Artery Disease After Exercise-Induced Ischemia. " Arterioscler Thromb Vasc Biol24 4 684 690 . - 4.
Asahara T. Masuda H. et al. 1999 "Bone Marrow Origin of Endothelial Progenitor Cells Responsible for Postnatal Vasculogenesis in Physiological and Pathological Neovascularization. " Circ Res85 3 221 228 . - 5.
Asahara T. Murohara T. et al. 1997 "Isolation of putative progenitor endothelial cells for angiogenesis ."275 5302 964 967 . - 6.
Bahlmann F. H. de Groot K. et al. 2005 "Stimulation of endothelial progenitor cells: a new putative therapeutic effect of angiotensin II receptor antagonists. "45 4 526 529 . - 7.
Belardinelli R. Paolini I. et al. 2001 "Exercise training intervention after coronary angioplasty: the ETICA trial. " J Am Coll Cardiol37 7 1891 1900 . - 8.
Bonetti P. O. Lerman L. O. et al. 2003 "Endothelial Dysfunction: A Marker of Atherosclerotic Risk. " Arterioscler Thromb Vasc Biol23 2 168 175 . - 9.
Britten M. B. Abolmaali N. D. et al. 2003 "Infarct Remodeling After Intracoronary Progenitor Cell Treatment in Patients With Acute Myocardial Infarction (TOPCARE-AMI): Mechanistic Insights From Serial Contrast-Enhanced Magnetic Resonance Imaging. "108 18 2212 2218 . - 10.
Brott T. G. Halperin J. L. et al. 2011 "2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery ." . - 11.
Brunner S. Hoellerl F. et al. 2011 "Circulating Angiopoietic Cells and Diabetic Retinopathy in Type 2 Diabetes Mellitus, with or without Macrovascular Disease. "52 7 4655 4662 . - 12.
Bulut D. Albrecht N. et al. 2007 "Hormonal status modulates circulating endothelial progenitor cells ."96 5 258 263 . - 13.
Chen J. Z. Zhang F. R. et al. 2004 "Number and activity of endothelial progenitor cells from peripheral blood in patients with hypercholesterolaemia ."107 3 273 280 . - 14.
Chen T. G. Zhong Z. Y. et al. 2011 "Effects of tumour necrosis factor-alpha on activity and nitric oxide synthase of endothelial progenitor cells from peripheral blood. "44 4 352 359 . - 15.
Chironi G. Walch L. et al. 2007 "Decreased number of circulating CD34+KDR+ cells in asymptomatic subjects with preclinical atherosclerosis ."191 1 115 120 . - 16.
Chobanian A. V. Bakris G. L. et al. 2003 "Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. "42 6 1206 1252 . - 17.
Churdchomjan W. Kheolamai P. et al. 2010 "Comparison of endothelial progenitor cell function in type 2 diabetes with good and poor glycemic control. " 10:5. - 18.
Comerota A. J. Link A. et al. 2010 "Upper extremity ischemia treated with tissue repair cells from adult bone marrow ." : official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter52 3 723 729 . - 19.
Danese S. Fiocchi C. 2003 "Atherosclerosis and inflammatory bowel disease: sharing a common pathogenic pathway? " 107(7):e52 . - 20.
Davignon J. Ganz P. 2004 "Role of Endothelial Dysfunction in Atherosclerosis. " 109(23_suppl_1): III-27-32. - 21.
De Vriese A. S. Verbeuren T. J. et al. 2000 "Endothelial dysfunction in diabetes ."130 5 963 974 . - 22.
Deanfield J. E. Halcox J. P. et al. 2007 "Endothelial Function and Dysfunction: Testing and Clinical Relevance. "115 10 1285 1295 . - 23.
Deanfield J. E. Halcox J. P. et al. 2007 "Endothelial function and dysfunction: testing and clinical relevance. "115 10 1285 1295 . - 24.
