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Circulating Progenitor Cells and Cardiovascular Disease Arshed A. Quyyumi, MD Professor of Medicine Emory Clinical Cardiovascular Research Institute (ECCRI)

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Presentation on theme: "Circulating Progenitor Cells and Cardiovascular Disease Arshed A. Quyyumi, MD Professor of Medicine Emory Clinical Cardiovascular Research Institute (ECCRI)"— Presentation transcript:

1 Circulating Progenitor Cells and Cardiovascular Disease Arshed A. Quyyumi, MD Professor of Medicine Emory Clinical Cardiovascular Research Institute (ECCRI) Emory University School of Medicine Atlanta, GA

2 Grant support: National Institutes of Health, American Heart Association, Woodruff Fund, Emory Heart and Vascular Center, Sanofi Aventis, Novartis, Lilly, Pfizer, Forest, Amgen, Genzyme Advisory Boards: Amorcyte/Neostem, Genway/Firstmark Soteria Stemedica

3 Circulating progenitor cells CD34+ cell populations Circulating progenitor cells and gender Circulating progenitor cells and ischemic syndromes Circulating progenitor cells and CVD outcomes CD34+ cells as therapy for vascular diseases

4 4 Adult Bone Marrow Stem Cell Plasticity Endodermal Progenitor Cells Bone Marrow Stem Cells Ectodermal Progenitor Cells Mesodermal Progenitor Cells Neural cells Epidermal cells Hepatocytes Hematopoeitic cells Endothelial Progenitor Cells Myocytes (Skeletal) (Cardiac) Osteocytes, Chondrocytes Stromal or Mesenchymal MAPC Blood cells Resident stem cells: Heart, skeletal muscle, Adipose tissue, brain, Lung etc.

5 5 Endothelial Progenitor Cell assays Progenitor Cells Culture Surface Epitopes CD45 med, CD34, CD133, VEGF2R, CXCR4 Direct Culture (CAC) Early Outgrowth (CFU-Hill) 4 days 15 days 5-7 days 0.0001% of circulating Mononuclear cells Endothelial Colony Forming Cells (ECFC)

6 Endothelial Progenitor Cell Colony Formation and Cardiovascular Risk Profile 45 healthy men aged >21 years (mean 50.3 ± 1.7) without cardiovascular diseases EPC-CFU Framingham Risk Score -5j05101520 0 10 20 30 40 50 60 70 r = –.393 P =.008 EPC-CFU = endothelial progenitor cell colony-forming units. Hill JM, et al. N Engl J Med. 2003;13:593-600. Hill, Quyyumi, Finkel N Engl J Med 2003;13:593

7 7 Functional assays for endothelial progenitor cells Senescence: Hill, Quyyumi, Finkel N Engl J Med 2003;13:593

8 8 Relation between endothelium- dependent function and EPCs EPC-CFU Flow mediated dilation –FMD Hill, Quyyumi, Finkel N Engl J Med 2003;13:593 45 Healthy Males, >21 years (mean age 50.3±1.7) without cardiovascular diseases Rest Reactive Hyperemia Flow-mediated vasodilation (FMD) EPC-CFU

9 Risk factors, Vascular Injury, and Regenerative Capacity Risk Factors Endothelial injury Endothelial dysfunction, Arterial stiffness Atherogenesis Vascular Repair Progenitor Cells

10 Circulating progenitor cells CD34+ cell populations Circulating progenitor cells and gender Circulating progenitor cells and ischemic syndromes Circulating progenitor cells and CVD outcomes CD34+ cells as therapy for vascular diseases

11 11 Gated on CD34+ within MNCs Within CD34+ gate, 4 quadrants for marker CD133 and VEGF-2R Gated on MNCs CD45 med Flow Cytometry

12 12 Fluorescent activated cell sorting (FACS) analysis for bone marrow derived progenitor cell populations CD34: Hematopoietic stem cell CD133: Immature progenitors CD133+/VEGF2R+: Differentiates between immature and mature endothelial PCs CD34+/CD133+/VEGF2R+: Presumed ‘EPC’ enriched CXCR4: Epitope that is associated with homing to areas of ischemia that express SDF-1 Peichev M et al Blood 2000; 95:952 Hirschi KK. et al ATVB 2008;28:1584

