? Both autologous skeletal myoblasts and bone marrow mononuclear cells have been used in Phase 1 clinical trials to treat CHF - sometimes with negative outcomes. We propose that these undesired results arise from a lack of understanding of the appropriate cell type and delivery conditions for a given cardiac injury. We hypothesize that different cell types, doses, locations for cell delivery and/or routes of administration are necessary to maximize function with minimal toxicity (e.g. electrical abnormalities) - depending on whether the injury is acute (MI) or chronic (HF). Our ultimate goal is to define cell delivery scenarios that increase function with a minimum of risk. We will test our hypothesis via three specific aims: 1) In both acute and chronic models of cardiac injury, we will alter cell type (myoblasts vs. bone marrow mononuclear cells) and delivery profiles (dose, location, route of delivery) and compare the ability to maximize regional and global contractility or to positively impact remodeling. 2) We will investigate the mechanism of functional improvement by quantifying cell retention, survival and biodistribution; by histologically analyzing the location, potential electromechanical connectivity, and phenotype of injected cells; and by determining the impact of cell type and delivery parameters on cardiac, skeletal muscle and peripheral blood indicators of cardiac injury and heart failure. 3) We will examine the impact of cell type and delivery on safety by: electrical (Holter) monitoring of animals for 1 week to 3 months after delivery of cells; comparing the inducibility and termination of sustained ventricular tachyarhythmias in animals receiving cells under various delivery conditions; correlating electrical findings with functional and histologic outcomes including biodistribution; and retrieving cells from center or periphery of infarcted myocardium for patch clamp analysis of threshold potential, current-voltage relationships and action potential properties. ? ? Accomplishing these aims should allow a comparison of how cell type and delivery affect the safety and efficacy of cardiac myogenesis or CCM in acute and chronic cardiac injury and allow us to better predict what cell profile may be useful in a given clinical scenario. Given the incidence of adverse electrical events observed clinically, determining the safety profile of specific modalities of cardiac cell therapy is critical to establishing cell based CCM as a legitimate therapeutic intervention for ischemic heart disease or congestive heart failure (CHF). ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063346-06
Application #
6936496
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Varghese, Jamie
Project Start
1999-08-01
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
6
Fiscal Year
2005
Total Cost
$371,250
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Biology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Robertson, Matthew J; Dries-Devlin, Jessica L; Kren, Stefan M et al. (2014) Optimizing recellularization of whole decellularized heart extracellular matrix. PLoS One 9:e90406
Seguin, Agathe; Baccari, Sonia; Holder-Espinasse, Muriel et al. (2013) Tracheal regeneration: evidence of bone marrow mesenchymal stem cell involvement. J Thorac Cardiovasc Surg 145:1297-1304.e2
Davis, Bryce H; Morimoto, Yoshihisa; Sample, Chris et al. (2012) Effects of myocardial infarction on the distribution and transport of nutrients and oxygen in porcine myocardium. J Biomech Eng 134:101005
McCue, Jonathan D; Swingen, Cory; Feldberg, Tanya et al. (2008) The real estate of myoblast cardiac transplantation: negative remodeling is associated with location. J Heart Lung Transplant 27:116-23
Zenovich, Andrey G; Taylor, Doris A (2008) Atherosclerosis as a disease of failed endogenous repair. Front Biosci 13:3621-36
Zenovich, A G; Davis, B H; Taylor, D A (2007) Comparison of intracardiac cell transplantation: autologous skeletal myoblasts versus bone marrow cells. Handb Exp Pharmacol :117-65
Taylor, Doris A; Zenovich, Andrey G (2007) Cell therapy for left ventricular remodeling. Curr Heart Fail Rep 4:3-10
Davis, Bryce H; Schroeder, Thies; Yarmolenko, Pavel S et al. (2007) An in vitro system to evaluate the effects of ischemia on survival of cells used for cell therapy. Ann Biomed Eng 35:1414-24
Ott, Harald C; Brechtken, Johannes; Swingen, Cory et al. (2006) Robotic minimally invasive cell transplantation for heart failure. J Thorac Cardiovasc Surg 132:170-3
Ott, H C; McCue, J; Taylor, D A (2005) Cell-based cardiovascular repair--the hurdles and the opportunities. Basic Res Cardiol 100:504-17

Showing the most recent 10 out of 18 publications