No abstract

The number one cause of mortality in the US is cardiovascular related disease. Future predictions do not see a reduction in this rate especially with the continued rise in obesity [1,2]. Even so, potential molecular therapeutic targets for cardiac gene delivery are in no short supply thanks to continuing advances in molecular cardiology. However, efficient and safe delivery remains a bottleneck in clinical gene therapy [3] Keywords myocardium; angiogenesis; non-viral gene delivery; ischemia Viral vectors are looked upon favorably for their high transduction efficiency, although their ability to elicit toxic immune responses remains [4]. However, this high transduction does not necessarily translate into improved efficacy [5]. Naked DNA remains the preferred method of DNA delivery to cardiac myocardium and has been explored extensively in clinical trials. The results from these trials have demonstrated efficacy in regards to secondary end-points of reduced symptomology and perfusion, but have failed to establish significant angiogenesis or an increase in myocardial function [6]. This may be due in part to reduced transfection efficiency but can also be attributed to use of suboptimal candidate genes.Correspondence should be addressed to: David A. Bull, M.D., Division of Cardiothoracic Surgery, Room 3C127, 30 North 1900 East, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, Phone 801-581-5311, FAX 801-585-3936, david.bull@hsc.utah.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. However, little development has been seen in the use of new gene agents for treatment of myocardial ischemia and infarction. Current treatment consists of using mitogenic factors, described decades earlier, alone or in combination to spur angiogenesis or modulating intracellular Ca2+ homeostasis through SERCA2a but have to date, failed to demonstrate clinical efficacy. Recent data suggests that axonal guidance cues also act on vasculature neogenesis and provide a new means of investigation for treatment. NIH Public Access Clinical Gene Therapy for Therapeutic Myocardial AngiogenesisIschemic heart disease is the leading cause of death in the United States today. Currently, the mainstay of therapy for ischemic heart disease (IHD) is revascularization. Nearly 2,000,000 cardiac catheterizations and 553,000 coronary artery bypass grafting procedures are performed annually [9]. Technological developments in these areas have led to an improved survival and quality of life for patients with IHD. However, increasing evidence suggests that revascularization alone is insuffici...

Aprotinin preserves myocardial biochemical function during cold storage. This preservation of biochemical function is mediated through suppression of the release, uptake, and activity of tumor necrosis factor alpha.

No abstract

Interleukin-18 (IL-18) and IL-12 have been shown to play an important role in the induction of interferon-gamma (IFN-gamma). IFN-gamma induces the proliferation of T cells and natural killer (NK) cells and augments the Th1 immune cascade. The role of IL-18 and IL-12 in the induction of IFN-gamma following allogeneic heart transplantation has not been described. We sought to characterize the IL-12 and IL-18 response to murine allogeneic heart transplantation, particularly with respect to IFN-gamma production and histologic transplant rejection. Forty-eight heterotopic heart transplants were performed in two groups of mice: syngeneic C3H/HeN to C3H/HeN mice and allogeneic BALB/C to C3H/HeN mice. Transplants were followed out to 2, 6, 10, and 14 days. Six transplants were performed in each group. Serum and splenic samples were used to evaluate the cytokine response by ELISA. Explanted heart tissue was processed for evidence of histologic rejection, and RT-PCR was performed to evaluate the IL-12, IL-18, and IFN-gamma signal qualitatively. Analysis of variance (ANOVA), Fisher's projected least significant difference (PLSD) was used for statistical analysis. Transplant rejection occurred in the allogeneic group histologically by day 6 and clinically by day 10. Serum IFN-gamma levels rose significantly by day 6 in the allogeneic group and then continued to rise in the splenocyte cultures. Serum IL-18 also rose significantly in the allogeneic group at day 6 compared with syngeneic group. RT-PCR revealed that the allogeneic tissue contained an increased signal for IL-12, IL-18, and IFN-gamma beginning at day 6 and peaking at day 10 after transplant. Beginning 6 days after transplantation, IL-12 and IL-18 appear to play a significant role in the induction of IFN-gamma in allogeneic heart transplants.