13 Cell Type: Isolated CD34⁺Cells Most Able to Improve Perfusion, Prevent Apoptosis and Rescue Hibernating Cardiomyocytes 13 Kawamoto et al., Circulation 2006;114;2163-2169 PBS = Phosphate-buffered saline loMNCs = 5x10^5 MNC hiMNCs = contains 5x10^5 CD34 + cells within MNCs CD34+ = 5x10^5 CD34+ cells Capillary Density (perfusion) is greatest in CD34 + cell cohort, and this correlates with decreased incidence of fibrosis. Effect increases with dose. CD34⁺ Cells Exhibit Increased Potency and Safety for Therapeutic Neovascularization after AMI Compared with Total Mononuclear Cells in Nude Rats:

14 Endothelial progenitor cell therapy for acute myocardial infarction Cell types: bone marrow mononuclear cells, CD34+, etc. CD34+ cells constitute 0.1 to 0.2% of bone marrow mononuclear cells FDG labeled bone marrow mononuclear cells and injected intracoronary in post MI patients Uptake of BM mononuclear cells: 1.3 to 2.6% in MI region Uptake of CD34+ cells: 14-39% in MI region BM mononuclear cells CD34+ cells Hofmann et al Circ 2005;111:2198-2202

15 15 Cell Type: Circulating CD34⁺Cell Levels and Migratory Capacity Correlate with Cardiac Function  Circulating CD34 + cell quantity 1 year post MI significantly correlates to LVEF, wall motion score index, end diastolic volume and end systolic volume.  The number of circulating CD34 +, CXCR4 +, CD117 + and c-met+ cells mobilized early (<12 hours) in AMI significantly correlated with LVEF for (P value < 0.004). (1)  In patients with LVEF 40% (p=0.02). (2,3)  Increases in circulating CD34 + cells is due to SDF (not VEGF). (4)  In the TOPCARE-AMI study, the migratory capacity of infused CXCR4 + progenitors induced by SDF-1 was the strongest independent predictor of the reduction of the infarct size assessed by contrast MRI (5) 1.Ceradini et al. Nature Medicine 2004: 10: 858-863 Progenitor Cell Trafficking is regulated by hypoxic gradients through HIF induction of SDF-1 2.Wojciech Wojakowski et al. European Heart Journal 2006; 27: 283-289. Mobilization of CD34+, CD117+, c-met+ stem cells is correlated with left ventricular ejection fraction and plasma NT-proBNP levels in patients with acute myocardial infarction 3.Leone Am, et al. Eur Heart J 2005; 26: 1196-1204 Mobilization of bone marrow derived stem cells after myocardial infarction and left ventricular function 4.Tomoda et al Clin Cardiol 2003: 26: 455-457 Bone Marrow stimulation and left ventricular function in acute myocardial infarction 5.Britten Mb, et al. Circulation 2003: 108; 2122-2218 Remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction

16 16 Fluorescent activated cell sorting (FACS) analysis for progenitor cell populations CD34: Hematopoietic stem cell CD133: Immature progenitors CD133+/VEGF2R+: Differentiates between immature and mature endothelial cells CD34+/CD133+/VEGF2R+: Presumed ‘EPC’ enriched These triple positive cells when CD45+ do not produce ECFCs Only CD34+/CD45- cells from marrow or umbilical cord blood produce ECFCs Cells expressing CD133 do not produce ECFCs Peichev M et al Blood 2000; 95:952 Hirschi KK. et al ATVB 2008;28:1584

17 Circulating progenitor cells CD34+ cell populations Circulating progenitor cells and gender Circulating progenitor cells and ischemic syndromes Circulating progenitor cells and CVD outcomes CD34+ cells as therapy for vascular diseases

18 18

19 19 P for trend = 0.003 r = - 0.421 P = 0.001 Endothelial progenitor enriched populations of circulating mononuclear cells: Intima-media thickness Lower numbers of circulating progenitor cells in subjects with increased arterial thickness

20 20 Relation between digital reactive hyperemia (PAT index) and Progenitor cells 430 subjects Pulsatile arterial tonometry (Endopat Inc.) Reactive hyperemia index (fRHI) Lower numbers of circulating progenitor cells in subjects with reduced digital reactive hyperemia log CD34+ cells log CD34+/CD133+ cells fRHI tertiles P<0.001 P=0.001

