Abstract 16601: Thymosin β4 Overexpression via Adeno-Associated Viral Vector induces Therapeutic Neovascularisation in aPorcine Model of Chronic Myocardial Ischemia
Induction of neovascularization using vascular growth factors is a promising novel approach for promoting cardiac repair and regeneration. Thymosin ß4 (Tß4), a small 4.9 kDa peptide influences cell motility, migration and differentiation. We investigated the role of long-term Tß4 overexpression using recombinant adeno-associated vector Tß4 (rAAV Tß4) in a pig model of normo- and hypercholesterinemic diet in chronic myocardial ischemia.
Methods: Chronic ischemia was induced via reduction stent graft in the circumflex artery, leading to a total occlusion on day 28 (d28). Regional application of saline or rAAV Tß4 (5x10E12 viral particles, d28) was compared with Tß4 transgenic pigs. Global myocardial function (EF, LVEDP) was obtained and of blood flow was measured via fluorescent microspheres (FMI). Regional myocardial function and post mortem angiography (collateral growth) were obtained on day 56. Histological analysis of capillary density (capillaries/field (C/F) was performed. Hypercholesterinemia was induced via high-fat diet (d0-56).
Results: Tß4 overexpression via rAAV significantly enhanced capillaries (142±4 vs. 67±3 C/F) and collaterals (9±1 vs. 3±1) in the ischemic area. Blood flow was significantly increased in ischemic area (d56, 91±2% vs. 78±3 % non-ischemic area). Furthermore, global (EF: 47±4 vs. 29±3 %; LVEDP: 12±2 vs. 19±2 mmHg) and regional myocardial function (SES at 150 b/min: 73±5 vs. 10±6 % of non-ischemic area) were increased. Similar results were obtained in transgenic pigs with ubiquitous Tß4 overexpression (EF: 45±2 %; LVEDP: 13±1 mmHg SES at 150 b/min: 76±3% of non-ischemic area). In the pig model of hypercholesterinemia, serum triglyceride level increased from 22±3 to 72±4 mg/dl. Increased neovascularization and heart function could be achieved after rAAV Tß4 application, albeit at a lower level (capillaries: 88±3 vs. 62±2 C/F; collaterals: 6±1 vs. 3±1; EF: 42±4 vs. 28±3 %; LVEDP: 14±1 vs. 18±2 mmHg).Long term Thymosin ß4 expression induced neovascularization and improved myocardial perfusion and function. A compareble effect wa seen after hypercholesterinemia, suggesting an attractive therapeutic potential for rAAV Tß4 in no-option patients with ischemic heart disease.
- © 2013 by American Heart Association, Inc.