Chronic Adaptations to Myocardial Ischemia

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.