Numbers of endothelial progenitor cells in peripheral blood are similar in younger and older patients with coronary artery disease

Letters to the Editor

References [1] Farrar Jr WE, Kagan IG, Everton FD, Sellers TF. Serologic evidence of human infection with Trypanosoma cruzi in Georgia. Am J Hyg 1963;78:166–72. [2] Rassi Jr A, Rassi A, Rassi SG. Predictors of mortality in chronic Chagas disease: a systematic review of observational studies. Circulation 2007;115:1101–8. [3] Benchimol-Barbosa PR. Noninvasive prognostic markers for cardiac death and ventricular arrhythmia in long-term follow-up of subjects with chronic Chagas' disease. Braz J Med Biol Res 2007;40:167–78. [4] Rassi Jr A, Rassi A, Little WC, et al. Development and validation of a risk score for predicting death in Chagas' heart disease. N Engl J Med 2006;355:799–808. [5] Retondaro FC, Dos Santos Costa PC, Pedrosa RC, Kurtenbach E. Presence of antibodies against the third intracellular loop of the m2 muscarinic receptor in the sera of chronic chagasic patients. FASEB J 1999;13:2015–20. [6] Benchimol-Barbosa PR, Barbosa-Filho J. Atrial mechanical remodeling and new onset atrial fibrillation in chronic Chagas' heart disease. Int J Cardiol 2008;127:e113–5.

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[7] Benchimol-Barbosa PR. The oral transmission of Chagas' disease: an acute form of infection responsible for regional outbreaks. Int J Cardiol 2006;112:132–3. [8] Dias JC. [Notes about of Trypanosoma cruzi and yours bio-ecology characteristics with agents of the transmission by meals]. Rev Soc Bras Med Trop 2006;39:370–5. [9] Perez-Gutierrez E, Agrelo RS, Figueroa R. [Technical recommendation on Chagas' disease epidemiology and prevention, focussing its transmission as a disease transmitted by food]. Rev Soc Bras Med Trop 2006;39:512–4. [10] [Amazon Health Surveillance Foundation announces Chagas disease outbreak] on April 27th, 2007. [In Portuguese]. http://www.saude.am. gov.br/noticias/noticia1.php?id=673. Assessed on August 19th, 2007. [11] Valente SA, Valente VC, Pinto AY, et al. [The Challenge of Chagas' disease in Amazonia] in 59th Annual Meeting of the Sociedade Brasileira para o Progresso da Ciência; 2007. [In Portuguese]. http:// iah.iec.pa.gov.br/iah/fulltext/eventos/palestras/2007/sbpc/aynpinto. pdf. Assessed on August 19th, 2007. [12] Dias JC, Dias E. [Monthly variations of the incidence of the evolution forms of Triatoma infestans and Panstrongylus megistus in the community of Bambui, State of Minas Gerais (II: 1951–1964)]. Mem Inst Oswaldo Cruz 1968;66(2):209–26.

0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.11.053

Numbers of endothelial progenitor cells in peripheral blood are similar in younger and older patients with coronary artery disease Francesco Pelliccia a,c,⁎, Vincenzo Pasceri a , Guido Meoni a , Christian Pristipino a , Cinzia Cianfrocca a,c , Xue Li a , Sebastiano La Rocca a , Giuseppe Rosano b , Giuseppe Mercuro c , Giuseppe Richichi a a

c

Department of Cardiovascular Diseases, San Filippo Neri Hospital, Rome, Italy b Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy Department of Cardiovascular and Neurologic Diseases, University of Cagliari, Cagliari, Italy

Received 17 August 2007; received in revised form 14 November 2007; accepted 14 November 2007 Available online 4 January 2008

Abstract To verify whether subpopulations of endothelial progenitor cells in peripheral blood are different in older and younger patients with coronary artery disease, we studied 30 patients aged 65 to 82 years and 30 matched patients aged 41 to 64 years. Older and younger patients were similar with regard to risk factors, clinical and angiographic characteristics, and medical therapy. Flow cytometric analysis showed that absolute numbers of CD34+, CD133+, CD105+, and CD14+ cells in older patients were not different from those recorded in younger patients and in the control group. In conclusion, aging per se is not associated with reductions in subpopulations of endothelial progenitor cells in patients with coronary artery disease. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Aging; Coronary artery disease; Endothelial progenitor cells

⁎ Corresponding author. Viale Liegi 49, 00198 Rome, Italy. Tel.: +39 06 3306 2504; fax: +39 06 3306 2516. E-mail address: [email protected] (F. Pelliccia).

