Mild elevations in serum homocysteine levels are associated with a two-four fold increased risk in myocardial infarctions and are present in over 40-50 percent of individuals with coronary artery disease. The investigators previously observed a defect in nitric oxide-mediated vasodilation in the peripheral vasculature of otherwise healthy humans with mild elevations in homocysteine. More recently, they employed positron emission tomography (PET) and demonstrated that homocysteine acutely impairs coronary microvascular dilation in healthy humans. Lowering homocysteine levels can be readily achieved with folic acid. However, the important question of whether or not lowering homocysteine levels in these individuals reduces the manifestations of coronary artery disease remains unanswered. The proposed series of investigations represent the logical next-step, by investigating the potential benefits of homocysteine-lowering with folic acid.
The first aim of this investigation tests the hypothesis that lowering mild, commonly encountered elevations of serum homocysteine improves coronary microvascular dilation, using PET.
The second aim of this study tests the hypothesis that lowering mildly elevated homocysteine concentrations decreases exercise-induced myocardial ischemia, using exercise stress testing.
The third aim tests the hypothesis that folic acid also acutely improves coronary micro vascular dilation independently of its homocysteine-lowering effects. As such, these investigations would appraise homocysteine's role in contributing to cardiac disease, and would assess whether patients with coronary disease might benefit from homocysteine-lowering with folic acid. In addition to addressing a question of the highest clinical importance, this proposed project would serve as a critical catalyst for the applicant's growth as a junior faculty member of the MGH and Harvard Medical School (HMS). Furthermore, this award would provide the applicant with an invaluable opportunity to advance the skills that are essential for his maturation as a significant contributor to patient oriented clinical research and to the understanding of coronary vascular physiology.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23RR016046-01A1
Application #
6435333
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Wilde, David B
Project Start
2002-05-01
Project End
2007-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
1
Fiscal Year
2002
Total Cost
$129,951
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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Tawakol, Ahmed; Migrino, Raymond Q; Bashian, Gregory G et al. (2006) In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J Am Coll Cardiol 48:1818-24
Tawakol, Ahmed; Castano, Ana P; Anatelli, Florencia et al. (2006) Photosensitizer delivery to vulnerable atherosclerotic plaque: comparison of macrophage-targeted conjugate versus free chlorin(e6). J Biomed Opt 11:021008
Tawakol, Ahmed; Migrino, Raymond Q; Hoffmann, Udo et al. (2005) Noninvasive in vivo measurement of vascular inflammation with F-18 fluorodeoxyglucose positron emission tomography. J Nucl Cardiol 12:294-301
Tawakol, Ahmed; Migrino, Raymond Q; Aziz, Kusai S et al. (2005) High-dose folic acid acutely improves coronary vasodilator function in patients with coronary artery disease. J Am Coll Cardiol 45:1580-4