Deng X. L. Li X. X. et al. 2010 "Comparative study on circulating endothelial progenitor cells in systemic lupus erythematosus patients at active stage ."30 11 1429 1436 . - 25.
Dessapt-Baradez C. Reza M. et al. 2011 "Circulating vascular progenitor cells and central arterial stiffness in polycystic ovary syndrome. " 6(5):e20317 . - 26.
Egan C. G. Caporali F. et al. 2008 "Endothelial progenitor cells and colony-forming units in rheumatoid arthritis: association with clinical characteristics ."47 10 1484 1488 . - 27.
Fadini G. P. Albiero M. et al. 2010 "Rosuvastatin stimulates clonogenic potential and anti-inflammatory properties of endothelial progenitor cells ."34 7 709 715 . - 28.
Fadini G. P. Coracina A. et al. 2006 "Peripheral Blood CD34+KDR+ Endothelial Progenitor Cells Are Determinants of Subclinical Atherosclerosis in a Middle-Aged General Population." Stroke37 9 2277 2282 . - 29.
Fadini G. P. de Kreutzenberg S. V. et al. 2006 "Circulating CD34+ cells, metabolic syndrome, and cardiovascular risk. " Eur Heart J27 18 2247 2255 . - 30.
Fadini G. P. Miorin M. et al. 2005 "Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. "45 9 1449 1457 . - 31.
Furchgott R. F. 1996 "The 1996 Albert Lasker Medical Research Awards. The discovery of endothelium-derived relaxing factor and its importance in the identification of nitric oxide. " Jama276 14 1186 1188 . - 32.
Ghani U. Shuaib A. et al. 2005 "Endothelial Progenitor Cells During Cerebrovascular Disease ."36 1 151 153 . - 33.
Green D. J. Maiorana A. et al. 2004 "Effect of exercise training on endothelium-derived nitric oxide function in humans. " J Physiol 561(Pt 1)1 25 . - 34.
Grisar J. Aletaha D. et al. 2007 "Endothelial progenitor cells in active rheumatoid arthritis: effects of tumour necrosis factor and glucocorticoid therapy. "66 10 1284 1288 . - 35.
Grisar J. Aletaha D. et al. 2005 "Depletion of endothelial progenitor cells in the peripheral blood of patients with rheumatoid arthritis. "111 2 204 211 . - 36.
Haffner S. M. Lehto S. et al. 1998 "Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. "339 4 229 234 . - 37.
Hambrecht R. Adams V. et al. 2003 "Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. "107 25 3152 3158 . - 38.
Hambrecht R. Walther C. et al. 2004 "Percutaneous Coronary Angioplasty Compared With Exercise Training in Patients With Stable Coronary Artery Disease: A Randomized Trial. "109 11 1371 1378 . - 39.
Heeschen C. Lehmann R. et al. 2004 "Profoundly Reduced Neovascularization Capacity of Bone Marrow Mononuclear Cells Derived From Patients With Chronic Ischemic Heart Disease. "109 13 1615 1622 . - 40.
Heidenreich P. A. Trogdon J. G. et al. 2011 "Forecasting the Future of Cardiovascular Disease in the United States: A Policy Statement From the American Heart Association ."123 8 933 944 . - 41.
Heiss C. Keymel S. et al. 2005 "Impaired progenitor cell activity in age-related endothelial dysfunction. "45 9 1441 1448 . - 42.
Herbrig K. Haensel S. et al. 2006 "Endothelial dysfunction in patients with rheumatoid arthritis is associated with a reduced number and impaired function of endothelial progenitor cells. "65 2 157 163 . - 43.
Hibbert B. Ma X. et al. 2011 "Pre-procedural atorvastatin mobilizes endothelial progenitor cells: clues to the salutary effects of statins on healing of stented human arteries. " 6(1):e16413 . - 44.