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Letters to the Editor

Endothelial progenitor cells (EPCs) are a heterologous population of bone marrow-derived cells that play a key role in maintaining homeostasis of the endothelium [1]. The popular concept is that a decrease in circulating EPCs may account for the progression of endothelial dysfunction and atherosclerosis that is commonly seen in the elderly [2], but previous research on the link between EPCs and aging has yielded conflicting results [3]. To verify whether numbers of subpopulations of EPCs in peripheral blood are actually lower in older than younger patients with coronary artery disease, we studied 30 consecutive patients of 65 years or older (21 men and 9 women; mean age: 72 ± 8 years; range: 65–82 years) and 30 sex-matched patients younger than 65 years (21 men and 9 women; mean age: 51 ± 7 years; range: 40–64 years). Patients were included in the study if they had stable effort angina, positive stress test, and indication for coronary angiography. For comparison, a control group of 10 normal subjects of 65 years or older with normal coronary angiography was selected (6 men and 4 women; mean age: 70 ± 5 years; range: 65–80 years). Flow cytometric analysis was performed with a FACS Calibur flow cytometer (Becton Dickinson, California, Table 1 Risk factors, clinical characteristics, quantitative coronary angiographic findings, and medical therapy in younger and older patients Older ≥65 years (n = 30)

Younger b 65 years (n = 30)

P

Risk factors Diabetes mellitus Systemic hypertension Total cholesterol N190 mg/dL Current smoker Family history Previous MI

6 (20%) 17 (57%) 18 (60%) 5 (17%) 6 (20%) 5 (17%)

5 (17%) 15 (50%) 17 (57%) 7 (23%) 8 (27%) 6 (20%)

NS NS NS NS NS NS

Clinical findings CCS anginal class I or II CCS anginal class III or IV LV ejection fraction (%) Creatinine (mg/dL)

19 (63%) 11 (37%) 56 ± 10 1.2 ± 0.5

21 (70%) 9 (30%) 52 ± 11 1.0 ± 0.4

NS NS NS NS

Significant coronary lesions Number of significant stenoses/patient Vessels with ≥1 stenosis N50% • 1-vessel • 2- or 3-vessels Left anterior descending artery Left circumflex artery Right coronary artery

1.39 ± 0.51

1.44 ± 0.57

NS

20 (67%) 10 (33%) 17 (57%) 7 (23%) 12 (40%)

19 (63%) 11 (37%) 15 (50%) 9 (30%) 13 (43%)

NS NS NS NS NS

Drug therapy Aspirin Ticlopidine/clopidogrel Beta-blockers ACE inhibitors Lipid lowering drug

27 (90%) 9 (30%) 19 (63%) 14 (47%) 26 (87%)

25 (83%) 8 (27%) 24 (80%) 17 (57%) 25 (83%)

NS NS NS NS NS NS

CCS: Canadian Cardiovascular Society; LV: left ventricular.

Table 2 Numbers of endothelial progenitor cells in the two groups of patients and in control subjects

White cells (103/mL) Monocytes (103/mL) CD34+ (cells/μL) CD133+ (cells/μL) CD105+ (cells/μL) CD14+ (cells/μL)

Older ≥65 years (n = 30)

Younger b65 years (n = 30)

Controls N65 years (n = 10)

P

5.21 ± 1.41 0.55 ± 0.15 1.22 ± 0.60 0.53 ± 0.29 1.53 ± 0.82 0.67 ± 0.51

5.62 ± 1.51 0.51 ± 0.19 1.34 ± 0.75 0.56 ± 0.38 1.67 ± 0.86 0.55 ± 0.46

5.76 ± 1.35 0.56 ± 0.15 1.05 ± 0.44 0.46 ± 0.25 1.48 ± 0.94 0.48 ± 0.39

NS NS NS NS NS NS

Values are expressed as mean ± standard deviation.

