Abstract 3446: Therapeutic Neovascularization by Catheter-Based, Intramyocardial Gene Transfer of Naked DNA Encoding Human Placental Growth Factor in Swine Chronic Myocardial Ischemia
Background: We have reported that intramyocardial transfer of plasmid encoding human placental growth factor (phPlGF) augments myocardial angiogenesis, inhibits myocardial apoptosis and left ventricular (LV) remodeling, preserves LV function and enhances recruitment of bone marrow-derived progenitors for myoangiogenesis in rats with acute myocardial infarction. However, therapeutic potential of phPlGF in chronic myocardial ischemia in large animals remains to be investigated.
Methods and Results: Chronic myocardial ischemia was induced by ameroid constrictor placement around left circumflex arteries of farm swine. Four weeks after the constrictor placement, ischemic area was identified by NOGA electromechanical mapping. Immediately after the mapping, 1,000 (Hi) or 500 (Lo) microgram of phPlGF or 1,000 microgram of empty vector (C) (n=7–10) was intramyocardially injected into the ischemic myocardium with Myostar catheters. Baseline parameters such as % ischemic area by NOGA mapping, LV ejection fraction (EF) and regional wall motion score (RWMS) by echocardiography and Rentrop collateral score by coronary angiography immediately before the gene therapy (GTx) were similar in all groups. However, improvement of % ischemic area, EF and RWMS during 4 weeks after the GTx was significantly greater in Hi and Lo groups than C group (delta % ischemic area: Hi, −25.2±7.4; Lo, −24.6±7.9; C, −14.1±7.2%, P<0.05) (delta EF: Hi, 13.9±8.2; Lo, 14.1±9.8; C, −2.8±5.4%, P<0.01) (delta RWMS: Hi, −3.3±1.8; Lo, −2.7±2.1; C, 1.3±1.7, P<0.05). Improvement of Rentrop score was significantly greater in Hi group and tended to be greater in Lo group than C group (Hi, 1.1±1.1; Lo, 0.7±0.8; C, −0.3±0.5, P<0.05). Histological capillary density at week 4 was also greater in Hi and Lo groups than C group (Hi, 2306.5±191.4; Lo, 2146.7±211.7; C, 1162.7±209.5, P<0.001). All parameters pre and post GTx were similar in Hi and Lo groups.
Conclusion: Intramyocardial gene transfer of phPlGF may attenuate chronic myocardial ischemia by enhancing neocapillary formation, resulting in significant functional recovery. The favorable outcomes in this preclinical study suggest efficacy of the novel gene therapy for patients with intractable coronary artery disease.