Therapeutic angiogenesis can be defined as a procedure which causes new blood vessel formation where there is low arterial blood flow, resulting in improved organ function. Angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), have been shown in animal models to produce new blood vessel growth. Dr. Todd K. Rosengart and colleagues at the Cornell Medical Center report the results of a Phase 1 study of VEGF use in patients with severe CAD. The goal is to study safety of direct heart VEGF use in patients having bypass surgery. 15 patients scheduled for elective bypass with ischemic but non-bypassable ventricular segment were enrolled. We used VEGF121, 1 of 4 VEGF isoforms with no heparin-binding activity. Using an adenovirus backbone, the vector coding for human cDNA of VEGF121 was administered. The 15 patients received direct myocardial VEGF121 injected in 10 places using a needle at the time of bypass surgery. They had clinical exam, EKG, resting and dobutamine echos, rest and stress MUGA, and angiograms at study start and after 30 days. The average patient age was 60 years. There were 11 men and 4 women. 60% had previous heart attack, 60% were diabetic, 80% had high blood pressure, 77% had heart failure, 27% had previous bypass, and 13% had previous angioplasty. The average EF was 45%. 14 of the 15 patients had successful bypass surgery plus VEGF injections, and the other patient received direct myocardial VEGF injections only. We did extensive safety testing and monitoring during the study. Testing ranged from EKGs, Holter recordings, echos, and blood tests to highly specific testing for unexpected adenovirus expression. There were no detectable bad effects related to the vector delivery system, the VEGF protein, or the adenovirus. This Phase 1 trial was not designed to determine how well direct myocardial VEGF121 injections worked. However, it does appear that there was improvement in collateral blood vessels. CONCLUSION: This Phase 1 trial shows the short term safety of direct myocardial VEGF121 cDNA using an adenovirus vector system in patients having elective bypass. Phase 2 trials to test effectiveness are being planned. Therapeutic angiogenesis is a promising approach to improving heart blood flow in patients who have angina after other treatments have failed. Title: Myocardial VEGF Gene Therapy in Conjunction With Coronary Bypass Surgery - A Phase I Trial Speaker: Todd K. Rosengart, MD, New York Hospital - Cornell Medical Center ---------------------------------- Angioplasty, stent, and bypass surgery are currently the only therapies for angina patients who get no relief from medications. Many patients get symptoms after successful surgery because of rstenosis. These patients may have no further surgical options. Intramuscular (IM) transfection of genes encoding angiogenic cytokines is a new way to treat angina. The VEGF gene encodes a signal sequence which permits the protein to be naturally secreted from intact cells. The hope is to encourage growth of new collateral blood vessels that will bypass artery blockages. This is called "therapeutic angiogenesis." Our lab recently studied a pig model of heart ischemia (poor blood flow), showing how direct into the heart gene transfer of VEGF can be safely done via a small chest wall incision. We did a Phase 1 clinical study to test the safety and result of direct to the heart gene transfer of naked plasmid DNA-encoding VEGF. Gene transfer was the only therapy, done without angioplasty, stent, or bypass surgery, in patients with heart ischemia and symptoms of same. VEGF gene transfer has been performed in 16 patients, aged 51-74 years. Most had several risk factors and a long cardiac history, including multiple bypass surgeries, prior heart attack, and angioplasty. Anti-anginal therapy consisted of nitrates, calcium channel blockers, and beta-blockers. All patients continued their routine medicines as needed after gene therapy. We used plasmid DNA encoding the 165-amino acid isoform of the human VEGF gene, regulated by the cytomegalovirus promoter/enhancer (phVEGF165). We gave it by direct injection into the heart using a small chest incision. Patients were monitored with transesophageal echocardiography (TEE) to track wall motion abnormalities associated with injections, and to be sure plasmid DNA was not injected into the left ventricular cavity. The procedure usually lasted no more than 1 hour, and there were no complications during. After the procedure, heart enzyme tests showed no evidence of heart damage, and patients maintained left ventricular function. Transient but significant increases in blood level of VEGF was monitored. Blood levels peaked at day 12. VEGF levels returned to baseline by day 90. All 16 patients showed improvement of symptoms and improved heart blood flow. At the latest follow-up of 90 days, 6 of 11 patients were free of angina. Sublingual nitro use fell from 60 per week to 9 per week at day 30, to 3 per week at day 90. Angina episodes fell from 50 per week to 8 per week at day 30, to 3 per week at day 90. 13 of 14 patients showed reduced ischemia at day 30. Angiogram showed new collateral vessel development in 12 of 13 patients at day 60. Anecdotal evidence: A 71 year old man was having 10-15 daily episodes of angina from minimal activity, including walking less than 100 yards. His coronary vessels were all blocked to some degree. On day 10 after gene transfer, he notied better exercise capacity and less nitro use. By day 30, the patient was requiring no nitro and had returned to his 5 hour per day job doing maintenance for his church. A 70 year old man was taking 100 nitro tablets per week for angina from minimal activity such as getting dressed. His coronary arteries were all blocked to some degree. He is now rebuilding tractor and car engines and not using any nitro. A 67 year old man restricted to a wheelchair due to a prior stroke had daily angina from mild activity, requiring an average of 8 nitro tablets per day. His coronary arteries were all blocked to some degree. On day 21 afte the procedure, he noticed a decrease in the frequency and severity of his angina. By day 60, he was no longer having angina and was no longer requiring nitro. He was able to engage in activities such as swimming. CONCLUSIONS: This Phase 1 study of 16 patients shows that direct into the heart injection of naked plasmid DNA encoding for VEGF is safe, raises blood levels of VEGF, and may be in patients with medically unmanageable angina. Because enrolled patients had long-standing, stable, severe angina, the improvements are unlikely to be by chance. This experience, although encouraging, leaves several issues unresolved. The precise injection site, number and dose of injections needs further study. Gene therapy alone administered via a small chest incision does not permit randomization against placebo. We await a catheter based delivery system for those type trials. Title: VEGF Gene Transfer Works as Sole Therapy for Medically Resistant Angina Speaker: Peter R. Vale, MD, Tufts University School of Medicine