USA). Mononuclear cells were isolated from peripheral venous blood by Ficoll density gradient centrifugation and prepared for fluorescent-activated cell sorting. We used a panel of monoclonal antibodies (anti-CD45, anti-CD34, antiCD133, anti-CD105, anti-CD14, and KDR). Analytical gates were used to enumerate total number and subsets of EPCs. Circulating EPCs were depicted by the lack of expression of CD45 and by the simultaneous expression of at least one marker of endothelial lineage and at least one marker of immaturity (CD34 and/or CD133) [4]. Also, analytical gates were used to enumerate subsets of circulating CD45−/ CD34− cells that expressed the antigen CD105 and the monocytic marker CD14 [5]. The number of EPCs was expressed as the absolute number of cells per 1 μL as whole blood. Older and younger patients were well matched and were similar with regard to risk factors, clinical presentation, quantitative coronary angiographic findings, and medical therapy (Table 1). Hematologic analysis (Table 2) showed that the two groups had similar white cell count, mononuclear cells, and absolute numbers of CD34+, CD133+, CD105+, and CD14+ cells. The results of our study indicate that aging per se is not associated with a decrease in the number of the most relevant subpopulations of EPCs. Aging is thought to be associated with a reduced number of circulating EPCs in patients with coronary artery disease [2], possibly as the result of their accelerated senescence and apoptosis caused by decreased vascular endothelial growth factor and nitric oxide production [3]. Progressive reduction of EPCs with aging, however, might be more correctly ascribed to the cluster of multiple risk factors that usually occurs in older patients and can affect EPCs mobilization and integration in injured vascular sites [1]. This modern concept is supported by the results of our study, as we did not find any significant difference between young and old patients matched for clinical factors in subpopulations of EPCs positive for the markers CD34, CD133, CD105, and CD14. Along with confirming the previous observation that the number of CD34+ cells is similar in young and older patients [3], our findings provide the first evidence that the elderly do not suffer from any decrease in the subpopulation of EPCs able to promote vasculogenesis and microvascular development [5].

Letters to the Editor

The clinical implications of these novel data appear relevant from a therapeutic point of view. Rather than testing potentially dangerous drugs to increase levels of circulating EPCs in the elderly [6], physicians should maximize their efforts in reducing the burden of cardiovascular risk factors, as they play a more proven role than stem cells in the development of coronary artery disease.

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References [1] Shantsila E, Watson T, Lip GY. Endothelial progenitor cells in cardiovascular disorders. J Am Coll Cardiol 2007;49:741–52. [2] Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 2003;108:457–63. [3] Heiss C, Keymel S, Niesler U, et al. Impaired progenitor cell activity in age-related endothelial dysfunction. J Am Coll Cardiol 2005;45:1441–8. [4] Fadini GP, de Kreutzenberg SV, Coracina A, et al. Circulating CD34+ cells, metabolic syndrome, and cardiovascular risk. Eur Heart J 2006;27: 2247–55.

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Coronary artery stenting in patients treated by clopidogrel without aspirin David Rott a,⁎, David Leibowitz a , Guy Amit b , Doron Zahger b , A. Teddy Weiss a a

Department of Medicine, Hadassah-Hebrew University Medical Center, Mt. Scopus, Jerusalem, Israel b Department of Cardiology, Soroka Medical Center, Beer-Sheva, Israel Received 8 September 2007; accepted 18 November 2007 Available online 21 February 2008

Abstract Background: Combined therapy with aspirin and clopidogrel is currently the standard treatment for patients undergoing coronary artery stenting. Some stented patients do not tolerate aspirin and are treated by clopidogrel only, the risk of major adverse clinical events (MACE) in such patients is unclear. Objective: To assess the risk of MACE in stented patients treated by clopidogrel only. Methods: We reviewed records of consecutive patients who underwent bare metal coronary stenting between 1999 and 2004, looking for patients that were treated by clopidogrel without aspirin. Our search revealed 43 such patients with adequate clinical follow-up for at least 1 year following the procedure. We collected information regarding stent thrombosis, acute MI, death or repeat PCI. Results: Two patients (4.7%) were admitted due to acute MI within 30 days of stenting. Stent thrombosis was documented by coronary angiography and target vessel revascularization was performed. Conclusions: Clopidogrel as a sole anti-platelet treatment after coronary stenting resulted in a relatively high percentage of subacute stent thrombosis. Even higher percentages may be expected when using drug eluting stents. More aggressive anti-platelet therapy may be needed in patients who cannot tolerate aspirin. PTCA alone may be preferable to stenting in such patients. © 2007 Elsevier Ireland Ltd. All rights reserved. Keyword: Clopidogrel; Aspirin; Stent

1. Introduction Combined anti-platelet therapy with aspirin and clopidogrel is currently the standard treatment for patients undergoing coronary artery stenting, in order to minimize the risk for stent thrombosis [1]. Some stented patients however, do ⁎ Corresponding author. Department of Medicine, Hadassah-Hebrew University Medical Center, Mt. Scopus, P.O. Box 24035, Jerusalem 91240, Israel. Tel.: +972 2 5844111; fax: +972 2 5817360. E-mail address: [email protected] (D. Rott).

not tolerate aspirin and therefore are treated by clopidogrel only; the risk of major adverse clinical events (MACE) in such patients is unclear. The aim of the current study was to assess the risk of MACE in patients treated by clopidogrel only following coronary stent placement. 2. Methods We reviewed medical records of two institutions looking for patients who underwent bare metal coronary stenting