Higashi Y. Matsuoka H. et al. 2010 "Endothelial function in subjects with isolated low HDL cholesterol: role of nitric oxide and circulating progenitor cells ." . Endocrinology and metabolism 298(2):E202 209 . - 45.
Higashi Y. Yoshizumi M. 2004 "Exercise and endothelial function: role of endothelium-derived nitric oxide and oxidative stress in healthy subjects and hypertensive patients. " Pharmacol Ther102 1 87 96 . - 46.
Hill J. M. Zalos G. et al. 2003 "Circulating Endothelial Progenitor Cells, Vascular Function, and Cardiovascular Risk. " N Engl J Med348 7 593 600 . - 47.
Hirsch A. T. Haskal Z. J. et al. 2006 "ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic) : a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation." 113(11):e463 654 . - 48.
Hoenig M. R. Bianchi C. et al. 2008 "Hypoxia inducible factor-1 alpha, endothelial progenitor cells, monocytes, cardiovascular risk, wound healing, cobalt and hydralazine: a unifying hypothesis. "9 5 422 435 . - 49.
Hoetzer G. L. MacEneaney O. J. et al. 2007 "Gender differences in circulating endothelial progenitor cell colony-forming capacity and migratory activity in middle-aged adults ."99 1 46 48 . - 50.
Hoetzer G. L. Van Guilder G. P. et al. 2007 "Aging, exercise, and endothelial progenitor cell clonogenic and migratory capacity in men ." J Appl Physiol102 3 847 852 . - 51.
Huang P. Li S. et al. 2005 "Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. "28 9 2155 2160 . - 52.
III. A. T. P. 2002 "Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. "106 25 3143 3421 . - 53.
Imanishi T. Hano T. et al. 2005 "Angiotensin II accelerates endothelial progenitor cell senescence through induction of oxidative stress. "23 1 97 104 . - 54.
Jaumdally R. J. Goon P. K. et al. 2010 "Effects of atorvastatin on circulating CD34+/CD133+/ CD45- progenitor cells and indices of angiogenesis (vascular endothelial growth factor and the angiopoietins 1 and 2) in atherosclerotic vascular disease and diabetes mellitus ."267 4 385 393 . - 55.
Jialal I. Devaraj S. et al. 2010 "Decreased number and impaired functionality of endothelial progenitor cells in subjects with metabolic syndrome: implications for increased cardiovascular risk ."211 1 297 302 . - 56.
Kalantaridou S. N. Naka K. K. et al. 2006 "Premature ovarian failure, endothelial dysfunction and estrogen-progestogen replacement ." Trends in endocrinology and metabolism: TEM17 3 101 109 . - 57.
Krankel N. Adams V. et al. 2005 "Hyperglycemia reduces survival and impairs function of circulating blood-derived progenitor cells. " , thrombosis, and vascular biology25 4 698 703 . - 58.
Kunz G. A. Liang G. et al. 2006 "Circulating endothelial progenitor cells predict coronary artery disease severity ."152 1 190 195 . - 59.
Kushner E. J. Maceneaney O. J. et al. 2011 "Aging Is Associated with a Proapoptotic Endothelial Progenitor Cell Phenotype ."48 5 408 414 . - 60.
Kushner E. J. Van Guilder G. P. et al. 2009 "Aging and endothelial progenitor cell telomere length in healthy men ." : CCLM / FESCC47 1 47 50 . - 61.
Kusuyama T. Omura T. et al. 2006 "Effects of treatment for diabetes mellitus on circulating vascular progenitor cells. "102 1 96 102 . - 62.
Lambiase P. D. Edwards R. J. et al. 2004 "Circulating Humoral Factors and Endothelial Progenitor Cells in Patients With Differing Coronary Collateral Support. "109 24 2986 2992 . - 63.
Laufs U. Urhausen A. et al. 2005 "Running exercise of different duration and intensity: effect on endothelial progenitor cells in healthy subjects. " Eur J Cardiovasc Prev Rehabil12 4 407 414 . - 64.
