Many patients with coronary artery disease have chronically reduced regional myocardial function distal to severe stenoses or in collateral dependent myocardium in the absence of subjective signs of ischemia or a history of prior myocardial infarction. While some of these dysfunctional states reflect the delayed recovery of function following an cute episode of ischemia or """"""""stunning"""""""", others occur without subjective signs of recent ischemia. These dysfunctional regions are associated with relative reductions in resting flow that are stable for long periods of time and are called """"""""hibernating myocardium"""""""" which is distinguished from irreversible injury by its improvement following revascularization. Despite a substantial knowledge base regarding physiological and molecular mechanisms involved in the myocardial response to acute ischemia, advances in our understanding of chronic adaptations to ischemia have been limited by the inability to reproduce the clinical state of hibernation or chronic stunning experimentally. Our laboratory has recently developed a model that can reproduce the salient features of clinically defined hibernation in pigs instrumented with a proximal coronary artery stenosis for 3 months. Using this, we propose to test the overall hypothesis that hibernation is an intrinsic myocardial adaptation to frequent episodes of reversible ischemia that maintains tissue viability at the expense of a reduced contractile function by down-regulating regional energy requirements. Furthermore, the adaptations associated with hibernation are accompanied by changes in gene expression that are distinct from those associated with myocardial stunning. An integrative approach will employ physiological studies in intact chronically instrumented animals with studied to examine molecular mechanisms using Northern and Western analysis.
Three specific aims are proposed. In the first aim, physiological studies will compare chronic adaptations in regional flow, function, metabolism and 18FDG uptake in models of hibernating myocardium vs. chronic stunning. These will be complimented with studies to compare the expression of candidate genes for stress proteins, calcium regulatory proteins and glucose transporters. Genes that are uniquely expressed in hibernating myocardium will be identified by RNA fingerprinting using differential display PCR.
The second aim will characterize the functional and metabolic responses of chronic hibernation to changes in myocardial metabolic demand.
The third aim will determine whether changes in regional expression of heat shock proteins or myocardial antioxidants are accompanied by physiological evidence of a state of chronic preconditioning. New information will come forth that leads to a better understanding of the intrinsic myocardial adaptations involved in chronic ischemic heart disease that could lead to new strategies to induce protection from irreversible injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055324-03
Application #
2750510
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1996-08-01
Project End
2001-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Lindsey, Merry L; Bolli, Roberto; Canty Jr, John M et al. (2018) Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 314:H812-H838
Canty Jr, John M (2018) Editorial commentary: Is it still important to evaluate patients with ischemic cardiomyopathy for viable dysfunctional myocardium prior to myocardial revascularization? Trends Cardiovasc Med 28:38-40
Techiryan, George; Weil, Brian R; Palka, Beth A et al. (2018) Effect of Intracoronary Metformin on Myocardial Infarct Size in Swine. Circ Res 123:986-995
Weil, Brian R; Suzuki, Gen; Young, Rebeccah F et al. (2018) Troponin Release and Reversible Left Ventricular Dysfunction After Transient Pressure Overload. J Am Coll Cardiol 71:2906-2916
Thygesen, Kristian; Alpert, Joseph S; Jaffe, Allan S et al. (2018) [Fourth universal definition of myocardial infarction (2018)]. Kardiol Pol 76:1383-1415
Weil, Brian R; Young, Rebeccah F; Shen, Xiaomeng et al. (2017) Brief Myocardial Ischemia Produces Cardiac Troponin I Release and Focal Myocyte Apoptosis in the Absence of Pathological Infarction in Swine. JACC Basic Transl Sci 2:105-114
Malhotra, Saurabh; Canty Jr, John M (2017) Vasodilator stress and left ventricular asynchrony. J Nucl Cardiol 24:53-56
Weil, Brian R; Young, Rebeccah F; Shen, Xiaomeng et al. (2017) Reply: Apoptosis, A Double-Edge Sword! JACC Basic Transl Sci 2:499
Canty Jr, John M; Weil, Brian R (2017) Cortical Bone Stem Cells Administered at Reperfusion Attenuate Remote Zone Myocyte Remodeling. Circ Res 121:1210-1212
Malhotra, Saurabh; Canty Jr, John M (2017) American perspective: Comparing the AHA/ACC and ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. J Nucl Cardiol 24:1904-1908

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