Cardiovascular disease is the leading cause of mortality worldwide. In the U.S., one million people die annually of cardiovascular disease, five million people live with congestive heart failure, and another five million have significant asymptomatic left ventricular dysfunction soon to progress to heart failure, numbers that are predicted to rise dramatically with the progressively aging population. Current therapies for heart failure consist of pharmacologic optimization of preload and afterload together with very limited reconstructive or replacement options. The overall objective of the proposed research project is to augment native cardiomyocyte function through two interrelated molecular strategies of inducing angiogenesis and localized myocardial growth. In a rodent model of ischemic cardiomyopathy, recombinant adenoviruses will be used to provide high-level, localized gene expression of the angiogenic agent hepatocyte growth factor and the trophic agent growth hormone. Effects on myocardial function will then be assessed in vivo with an intracavitary pressure volume conductance microcatheter and an ascending aortic cardiac output monitor. Effects on ventricular remodeling will also be evaluated. Specific mechanisms of action pertaining to reversal of myocardial ischemia, anti-apoptosis, and hypercontractility will be studied in-depth. The ultimate goal will be to develop an integrated heart failure therapy which promotes native cardiomyocyte growth coupled with enhanced myocardial blood flow. The candidate seeks to utilize the time and opportunities provided by this proposed research career award to engage in a concentrated period of scholarly activity dedicated to studying basic molecular and cellular mechanisms in heart failure, to design innovative treatment strategies pertinent to clinical care, to obtain additional structured didactic education and training, to acquire new scientific knowledge and research techniques, and to develop critical skills towards becoming a competitive, independent investigator. The candidate's institution, sponsor, and chairman provide a uniquely supportive, high-caliber, educationally stimulating environment highly conducive to the achievement of these goals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL072812-02
Application #
6888086
Study Section
Special Emphasis Panel (ZHL1-CSR-M (F1))
Program Officer
Commarato, Michael
Project Start
2004-05-01
Project End
2009-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$132,462
Indirect Cost
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hiesinger, William; Brukman, Matthew J; McCormick, Ryan C et al. (2012) Myocardial tissue elastic properties determined by atomic force microscopy after stromal cell-derived factor 1? angiogenic therapy for acute myocardial infarction in a murine model. J Thorac Cardiovasc Surg 143:962-6
Hiesinger, William; Goldstone, Andrew B; Woo, Y Joseph (2012) Re-engineered stromal cell-derived factor-1? and the future of translatable angiogenic polypeptide design. Trends Cardiovasc Med 22:139-44
Hiesinger, William; Vinogradov, Sergei A; Atluri, Pavan et al. (2011) Oxygen-dependent quenching of phosphorescence used to characterize improved myocardial oxygenation resulting from vasculogenic cytokine therapy. J Appl Physiol 110:1460-5
Hiesinger, William; Perez-Aguilar, Jose Manuel; Atluri, Pavan et al. (2011) Computational protein design to reengineer stromal cell-derived factor-1? generates an effective and translatable angiogenic polypeptide analog. Circulation 124:S18-26
Fitzpatrick 3rd, J Raymond; Frederick, John R; McCormick, Ryan C et al. (2010) Tissue-engineered pro-angiogenic fibroblast scaffold improves myocardial perfusion and function and limits ventricular remodeling after infarction. J Thorac Cardiovasc Surg 140:667-76
Hiesinger, William; Frederick, John R; Atluri, Pavan et al. (2010) Spliced stromal cell-derived factor-1? analog stimulates endothelial progenitor cell migration and improves cardiac function in a dose-dependent manner after myocardial infarction. J Thorac Cardiovasc Surg 140:1174-80
Atluri, Pavan; Panlilio, Corinna M; Liao, George P et al. (2010) Acute myocardial rescue with endogenous endothelial progenitor cell therapy. Heart Lung Circ 19:644-54
Frederick, John R; Fitzpatrick 3rd, J Raymond; McCormick, Ryan C et al. (2010) Stromal cell-derived factor-1alpha activation of tissue-engineered endothelial progenitor cell matrix enhances ventricular function after myocardial infarction by inducing neovasculogenesis. Circulation 122:S107-17
Fitzpatrick 3rd, J Raymond; Frederick, John R; Hiesinger, William et al. (2009) Early planned institution of biventricular mechanical circulatory support results in improved outcomes compared with delayed conversion of a left ventricular assist device to a biventricular assist device. J Thorac Cardiovasc Surg 137:971-7
Atluri, Pavan; Kozin, Elliott D; Hiesinger, William et al. (2009) Off-pump, minimally invasive and robotic coronary revascularization yield improved outcomes over traditional on-pump CABG. Int J Med Robot 5:1-12

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