Liao Y. F. Chen L. L. et al. 2010 "Number of circulating endothelial progenitor cells as a marker of vascular endothelial function for type 2 diabetes ."15 4 279 285 . - 65.
Luk T. H. Dai Y. L. et al. 2009 "Habitual physical activity is associated with endothelial function and endothelial progenitor cells in patients with stable coronary artery disease ." : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology16 4 464 471 . - 66.
Makino H. Okada S. et al. 2008 "Pioglitazone treatment stimulates circulating CD34-positive cells in type 2 diabetes patients ."81 3 327 330 . - 67.
Manzi S. Meilahn E. N. et al. 1997 "Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. "145 5 408 415 . - 68.
Mattila K. J. Nieminen M. S. et al. 1989 "Association between dental health and acute myocardial infarction. "298 6676 779 781 . - 69.
Metharom P. Caplice N. M. 2007 "Vascular disease: a new progenitor biology. "5 1 61 68 . - 70.
Mottillo S. Filion K. B. et al. 2010 "The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. "56 14 1113 1132 . - 71.
Nieuwdorp M. Vergeer M. et al. 2008 "Reconstituted HDL infusion restores endothelial function in patients with type 2 diabetes mellitus ."51 6 1081 1084 . - 72.
Ogami M. Ikura Y. et al. 2004 "Telomere shortening in human coronary artery diseases. " , thrombosis, and vascular biology24 3 546 550 . - 73.
Patschan D. Patschan S. et al. 2009 "LDL lipid apheresis rapidly increases peripheral endothelial progenitor cell competence ."24 5 180 185 . - 74.
Penno G. Pucci L. et al. 2011 "Circulating endothelial progenitor cells in women with gestational alterations of glucose tolerance. " . - 75.
Ramunni A. Brescia P. et al. 2010 "Effect of low-density lipoprotein apheresis on circulating endothelial progenitor cells in familial hypercholesterolemia ."29 4 383 389 . - 76.
Rauramaa R. Halonen P. et al. 2004 "Effects of Aerobic Physical Exercise on Inflammation and Atherosclerosis in Men: The DNASCO Study: A Six-Year Randomized, Controlled Trial. " Ann Intern Med140 12 1007 1014 . - 77.
Rehman J. Li J. et al. 2004 "Exercise acutely increases circulating endothelial progenitor cells and monocyte-/macrophage-derived angiogenic cells. " J Am Coll Cardiol43 12 2314 2318 . - 78.
Roger V. L. Go A. S. et al. 2011 "Heart disease and stroke statistics--2011 update: a report from the American Heart Association ." 123(4):e18 e209 . - 79.
Roman M. J. Shanker B. A. et al. 2003 "Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. "349 25 2399 2406 . - 80.
Ross R. 1993 "The pathogenesis of atherosclerosis: a perspective for the 1990s. "362 6423 801 809 . - 81.
Rousseau A. Ayoubi F. et al. 2010 "Impact of age and gender interaction on circulating endothelial progenitor cells in healthy subjects ."93 3 843 846 . - 82.
Sanada M. Higashi Y. et al. 2003 "A comparison of low-dose and standard-dose oral estrogen on forearm endothelial function in early postmenopausal women. "88 3 1303 1309 . - 83.
Sandri M. Adams V. et al. 2005 "Effects of Exercise and Ischemia on Mobilization and Functional Activation of Blood-Derived Progenitor Cells in Patients With Ischemic Syndromes: Results of 3 Randomized Studies. "111 25 3391 3399 . - 84.
Sattelmair J. Pertman J. et al. 2011 "Dose Response Between Physical Activity and Risk of Coronary Heart Disease." Circulation. - 85.
Scheubel R. J. Zorn H. et al. 2003 "Age-dependent depression in circulating endothelial progenitor cells in patients undergoing coronary artery bypass grafting. "42 12 2073 2080 . - 86.