21 21 Relation between arterial stiffness and Progenitor cells P=0.001 Log CD34+/CD133+/VEGFR+ cells Augmentation index (tertiles) Log CD34+/VEGFR+ cells P=0.009 P=0.003 430 subjects Arterial Stiffness (SphygmaCor Inc.) Augmentation index Lower numbers of circulating progenitor cells in subjects with increased arterial stiffness Bone Artery Sensor Brachial Blood Pressure SphygmaCor Inc. 140 70 Radial Transfer function Central Aortic 140 70 Arterial Stiffness:

22 Subclinical vascular disease is associated with lower circulating levels of progenitor cells

23 Circulating progenitor cells CD34+ cell populations Circulating progenitor cells and ischemic syndromes Circulating progenitor cells and CVD outcomes CD34+ cells as therapy for vascular diseases

24  90 ACS patients (mean age 65±15 yrs, 73% male, 10% STEMI, 76% NSTEMI, and 13% unstable angina)  Blood samples were obtained at the time of cardiac catheterization for enumeration of CPCs as CD45 dim cells using flow cytometry.  An age- and gender-matched (1:2) cohort of stable CAD patients were randomly selected as a control group Circulating progenitor cells in acute coronary syndromes: comparison with stable CAD

25 * * * *P<0.05 when compared to stable CAD UA NSTEMI STEMI Stable CAD CD34+/VEGF2R+ in CD45 dim (cells/µL) Comparison of VEGF2R-expressing CPCs between stable CAD and ACS categories * *

26 Mental Stress  Standardized public speaking task  Role playing a difficult interpersonal situation where a close relative in a nursing home is being mistreated.  Hemodynamic and electrocardiographic monitoring Mental stressPhysical stress Mental Stress Rest Physical Stress Rest

27 Myocardial Perfusion Study (SPECT) Mental stressPhysical stress Mental Stress Rest Physical Stress Rest Can be induced by lab stressors in a substantial subset of CAD patients Usually silent (asymptomatic) Occurs at lower heart rate threshold than standard exercise testing Often not detected by ECG markers in the laboratory

28 Results  Effect of mental stress on acute mobilization of progenitor cells MS challenge provoked an average 21% increase in the number of circulating CD34+/VEGF2R+/CXCR4+ cells

29  Relationship between progenitor cells and ischemia during mental stress  Patients with mental stress ischemia had higher circulating number of CXCR4-expressing cells at baseline

30 Patients: 160 women enrolled in the WISE-CVD Study with ischemia during stress testing No obstructive CAD Protocol: CFR measured as ratio of hyperemic average peak velocity (APV) in response to intracoronary adenosine to baseline APV Lower CFR with adenosine correlated significantly with higher levels of CD34+, CD34+/CD133+ and CD34+/CXCR4+ cells Circulating Progenitor Cells and Coronary Microvascular Dysfunction: Results from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction (WISE-CVD) Study

31 Patients: 160 women enrolled in the WISE-CVD Study with ischemia during stress testing No obstructive CAD Protocol: Microvascular endothelial function measured as the CBF response to intracoronary acetylcholine (n=48) Lower CBF with acetylcholine correlated significantly with higher CD34+/CXCR4+ and CD34+/VEGF+. Circulating Progenitor Cells and Coronary Microvascular Dysfunction: Results from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction (WISE-CVD) Study

32 Patients: 160 women enrolled in the WISE- CVD Study with ischemia during stress testing No obstructive CAD Protocol: Microvascular endothelial function measured as the CBF response to intracoronary acetylcholine (n=48) Compared to the group with both normal endothelial function (EFx) and CFR, subjects with endothelial dysfunction and abnormal CFR (i.e., MCD) had higher CD34+, CD34+/CD133+ (p=0.004), CD34+/ CXCR4+ and CD34+/ VEGF+ cell counts. Circulating Progenitor Cells and Coronary Microvascular Dysfunction: Results from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction (WISE-CVD) Study

33 ACS is associated with mobilization of VEGF2R and CXCR4 expressing PCs Subjects with microvascular coronary ischemia with reduced flow reserve and endothelial dysfunction have higher circulating PC subsets PC expressing CXCR4, denoting cells with a capacity to home to areas of ischemia, are increased in those who develop ischemia during MS. This suggests that even mild ischemia during daily living may stimulate PC mobilization. Progenitor Cells and ischemic syndromes

34 Circulating progenitor cells CD34+ cell populations Circulating progenitor cells and sub-clinical vascular disease Circulating progenitor cells and ischemic syndromes Circulating progenitor cells and CVD outcomes CD34+ cells as therapy for vascular diseases

