The current understanding of myocardial ischemia emphasizes that the degree of damage is related to the duration and severity of coronary occlusion. Consequently, therapeutic management has been directed toward limiting ischemic damage by reducing the duration and severity of oxygen supply and demand disparity. We hypothesize that the total damage following coronary occlusion is caused by alterations set up during ischemia but then further extended during reperfusion. This hypothesis suggests that reperfusion injury can be avoided by modifying the reperfusion phase. Surgical revascularization of acute evolving myocardial infarction using cardioplegia allows control of the composition of the initial reperfusate as well as the conditions of its delivery. When delivered into the ischemic segment, cardioplegia is the first reperfusate to which that segment is exposed. Control of reperfusion can avoid this reperfusion injury to a large extent. Such control of reperfusion is not possible with nonsurgical revascularization using thrombolysis and/or angioplasty. Although well tested in global models, the role of surgical revascularization of acute evolving myocardial infarction remains unclear. The studies outlined in the following application will demonstrate that the fate of the ischemic myocardium is related not only to the ischemic phase, but is in large part determined by events occurring during reperfusion. In a canine model of 1, 3 and 6 hour left anterior descending coronary artery occlusions, we will a) determine the functional, metabolic , and morphological characteristics of ischemic and reperfusion injury, b) determine the pathophysiological mechanisms underlying """"""""stunned"""""""" myocardium and describe stunning as as manifestation of reperfusion injury, c) provide insight on the failure of nonsurgical revascularization to restore postischemic function, d) show that reperfusion injury can be avoided by modifying the conditions and composition of reperfusion with surgical revascularization using cardioplegia, resulting in immediate restoration of postischemic function and metabolism, e) determine the optimal cardioplegia for the setting of evolving infarction, f) determine the long-tem benefits of surgical versus nonsurgical revascularization in chronic studies, g) and examine the benefits of retrograde coronary sinus cardioplegia over antegrade delivery.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036377-04
Application #
3351346
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1987-08-01
Project End
1992-07-31
Budget Start
1990-08-01
Budget End
1992-07-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
Schools of Medicine
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106
Larsen, G L; Fame, T M; Renz, H et al. (1994) Increased acetylcholine release in tracheas from allergen-exposed IgE-immune mice. Am J Physiol 266:L263-70
Nakanishi, K; Zhao, Z Q; Vinten-Johansen, J et al. (1994) Coronary artery endothelial dysfunction after global ischemia, blood cardioplegia, and reperfusion. Ann Thorac Surg 58:191-9
Johnston, W E; Vinten-Johansen, J; Shugart, H E et al. (1993) Collateral perfusion through overlapping vessels reduces canine right ventricular ischemic injury from positive end-expiratory pressure. Crit Care Med 21:721-32
Toombs, C F; McGee, D S; Johnston, W E et al. (1993) Protection from ischaemic-reperfusion injury with adenosine pretreatment is reversed by inhibition of ATP sensitive potassium channels. Cardiovasc Res 27:623-9
Lefer, D J; Nakanishi, K; Johnston, W E et al. (1993) Antineutrophil and myocardial protecting actions of a novel nitric oxide donor after acute myocardial ischemia and reperfusion of dogs. Circulation 88:2337-50
Vinten-Johansen, J; Nakanishi, K; Zhao, Z Q et al. (1993) Acadesine improves surgical myocardial protection with blood cardioplegia in ischemically injured canine hearts. Circulation 88:II350-8
Zhao, Z Q; McGee, S; Nakanishi, K et al. (1993) Receptor-mediated cardioprotective effects of endogenous adenosine are exerted primarily during reperfusion after coronary occlusion in the rabbit. Circulation 88:709-19
Johnston, W E; Vinten-Johansen, J; Shugart, H E et al. (1992) Positive end-expiratory pressure potentiates the severity of canine right ventricular ischemia-reperfusion injury. Am J Physiol 262:H168-76
Rashid, A; Auchincloss Jr, H; Sharon, J (1992) Comparison of GK1.5 and chimeric rat/mouse GK1.5 anti-CD4 antibodies for prolongation of skin allograft survival and suppression of alloantibody production in mice. J Immunol 148:1382-8
Applegate, R J; Johnston, W E; Vinten-Johansen, J et al. (1992) Restraining effect of intact pericardium during acute volume loading. Am J Physiol 262:H1725-33

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