Background: Patients presenting with medically intractable angina who have undergone previous coronary bypass (CABG) and/or percutaneous revascularization procedures are frequently deemed "inoperable" based on angiographic findings of diffuse distal disease or a lack of available conduits. We initiated a phase I clinical trial to assess the safety and bioactivity of intramyocardial transfection of plasmid DNA encoding for the angiogenic mitogen vascular endothelial growth factor (ph-VEGF165) in such patients.
Methods: phVEGF165 (125 microg, n = 10; 250 microg, n = 10) was injected directly into the myocardium through a mini left anterior thoracotomy as sole therapy in 20 patients (15 male, 5 female, age 48 to 74 years) with class III or IV angina, reversible ischemia on stress sestamibi scans, and "inoperable" coronary artery disease.
Results: All patients tolerated surgery uneventfully and were extubated on the table. No perioperative myocardial infarction, hemodynamic instability, or change in ventricular function occurred. Mean hospital stay was 3.9 days. There was one late death (4 months). Plasma VEGF protein level increased from 30.6+/-4.1 pg/mL pretreatment to 73.7+/-10.1 pg/mL 14 days posttreatment (p = 0.0002) and returned to baseline by day 90. All 16 patients followed to day 90 reported a reduction in angina (nitroglycerin use/week = 60.2+/-4.9 preop vs 3.5+/-1.6 at 90 days; p<0.0001). Seventy percent (7 of 10) patients were completely angina free at 6 months. A reduction in ischemic defects on single photon emission computerized tomography sestamibi scans was observed in 13 of 17 patients at 60 days (7 of 8 in the 250-microg group). Stress perfusion score decreased from 19.4+/-3.7 at baseline to 15.9+/-3.4 at 60 days (p = 0.025). Angiographic evidence of improved collateral filling of at least one occluded vessel was observed in all patients evaluated at day 60.
Conclusions: Direct myocardial gene transfer with phVEGF165 via a mini-thoracotomy can be performed safely and may result in significant symptomatic improvement in patients with "inoperable" coronary artery disease.