35 Risk factors, Vascular Injury, and Regenerative Capacity Risk Factors Endothelial injury Endothelial dysfunction, Arterial stiffness Atherogenesis Vascular Repair Progenitor Cells

36 The Courage Trial Outcomes in Patients with stable CAD End point: Death or AMI All patients had significant angiographic disease No difference between PCI or medical Rx as initial strategy Highly select cohort >10% had death or MI after 2 years despite medical Rx

37 37 Relationship Between circulating Progenitor Cell Counts and Long term CVD outcomes (Death/MI) Patients undergoing coronary angiography: Treated with guideline based therapies 502 patients in a Discovery cohort ; 403 patients in a Validation cohort. Total Pooled 905; age 63yrs; 65% male PCs were enumerated by flow cytometry as CD45 med+ blood mononuclear cells expressing CD34, CD133, VEGFR2 and/or CXCR4 Followed patients in each cohort for a mean of 2.7 & 1.2 years, for the primary endpoint of death or myocardial infarction (MI). 92 death/MI (10%) Higher counts of CD34+ and CD34+/CD133+ cells correlated with: younger age (p<0.001 both), male gender (p=0.04 and p<0.011) higher GFR (p<0.001 both) Higher CD34+/CD133+ also with greater BMI (p<0.001).

38 38 Relationship Between circulating Progenitor Cell Counts and Event Free Survival (Major Events - Death/MI) C statistic improved from 0.713 to 0.752, p=0.024 for CD34/133+ CD34+

39 39 Relationship Between circulating Progenitor Cell Counts and Long term CVD outcomes (Death/MI) Patients undergoing coronary angiography 502 patients in a Discovery cohort ; 403 patients in a Validation cohort. Total Pooled 905; age 63yrs; 65% male PCs were enumerated by flow cytometry as CD45 med+ blood mononuclear cells expressing CD34, CD133, VEGFR2 and/or CXCR4 Followed patients in each cohort for a mean of 2.7 & 1.2 years, for the primary endpoint of death or myocardial infarction (MI). 92 death/MI Cell PopulationOutcomeLow v High ROC CD34+ Death/MI Death CV Death 2.76 (1.65-4.61) 2.60 (1.45-4.66) 2.35 (1.28-4.35) CD34+/133+ Death/MI Death CV Death 2.98 (1.68-5.30) 2.66 (1.40-5.03) 2.49 (1.28-4.86) CD34+/VEGF+ Death/MI Death CV Death 1.01(0.60-1.69) 1.18 (0.65-2.14) 1.34 (0.71-2.50) CD34+/133+/VEGF Death/MI Death CV Death 0.97 (0.59-1.59) 0.83 (0.47-1.47) 0.83(0.45-1.50) CD34+/CXCR4+Death/MI Death CV death 2.50 (1.19-5.23) 2.15 (1.00-4.62) 1.82(0.82-3.96)

40 40 Relationship Between circulating Progenitor Cell Counts and Event Free Survival (Major Events - Death/MI)

41 41 Relationship Between circulating Progenitor Cell Counts and Long term CVD outcomes (Death/MI) Conclusion: Low levels of circulating PCs, defined as co-expression of CD34 and CD133 and CXCR4 epitopes are robustly associated with risk of future death/MI in patients with CAD. Implications; (1)CD34+/CD133+ cells that are enriched for bone marrow-derived hematopoietic and endothelial progenitors, may represent an index of global regenerative potential (2)PCs protect or regenerate damaged endothelium by local or systemic paracrine effects, (3)The predictive value of PCs as risk markers was equal or greater than conventional risk factors such as smoking.

42 Circulating progenitor cells CD34+ cell populations Circulating progenitor cells and gender Circulating progenitor cells and ischemic syndromes Circulating progenitor cells and CVD outcomes CD34+ cells as therapy for vascular diseases

43 Chest pain + STEMI 72 hours pre-admission Stenting + Usual medical Rx SPECT MRI Screening Echo Day 4 Day 5-6 Bone marrow harvest Y Ab with magnetic beads CD34+ cell product Day 6-8 Intracoronary CD34+ cell product infusion Day 7-10 Assessments: Safety Functional Class Holter monitoring Treadmill Cardiac function: MRI, Echo Perfusion: SPECT, MRI AMORCYTE MYOCARDIAL REPAIR STUDY- A Phase I Trial of Intra- Coronary Infusion of Bone Marrow Derived Autologous CD34+ Selected Cells in Patients With Acute Myocardial Infarction. (AMR) Quyyumi AA, Waller EK, et al; Am Heart J. 2011 Jan;161(1):98-105.

