Low-dose (7 to 14 Gy) endovascular irradiation (brachytherapy) has been shown to be effective in animal models, for inhibiting the formation of proliferative neointimal lesions after vascular injury. At higher radiation doses (greater than or equal to 28 Gy) an inhibition of negative remodeling or chronic vessel constriction is also seen. Such findings have prompted several clinical trials of vascular brachytherapy for prevention of restenosis after balloon angioplasty and endovascular stenting; preliminary results available in some studies have documented a reduction in restenosis rate. While the suppression of vascular cell cycling has been suggested as one mechanism for the inhibition of neointima, the effects of radiation on arterial cellular functions and the response to vascular injury are still poorly understood. The purpose of the proposed investigation is to study effects of endovascular ionizing radiation on arterial cell, molecular, and physiologic mechanisms regulating: 1) potential changes in functional aspects of arterial biology consequent to ionizing radiation in the presence and absence of angioplasty injury, especially a) vasomotor reactivity and b) thrombogenicity of the luminal surface; and 2) alterations in extracellular matrix content which would influence vessel integrity and architecture. These studies will employ a relevant animal model system, with defined physiologic and pathologic outcomes. With respect to arterial healing events, influences of brachytherapy on thrombosis, re-endothelialization, and extracellular matrix composition will be examined. Determinants of vasomotor function will also be assessed, including effects of brachytherapy on superoxide production, endothelium-dependent and -independent relaxation responses, and nitric oxide synthesis. These studies will therefore determine, using an established pig coronary artery model system, the role of endovascular irradiation in modifying key functional and structural components of the coronary arteries in the presence and absence of a balloon catheter- induced arterial injury and healing response analogous to restenosis. The investigations will thus help fill crucial missing gaps in our knowledge about the new technique of endovascular brachytherapy for restenosis prevention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL060184-01
Application #
2602850
Study Section
Radiation Study Section (RAD)
Project Start
1998-06-01
Project End
2003-05-30
Budget Start
1998-06-01
Budget End
1999-05-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Li, Jinsheng; De Leon, Hector; Ueno, Takafumi et al. (2003) Vasomotor function of pig coronary arteries after chronic coronary occlusion. J Cardiovasc Pharmacol 41:600-8
Li, Jinsheng; De Leon, Hector; Ebato, Bunken et al. (2002) Endovascular irradiation impairs vascular functional responses in noninjured pig coronary arteries. Cardiovasc Radiat Med 3:152-62
Robinson, K A (2001) Preclinical cardiovascular research projects and capabilities at the Atlanta Cardiovascular Research Institute. J Med Assoc Ga 90:27-31
Coussement, P K; de Leon, H; Ueno, T et al. (2001) Intracoronary beta-radiation exacerbates long-term neointima formation in balloon-injured pig coronary arteries. Circulation 104:2459-64
Salame, M Y; Verheye, S; Mulkey, S P et al. (2000) The effect of endovascular irradiation on platelet recruitment at sites of balloon angioplasty in pig coronary arteries. Circulation 101:1087-90