While symptomatic congestive heart failure from coronary artery disease is increasing in prevalence, there are even more patients that have asymptomatic left ventricular systolic dysfunction (LVSD). Asymptomatic LVSD (or Stage B heart failure) accounts for the majority of patients with a depressed ejection fraction and coronary artery disease. Some of these patients have prior myocardial infarctions and nontransmural scars from the contemporary management of ST elevation MI with reperfusion therapy. Others have viable dysfunctional myocardium reflecting the slow but cumulative myocyte loss from repetitive ischemia and left ventricular re- modeling. This proposal is intended to determine whether intracoronary cell based therapy can ameliorate re- gional LV dysfunction at a stage of disease where clinical heart failure is absent and ongoing myocyte death and neurohormonal activation are minimal. The central hypothesis is that a myocardial microenvironment de- void of ongoing stressors promoting cell death will facilitate exogenous and endogenous myocyte regeneration from cell based therapy. Our completed work in a model of hibernating myocardium devoid of infarction sup- ports this hypothesis and demonstrates that intracoronary mesenchymal stem cells (icMSCs) stimulate en- dogenous myocyte proliferation through a paracrine mechanism with a resultant increase in myocyte nuclear density. Cardiosphere derived cells (CDCs) isolated from myocardial biopsies provide an alternative source of adult stem cells that have been demonstrated to improve function after intracoronary injection through both di- rect differentiation into cardiac myocytes as well as by stimulating endogenous myocyte proliferation. In a head-to-head fashion, this proposal will determine the relative efficacy of these two therapies in viable dysfunc- tional myocardium vs. reperfused myocardial infarcts prior to the development of heart failure. To ultimately enhance translation, studies will be conducted in swine with a heart size similar to humans.
Aim 1 will deter- mine whether icCDCs are superior to icMSCs in chronic regional LV dysfunction. They will also define whether treatments are more efficacious when administered to hibernating vs. infarcted myocardium. Physiological end-points will include improvement in regional LV function and myocardial perfusion at rest and vasodilation.
Aim 2 will evaluate the role of icMSCs and CDCs to amplify endogenous myocyte proliferation vs. differentia- tion of stem cells into a cardiac phenotype. Serial stem cell fate will be tracked in vivo using PET/CT 18[F]- FHBG imaging of cells transfected with a lentiviral triple reporter construct complimented with fluorescence and bioluminescence in tissue samples. Serial assessment of LV mass, volumes and infarct size from imaging will be complimented with immunohistochemistry to quantify the amount of new myocardium regenerated.
Aim 3 will use a discovery based proteomic approach employing label free LC/MS to identify paracrine factors differ- entially upregulated following icCDCs and icMSCs. The results will identify the stem cell and pathological sub- strate most likely to benefit patients with asymptomatic LVSD before clinical heart failure develops.

Public Health Relevance

This project is highly relevant to the contemporary management of the vast majority of patients following reper- fused myocardial infarction as well as chronic coronary artery disease where LV systolic function is mildly de- pressed without symptomatic heart failure. Demonstrating a beneficial effect of stem cell therapies on myocar- dial regeneration could change our current treatment paradigm which focuses on advanced end-stage disease to one that employs cell based therapy to prevent the progression of asymptomatic LV systolic dysfunction to clinical heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055324-12
Application #
8204904
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
1996-08-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
12
Fiscal Year
2012
Total Cost
$442,419
Indirect Cost
$163,290
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
Thygesen, Kristian; Alpert, Joseph S; Jaffe, Allan S et al. (2018) [Fourth universal definition of myocardial infarction (2018)]. Kardiol Pol 76:1383-1415
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
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

Showing the most recent 10 out of 70 publications