44 Mini Bone Marrow Harvest 07 Days post PTCA 304 ml Harvested

45 ISOLEX is a trademark of Baxter International Inc. Progenitor cell Therapeutics, NJ Sterility Pyrogenicity Ex vivo viability

46 Paramagnetic CD34 Positive Cell Selection S S S S S S S S S S S S S Magnet S S S S S S Anti-CD34 mAb Paramagnetic bead SAM Ig antibody MNC Fraction Containing CD34+ Stem Cells Purified CD34+ Cells PR34+ Release Agent S S

47 CD34+ cells are infused via the infarct related artery 6 to 9 days following successful coronary artery stenting. Intracoronary cell therapy trial : bone marrow CD34+ cell injection post acute ST elevation MI (AMR 1) Quyyumi AA, Waller EK, et al; Am Heart J. 2011 Jan;161(1):98-105.

48 Higher Doses of AMR-001 Reduce Hypoperfusion RTSS (Hypo-Perfusion) CohortBase Line6 monthsDelta% Change Control259273.5+14.5+5.6 5 M714.2722.0+7.8+1.1 10 M998.6635.8-362.8-36.4 15 M584.0462.0-122.0-20.9 48 RTSS results show promising changes consistent with hypoperfusion mechanism of action and establish a threshold dose at 10 Million Cells

49 Above Threshold Dose vs. Below Threshold Dose 49 RTSS (Hypo-Perfusion) 6 month BL6 Mo.Δ% Δ Below Threshold 385.4398.1+12.6+3.3 Above Threshold 814.3558.6-255.8 -31.4 (p=0.01)* * change in 10/15 group significant compared to 5M/Control Patients dosed at or above Threshold Dose show significant improvement in perfusion and positive trends in other tests of cardiac function G ROUPS P OOLED : B ELOW T HRESHOLD = 5 & C ONTROL A BOVE T HRESHOLD = 10 & 15 Ejection Fraction 6 month BL6 Mo.Δ%Δ% Δ Below Threshold 51.051.80.7+1.3 Above Threshold 48.252.7+4.5+9.4 End Systolic Volume 6 month BL6 Mo.Δml% Δ Below Threshold 77.781.3+3.6+4.6 Above Threshold 94.188.4-5.7-6.1 Quyyumi AA, Waller EK, et al; Am Heart J. 2011 Jan;161(1):98-105.

50 50 Greater improvement in both perfusion (Resting total severity score) and infarct size in patients given higher total CD34+/SDF-1 mobile cells Bone marrow CD34+ cell injection after STEMI (AMRS 1) CONCLUSIONS Intracoronary infusion of autologous bone marrow CD34+ cells during the repair phase after STEMI at higher doses than previously administered is safe, and may be associated with improved functional recovery from enhanced perfusion to the peri-infarct zone. Quyyumi AA, Waller EK, et al; Am Heart J. 2011 Jan;161(1):98-105.

51 Phase 2 PRESERVE STUDY: Clinical Plan IndicationPost-AMI Preservation of Cardiac Function Primary EndpointsIncreased Cardiac Perfusion (RTSS) measured by SPECT, preservation of LVEF by CMR, and Safety Other EndpointsReduction in cumulative MACE and adverse vascular events at 12 months and 18, 24 and 36 months (recurrent AMI, hospitalization for CHF, cardiac-related death and other vascular events) Dosing FrequencySingle dose Dosing and RandomizationMinimum dose for release >10 M cells Randomized 1:1 treatment to sham placebo control Number of Subjects Principal Investigtor 160 Quyyumi; Emory Number of Sites34 GeographyUnited States Trial Duration 18 months (Perfusion, Cardiac Function, QOL) 24, 30, and 36 months (MACE and other vascular events ) 51