Schmidt-Lucke C. Rossig L. et al. 2005 "Reduced Number of Circulating Endothelial Progenitor Cells Predicts Future Cardiovascular Events: Proof of Concept for the Clinical Importance of Endogenous Vascular Repair. "111 22 2981 2987 . - 87.
Schulz E. Gori T. et al. 2011 "Oxidative stress and endothelial dysfunction in hypertension ." : official journal of the Japanese Society of Hypertension34 6 665 673 . - 88.
Smith S. C. Jr. Allen J. et al. 2006 "AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. "113 19 2363 2372 . - 89.
Spadaccio C. Pollari F. et al. 2010 "Atorvastatin increases the number of endothelial progenitor cells after cardiac surgery: a randomized control study ."55 1 30 38 . - 90.
Steg P. G. Bhatt D. L. et al. 2007 "One-year cardiovascular event rates in outpatients with atherothrombosis. " Jama297 11 1197 1206 . - 91.
Steiner S. Niessner A. et al. 2005 "Endurance training increases the number of endothelial progenitor cells in patients with cardiovascular risk and coronary artery disease. "181 2 305 310 . - 92.
Taylor R. S. Brown A. et al. 2004 "Exercise-based rehabilitation for patients with coronary heart disease: systematic review and meta-analysis of randomized controlled trials. " Am J Med116 10 682 692 . - 93.
Tepper O. M. Galiano R. D. et al. 2002 "Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. "106 22 2781 2786 . - 94.
Umemura T. Soga J. et al. 2008 "Aging and hypertension are independent risk factors for reduced number of circulating endothelial progenitor cells. "21 11 1203 1209 . - 95.
Urowitz M. B. Bookman A. A. et al. 1976 "The bimodal mortality pattern of systemic lupus erythematosus. "60 2 221 225 . - 96.
Valgimigli M. Merli E. et al. 2003 "Endothelial dysfunction in acute and chronic coronary syndromes: evidence for a pathogenetic role of oxidative stress. " Cardiac Ischemia/Reperfusion and Free Radicals420 2 255 261 . - 97.
van Leuven S. I. Sankatsing R. R. et al. 2007 "Atherosclerotic vascular disease in HIV: it is not just antiretroviral therapy that hurts the heart! "2 4 324 331 . - 98.
Vasa M. Fichtlscherer S. et al. 2001 "Number and Migratory Activity of Circulating Endothelial Progenitor Cells Inversely Correlate With Risk Factors for Coronary Artery Disease. " Circ Res 89(1): 1e-7. - 99.
Verma S. Kuliszewski M. A. et al. 2004 "C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease. "109 17 2058 2067 . - 100.
Waltenberger J. 2001 "Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications. "49 3 554 560 . - 101.
Wang H. Y. Gao P. J. et al. 2007 "Circulating endothelial progenitor cells, C-reactive protein and severity of coronary stenosis in Chinese patients with coronary artery disease ." : official journal of the Japanese Society of Hypertension30 2 133 141 . - 102.
Werner N. Kosiol S. et al. 2005 "Circulating Endothelial Progenitor Cells and Cardiovascular Outcomes. " N Engl J Med353 10 999 1007 . - 103.
Wrigley B. J. Lip G. Y. et al. 2010 "Coronary atherosclerosis in rheumatoid arthritis: could endothelial progenitor cells be the missing link? "37 3 479 481 . - 104.
Xu M. G. Men L. N. et al. 2010 "The number and function of circulating endothelial progenitor cells in patients with Kawasaki disease ."169 3 289 296 . - 105.
Yusuf S. Sleight P. et al. 2000 "Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. "342 3 145 153 . - 106.
Zhang Z. G. Zhang L. et al. 2002 "Bone Marrow-Derived Endothelial Progenitor Cells Participate in Cerebral Neovascularization After Focal Cerebral Ischemia in the Adult Mouse. " Circ Res90 3 284 288 .