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 #
5R01HL055324-14
Application #
8588949
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
2013-12-01
Budget End
2014-11-30
Support Year
14
Fiscal Year
2014
Total Cost
$398,179
Indirect Cost
$146,962
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
Weil, Brian R; Canty Jr, John M (2014) Ceramide signaling in the coronary microcirculation: a double-edged sword? Circ Res 115:475-7
Qu, Jun; Young, Rebeccah; Page, Brian J et al. (2014) Reproducible ion-current-based approach for 24-plex comparison of the tissue proteomes of hibernating versus normal myocardium in swine models. J Proteome Res 13:2571-84
Sharma, Umesh C; Canty Jr, John M (2014) Myocardial repair around-the-clock. Circ Res 114:1675-7
Shen, Xiaomeng; Young, Rebeccah; Canty, John M et al. (2014) Quantitative proteomics in cardiovascular research: global and targeted strategies. Proteomics Clin Appl 8:488-505
Fallavollita, James A; Heavey, Brendan M; Luisi Jr, Andrew J et al. (2014) Regional myocardial sympathetic denervation predicts the risk of sudden cardiac arrest in ischemic cardiomyopathy. J Am Coll Cardiol 63:141-9
Page, Brian J; Young, Rebeccah F; Suzuki, Gen et al. (2013) The physiological significance of a coronary stenosis differentially affects contractility and mitochondrial function in viable chronically dysfunctional myocardium. Basic Res Cardiol 108:354
Weil, Brian R; Canty Jr, John M (2013) Stem cell stimulation of endogenous myocyte regeneration. Clin Sci (Lond) 125:109-19
Pizzuto, Matthew F; Suzuki, Gen; Banas, Michael D et al. (2013) Dissociation of hemodynamic and electrocardiographic indexes of myocardial ischemia in pigs with hibernating myocardium and sudden cardiac death. Am J Physiol Heart Circ Physiol 304:H1697-707
Canty Jr, John M; Suzuki, Gen (2012) Myocardial perfusion and contraction in acute ischemia and chronic ischemic heart disease. J Mol Cell Cardiol 52:822-31
Suzuki, Gen; Iyer, Vijay; Lee, Te-Chung et al. (2011) Autologous mesenchymal stem cells mobilize cKit+ and CD133+ bone marrow progenitor cells and improve regional function in hibernating myocardium. Circ Res 109:1044-54

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