Diabetes and hypercholesterolemia are two of the major risk factors for developing cardiovascular disease, especially in combination with chronic myocardial ischemia it represents one of the most common causes of disability or death. New pro-angiogenic factors like Thymosin ß4 (Tß4), a small 4.9 kDa peptide influences cell motility and migration might be suitable for inducing therapeutic neovascularization in chronic myocardial ischemia a cardiovascular risk factors.
Methods:
Chronic ischemia was induced via reduction stent graft in the circumflex artery, leading to a total occlusion on day 28 (d28). Beside wildtyp animals (wt) ± high fat diet (hypercholesteric (hyp), choselsterol 78±1 wt vs 90±2 hyp), d
iabetic transgenic pigs were used (increased blood glucose 305
±12 mg/dL)
.
Regional application of rAAV Tß4 (5x10E12 viral particles, d28) was performed in wt, hyp and diabetic pigs respectively. Global myocardial function was obtained at day 28 and 56. Regional myocardial function and post mortem angiography were examined on day 56. Histological analysis of capillary density (capillaries/field (C/F)) was performed
in the ischemic tissue.
Results:
rAAV.Tß4 transduction significantly enhanced capillaries (278±6 vs. 148±6 c/hpf) and collaterals (9±1 vs. 3±1) compared to control wt animals. Furthermore, global (EF: 47±4 vs. 29±3 %); and regional myocardial function (SES at 150 b/min: 73±5 vs. 10±6 % of non-ischemic area) were increased after Tß4 overexpression. In the models of cardiovascular risk factors and chronic myocardial ischemia increased neovascularization and improved myocardial function could be achieved after rAAV Tß4 application, albeit at a lower level (capillaries: diabetic: 190±4 (Tß4) vs. 120±5 (control) c/hpf hyp: 188±6 (Tß4) vs 130±12 (control) c/hpf; collaterals: diabetic: 4±1 (Tß4) vs. 2±1 (control) hyp: 6±1 (Tß4) vs 3±1 (control); EF: diabetic: 32±2 % (Tß4) vs. 27±1 % (control) hyp: 42±4 % (Tß4) vs 28±3 % (control)).
Conclusion:
Long term Thymosin ß4 expression induced neovascularization and improved myocardial perfusion and function even in pigs with additional risk factors. Therefore, rAAV.Tß4 appears suitable for treatment of ischemic cardiomyopathy associated with these cardiovascular risk factors.
Impact of hypertension on regional myocardial function in diabetic patients: analysis by Doppler myocardial imaging
