The applicant's professional career demonstrates a long-term committment to patient-oriented research, extensive experience in the study of the role of the vascular endothelium in the regulation of peripheral vasomotor tone in patients with heart failure, and a strong record in mentoring fellows for careers in patient-oriented research. The Division of Circulatory Physiology at Columbia has committed to protect 50 percent of the applicant's time for grant-supported research. The applicant's research efforts are further supported by the Department of Medicine and ongoing NIH and AHA grants. This Midcareer Investigator Award in Patient-Oriented Research will provide support to expand ongoing research efforts into new directions and create a comprehensive mentoring program for young clinical investigators. The overall aim of this research proposal is to characterize the pathophysiology of endothelial dysfunction in heart failure in order to devise new therapeutic strategies for the treatment of heart failure. Preliminary data demonstrate that endothelial function can be assessed non-invasively by measurement of flow-mediated vasodilation (venous occlusion plethysmography and Doppler ultrasongography) and by measurement of nitric oxide synthesis (stable isotope tracer techniques with 15N-L-arginine and measurement of nitric oxide in exhaled gases), that endothelial dysfunction in heart failure is partly attributable to a diffusable factor present in the serum, and that endothelial dysfunction may be linked to increased oxidative stress. We now propose 1) to characterize the prevalence, natural history, and prognostic implications of endothelial dysfunction in heart failure; 2) to characterize the effects of the diffusable serum factor present in patients with heart failure in cultured endothelial cells; and 3) to determine whether specific antioxidant therapies can reverse endothelial dysfunction in patients with heart failure. The mentoring program will consist of three key components: 1) intensive practical training in patient-oriented research (participation in the protocols described in this research plan and creation of an independent research project); 2) Columbia University didactic programs on clinical trial design, data analysis in clinical research, grant writing, and ethical issues in clinical research; 3) ongoing review of trainee progress by a committee of internationally-recognized patient-oriented research experts at Columbia.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Special Emphasis Panel (ZHL1-CSR-F (F1))
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Jelani, Qurat-ul-ain; Katz, Stuart D (2010) Treatment of anemia in heart failure: potential risks and benefits of intravenous iron therapy in cardiovascular disease. Cardiol Rev 18:240-50
Tang, Yi-Da; Hasan, Faisal; Giordano, Frank J et al. (2009) Effects of recombinant human erythropoietin on platelet activation in acute myocardial infarction: results of a double-blind, placebo-controlled, randomized trial. Am Heart J 158:941-7
Tang, Yi-Da; Dewland, Thomas A; Wencker, Detlef et al. (2009) Post-exercise heart rate recovery independently predicts mortality risk in patients with chronic heart failure. J Card Fail 15:850-5
Zheng, Haoyi; Patel, Milan; Cable, Ritchard et al. (2007) Insulin sensitivity, vascular function, and iron stores in voluntary blood donors. Diabetes Care 30:2685-9
Tang, Yi-Da; Rinder, Henry M; Katz, Stuart D (2007) Effects of recombinant human erythropoietin on antiplatelet action of aspirin and clopidogrel in healthy subjects: results of a double-blind, placebo-controlled randomized trial. Am Heart J 154:494.e1-7
Dewland, Thomas A; Androne, Ana Silvia; Lee, Forrester A et al. (2007) Effect of acetylcholinesterase inhibition with pyridostigmine on cardiac parasympathetic function in sedentary adults and trained athletes. Am J Physiol Heart Circ Physiol 293:H86-92
Androne, Ana Silvia; Hryniewicz, Katarzyna; Hudaihed, Alhakam et al. (2006) Comparison of metabolic vasodilation in response to exercise and ischemia and endothelium-dependent flow-mediated dilation in African-American versus non-African-American patients with chronic heart failure. Am J Cardiol 97:685-9
Katz, Stuart D; Hryniewicz, Katarzyna; Hriljac, Ingrid et al. (2005) Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation 111:310-4
Hryniewicz, Katarzyna; Dimayuga, Clarito; Hudaihed, Alhakam et al. (2005) Inhibition of angiotensin-converting enzyme and phosphodiesterase type 5 improves endothelial function in heart failure. Clin Sci (Lond) 108:331-8
Zheng, Haoyi; Cable, Ritchard; Spencer, Bryan et al. (2005) Iron stores and vascular function in voluntary blood donors. Arterioscler Thromb Vasc Biol 25:1577-83

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