Therapeutic Angiogenesis by Intramyocardial Injection of pCK-VEGF165 in Pigs

Choi, Jae Sung; Kim, Ki Bong; Han, Woong; Kim, Dong Sik; Park, Jin Sik; Lee, Jong Jin; Lee, Dong Soo

Abstract

BACKGROUND: Gene therapy is a new and promising option for the treatment of severe myocardial ischemia by therapeutic angiogenesis. The goal of this study was to elucidate the efficacy of therapeutic angiogenesis by using VEGF165 in large animals. MATERIALS AND METHOD: Twenty-one pigs that underwent ligation of the distal left anterior descending coronary artery were randomly allocated to one of two treatments: intramyocardial injection of pCK-VEGF (VEGF) or intramyocardial injection of pCK-Null (Control). Injections were administered 30 days after ligation. Seven pigs died during the trial, but eight pigs from VEGF and six from Control survived. Echocardiography was performed on day 0 (preoperative) and on days 30 and 60 following coronary ligation. Gated myocardial single photon emission computed tomography imaging (SPECT) with 99mTc-labeled sestamibi was performed on days 30 and 60. Myocardial perfusion was assessed from the uptake of 99mTc-labeled sestamibi at rest. Global and regional myocardial function as well as post-infarction left ventricular remodeling were assessed from segmental wall thickening; left ventricular ejection fraction (EF); end systolic volume (ESV); and end diastolic volume (EDV) using gated SPECT and echocardiography. Myocardium of the ischemic border zone into which pCK plasmid vector had been injected was also sampled to assess micro-capillary density. RESULT: Micro-capillary density was significantly higher in the VEGF than in Control (386+/-110/mm2 vs. 291+/-127/mm2; p <0.001). Segmental perfusion increased significantly from day 30 to day 60 after intramyocardial injection of plasmid vector in VEGF (48.4+/-15.2% vs. 53.8+/-19.6%; p <0.001), while no significant change was observed in the Control (45.1+/-17.0% vs. 43.4+/-17.7%; p=0.186). This resulted in a significant difference in the percentage changes between the two groups (11.4+/-27.0% increase vs. 2.7+/-19.0% decrease; p=0.003). Segmental wall thickening increased significantly from day 30 to day 60 in both groups; the increments did not differ between groups. ESV measured using echocardiography increased significantly from day 0 to day 30 in VEGF (22.9+/-9.9 mL vs. 32.3+/-9.1 mL; p=0.006) and in Control (26.3+/-12.0 mL vs. 36.8+/-9.7 mL; p=0.046). EF decreased significantly in VEGF (52.0+/-7.7% vs. 46.5+/-7.4%; p=0.004) and in Control (48.2+/-9.2% vs. 41.6+/-10.0%; p=0.028). There was no significant change in EDV. The interval changes (days 30~60) of EF, ESV, and EDV did not differ significantly between groups both by gated SPECT and by echocardiography.
CONCLUSION
Intramyocardial injection of pCK-VEGF165 induced therapeutic angiogenesis and improved myocardial perfusion. However, post-infarction remodeling and global myocardial function were not improved.