|Collaborator:||Robert Akins, Ph.D., Nemours Biomedical Research|
|Mentors:||Thomas H. Shaffer, MS.E., Ph.D., Nemours Biomedical Research
Robert Sikes, Ph.D., University of Delaware
Jeffery Twiss, M.D., Ph.D., Nemours Biomedical Research
Heart failure is a major clinical and public health problem in the US with considerable morbidity and mortality. Approximately, 4.7 Million people are involved with 400,000 to 700,000 new cases/yr costing $15 to 40 Billion/Yr. As such, this problem is a major complication in patients with congenital heart disease and the mechanisms of heart failure are heterogeneous, complex, and poorly understood. Following myocardial injury and/or mechanical overload, the heart can initially maintain cardiac output by enhancing intrinsic compensatory capacity. However, a persistent mismatch between intrinsic compensatory capacity and increased workload will eventually induce further functional deterioration and alteration in ventricular geometry (ventricular remodeling). The current project addresses the factors and mechanisms which regulate the transition from benign compensatory hypertrophy to heart failure.
In order to study these mechanistic pathways, we propose to study In vivo mouse models [fibulin-2 knock out (F2KO) and wild type (WT)] to experimentally induce heart failure by: 1) Myocardial infarction and 2) Chronic pressure overload. In addition, In vitro cell culture models will be studied to address the underlying cellular mechanisms by utilizing: 1) Adult mouse cardiac fibroblasts (F2KO and WT) and 2) Neonatal rat ventricular cardiomyocytes. Thus, the project is directed at the regulation of cardiovascular function from compensation to failure.
|Figure 1. Schematic of the pathway for myocardial injury and/or mechanical overload to heart failure. As shown, the schematic suggests Angiotensin II (Ang II)/ TGF- Î²1 interaction with cardiac fibroblasts and myocytes, leading to extracellular matrix (ECM) remodeling, myocyte hypertrophy and apoptosis. The end result of these interactions is heart failure.|
|Figure 2. Histological results of collagen type I (percent wall area) in wild type (WT) and fibulin -2 knock out (Fbin 2 KO) mice after induced heart failure.|
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