Cardiovascular disease is the leading cause of mortality worldwide. The ultimate goal of this project is to evaluate the feasibility of gene therapy for ischemic cardiomyopathy in humans, and to elucidate some of the underlying mechanisms at the molecular level. It is becoming clear that apoptosis, or programmed cell death, plays a significant role in ischemic injury and long-term cardiac remodeling. By blocking apoptosis, it may be possible to delay or prevent the cycle of progressive cardiac ventricular dilation and worsening function on conjunction with myocyte cell loss. It is this progressive development of cardiomyopathy that is responsible for a significant portion of cardiac morbidity and mortality worldwide. Several possible gene targets for over-expression have been implicated in the apoptosis pathway. A transient myocardial ischemia model in the rabbit will be employed in this investigation, and adenoviral vectors will be utilized to affect transfection and over-expression of genes of interest. The endpoints of myocyte apoptosis salvage, fractional shortening of sonomicrocrystal probes, and preservation of cardiac function will be assessed. In addition, all animals will be sacrificed at the six week time point following ischemic insult to allow gross and histologic examination of the heart. In addition, all animals will be sacrificed at the six week time point following ischemic insult to allow gross and histologic examination of the heart. Viral delivery of genes at the time of ischemic insult will be compared to treatment 24-72 hours after insult to more accurately model the clinical scenario in humans. By blocking the deleterious effects of apoptosis in myocardial ischemia, it may be possible to utilize gene therapy for those with ischemic cardiac disease in order to prevent the eventual loss of myocytes and cardiac function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL069597-01
Application #
6445251
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Commarato, Michael
Project Start
2002-02-22
Project End
Budget Start
2002-02-22
Budget End
2003-02-21
Support Year
1
Fiscal Year
2002
Total Cost
$46,192
Indirect Cost
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Jayasankar, Vasant; Woo, Y Joseph; Pirolli, Timothy J et al. (2005) Induction of angiogenesis and inhibition of apoptosis by hepatocyte growth factor effectively treats postischemic heart failure. J Card Surg 20:93-101
Jayasankar, Vasant; Pirolli, Timothy J; Bish, Lawrence T et al. (2004) Targeted overexpression of growth hormone by adenoviral gene transfer preserves myocardial function and ventricular geometry in ischemic cardiomyopathy. J Mol Cell Cardiol 36:531-8
Jayasankar, Vasant; Bish, Lawrence T; Pirolli, Timothy J et al. (2004) Local myocardial overexpression of growth hormone attenuates postinfarction remodeling and preserves cardiac function. Ann Thorac Surg 77:2122-9; discussion 2129
Jayasankar, Vasant; Woo, Y Joseph; Bish, Lawrence T et al. (2004) Inhibition of matrix metalloproteinase activity by TIMP-1 gene transfer effectively treats ischemic cardiomyopathy. Circulation 110:II180-6
Jayasankar, Vasant; Woo, Y Joseph; Bish, Lawrence T et al. (2003) Gene transfer of hepatocyte growth factor attenuates postinfarction heart failure. Circulation 108 Suppl 1:II230-6