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Jacob Joseph, MD Veterans Affairs Healthcare System- Boston and Boston University

Safety and effectiveness of granulocyte-colony stimulating factor in advanced chronic heart failure. Jacob Joseph, MD Veterans Affairs Healthcare System- Boston and Boston University. Am J Cardiol 2006; 97: 681-684. Activated homing signals Better mobilization Poor vascularity

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Jacob Joseph, MD Veterans Affairs Healthcare System- Boston and Boston University

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  1. Safety and effectiveness of granulocyte-colony stimulating factor in advanced chronic heart failure Jacob Joseph, MD Veterans Affairs Healthcare System- Boston and Boston University Am J Cardiol 2006; 97: 681-684

  2. Activated homing signals Better mobilization Poor vascularity Less electrical heterogeneity if successful myocardial regeneration Safety (Collagenolysis due to neutrophil proteases) Weak homing signals Less mobilization Better myocardial milieu Significant electrical heterogeneity Safety (electrical heterogeneity, neutrophil mobilization) Stem cell mobilization inAMI vs CHF

  3. Rationale for a phase I study of G-CSF in advanced heart failure • Stem cells may not be adequately mobilized in advanced heart failure • Bone Marrow Hypoperfusion • Cytokines • Microscopic myocardial injury (ongoing myocyte necrosis with replacement fibrosis due to neurohormonal stimulation and ischemia) may produce homing of stem cells • Safety issues unknown

  4. Escalating Dose Protocol

  5. Inclusion and Exclusion Criteria INCLUSION • Age ≥ 18 years; NYHA III or IV; LVEF < 35% • Background treatment with standard therapy for heart failure ≥ 3 months • ICD in situ EXCLUSION • Unstable ischemic syndrome • Stroke or transient ischemic attacks within last 3 months • Severe organ dysfunction/illnesses limiting survival ≤ 6 months

  6. Study Protocol

  7. Endpoints Primary endpoint • CD 34+ cells above 10 cells/microliter Secondary endpoints • Lack of significant changes (twice baseline measurements) in laboratory parameters during the entire study (safety endpoint) • Increase in LVEF at 9 months • Changes in cytokine levels

  8. Baseline Characteristics

  9. Hematologic parameters

  10. CD 34+ cell mobilization

  11. CD34+ cell mobilization vs. WBC increase

  12. Side Effects

  13. Effects on LV structure and function

  14. Cytokines in Heart failure • Proinflammatory cytokine levels are increased in heart failure • IL-6 and TNF alpha • Anti-inflammatory cytokines are decreased in advanced chronic heart failure • IL-10 and IL-10/TNF ratio • IL-10/TNF alpha ratio correlates with response to treatment of CHF • Clin Sci 2003; 105: 45-50; Eur Heart J 2003; 24: 2186-2196

  15. Mean cytokine levels in study patients

  16. Conclusions • A low dose of GCSF (5 mg/kg/day) for 5 days can safely mobilize stem cells in advanced systolic heart failure • WBC counts should be monitored for safety • GCSF-induced stem cell mobilization may result in favorable long term effects on left ventricular function, especially in ischemic heart failure • GCSF has a favorable effect on cytokine profile

  17. Future directions • Could there be differences in response of ischemic vs. non-ischemic cardiomyopathy? • What is the optimal frequency of repeated cycles of GCSF? • What is the role of cytokine modulation by GCSF mobilized cells? • What is the mechanism of and clinical predictors of improvement in LV function?

  18. Acknowledgements • Asem Rimawi, MD • Jawahar L .Mehta, MD, PhD • Paulette Mehta, MD • Michele Cottler-Fox, MD

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