52 Phase 2 PRESERVE STUDY Clinical Trial Process 52 1. Patient presents with chest pain + STEMI, and is assessed via Ventriculography (EF <45%) Day 1 2. Patient receives stenting and usual medical Rx Day 1 - 3 5. Patient Bone Marrow Harvested Day 5-8 6. CD34 +CXCR4 + isolated using patented technology Isolex Day 6-8Day 6-10 7. Intracoronary CD34 +CXCR4 + cell product infusion or media 3. Patient screened, and enrolled in trial if Ejection Fraction (EF) ≤ 48% VentriculographyCMR Day 4 8. Cardiac function measures by SPECT MPI and MRI 6 Months 4. Patient randomized into Treatment or Control RTSS EF ESV EDV 9. Major Adverse Cardiac Events Mortality AMI Admission for CHF Vascular events 12,18, 24,36 Months Day 4

53 PreSERVE AMI Trial Endpoints Primary Endpoint: Perfusion (SPECT –RTSS) Secondary Endpoint: Cardiac Function and Remodeling (CMR), Quality of Life at 6months: MACE and other clinical vascular endpoints (reperfusion, coronary syndrome) at 6, 12, 18, 24 and 36 months Tertiary endpoints: Quality and Quantity of SDF-1 mobile CD34 cells infused and effect

54 PreSERVE AMI Trial Endpoints Primary Endpoint: Perfusion (SPECT –RTSS) Secondary Endpoint: Cardiac Function and Remodeling (CMR), Quality of Life at 6months: MACE and other clinical vascular endpoints (reperfusion, coronary syndrome) at 6, 12, 18, 24 and 36 months Tertiary endpoints: Quality and Quantity of SDF-1 mobile CD34 cells infused and effect

55 Cell Therapy for Peripheral arterial disease

56 Peripheral Arterial Disease Affects 5% of the U.S. population >50 years and >20% of >75 years Causes intermittent claudication, rest pain, ulceration, gangrene, amputation Treatment options ► Antiplatelet Agents ► Exercise ► Smoking Cessation ► Statins and ACE inhibitors ► Cilostazol ► Pentoxifylline ► Revascularization

57 Investigate the effects of incremental doses of s.c. GM-CSF on: Safety: Adverse effects Hematological Immune Constitutional Markers of inflammation Efficacy: Exercise duration Calf blood flow Ankle-brachial index Questionnaire Mechanisms: Mobilization of endothelial progenitor cells Endothelial function G-PAD1: Mobilization of endothelial progenitor cells with GM-CSF in PAD Subramaniyam V AHJ 2009; 158:53

58 Double-blind placebo controlled design Dose escalation study Forty-five subjects 3 cohorts of 15 subjects each 2:1 randomization within each group (drug:placebo) Randomly assigned to treatment with GM-CSF at 3, 6 or 10 µg/kg 3 times a week for 2 weeks or placebo in double-blinded manner Followed for 3 months Mobilization of endothelial progenitor cells with GM-CSF in PAD Subramaniyam V AHJ 2009; 158:53

59 CD34+ Mononuclear Cells +46%, p<0.036 Mobilization of endothelial progenitor cells with GM-CSF in PAD Subramaniyam V AHJ 2009; 158:53

60 Effect on EPC colonies +31%,p<0.026 Mobilization of endothelial progenitor cells with GM-CSF in PAD N=29 N=16 Subramaniyam V, Quyyumi A AHJ 2009(in press)

61 61 GM-CSF Increases Exercise Capacity Pain-free Walking Time +38 sec, p=0.008 Total Walking Time +55 sec, p=0.016 Subramaniyam V AHJ 2009; 158:53

62 62 GM-CSF Improves Endothelium-dependent Vasodilation +59%, p<0.01 Mobilization of endothelial progenitor cells with GM-CSF in PAD Subramaniyam V AHJ 2009; 158:53

63 Repair PCs AtherosclerosisIncidence Age or Risk Factor Years Risk Repair Risk PCs

64 Arshed Quyyumi Riyaz Patel Danny Eapen Nima Ghassemzadeh Ronnie Ramadan Ibhar Al Mheid Girum Mekonnen Joseph Poole Robert Neuman Pankaj Manocha Hatem Kassem Alanna Morris Ayaz Rahman Saurabh Dhawan Salman Sher Ying Liu Nino Kavtaradze Elizabeth Rocco Sherri Mcdonald Cath Lab Attendings and Staff Fellows/ Research Volunteers Acknowledgements Emory Clinical Cardiovascular Research institute  Viola Vaccarino  Emir Veledar  A Maziar Zafari  Laurence Sperling  Edmund Waller  Qunna Li  DeCode Genetics  Dean Jones PhD (Metabolomics)  Charles Searles (miRNA)  Greg Gibson PhD (Transcriptomics)


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