title: Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia.
abstract: BACKGROUND
  We initiated a phase 1 clinical study to determine the safety and bioactivity of direct myocardial gene transfer of vascular endothelial growth factor (VEGF) as sole therapy for patients with symptomatic myocardial ischemia.
  
  
  RESULTS
  VEGF gene transfer (GTx) was performed in 5 patients (all male, ages 53 to 71) who had failed conventional therapy; these men had angina (determined by angiographically documented coronary artery disease). Naked plasmid DNA encoding VEGF (phVEGF165) was injected directly into the ischemic myocardium via a mini left anterior thoracotomy. Injections caused no changes in heart rate (pre-GTx=75+/-15/min versus post-GTx=80+/-16/min, P=NS), systolic BP (114+/-7 versus 118+/-7 mm Hg, P=NS), or diastolic BP (57+/-2 versus 59+/-2 mm Hg, P=NS). Ventricular arrhythmias were limited to single unifocal premature beats at the moment of injection. Serial ECGs showed no evidence of new myocardial infarction in any patient. Intraoperative blood loss was 0 to 50 cm3, and total chest tube drainage was 110 to 395 cm3. Postoperative cardiac output fell transiently but increased within 24 hours (preanesthesia=4.8+/-0.4 versus postanesthesia=4.1+/-0.3 versus 24 hours postoperative=6. 3+/-0.8, P=0.02). Time to extubation after closure was 18.4+/-1.4 minutes; average postoperative hospital stay was 3.8 days. All patients had significant reduction in angina (nitroglycerin [NTG] use=53.9+/-10.0/wk pre-GTx versus 9.8+/-6.9/wk post-GTx, P<0.03). Postoperative left ventricular ejection fraction (LVEF) was either unchanged (n=3) or improved (n=2, mean increase in LVEF=5%). Objective evidence of reduced ischemia was documented using dobutamine single photon emission computed tomography (SPECT)-sestamibi imaging in all patients. Coronary angiography showed improved Rentrop score in 5 of 5 patients.
  
  
  CONCLUSIONS
  This initial experience with naked gene transfer as sole therapy for myocardial ischemia suggests that direct myocardial injection of naked plasmid DNA, via a minimally invasive chest wall incision, is safe and may lead to reduced symptoms and improved myocardial perfusion in selected patients with chronic myocardial ischemia.
authors.affiliation: Departments of Medicine, Biomedical Research, Surgery, and Anesthesiology, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass 02135, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Losordo
authors.forename: P R
authors.initials: PR
authors.lastname: Vale
authors.forename: J F
authors.initials: JF
authors.lastname: Symes
authors.forename: C H
authors.initials: CH
authors.lastname: Dunnington
authors.forename: D D
authors.initials: DD
authors.lastname: Esakof
authors.forename: M
authors.initials: M
authors.lastname: Maysky
authors.forename: A B
authors.initials: AB
authors.lastname: Ashare
authors.forename: K
authors.initials: K
authors.lastname: Lathi
authors.forename: J M
authors.initials: JM
authors.lastname: Isner
mesh_terms: D000368:Aged; D017023:Coronary Angiography; D016228:Endothelial Growth Factors / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D015552:Injections, Intralesional; D008222:Lymphokines / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D019060:Minimally Invasive Surgical Procedures; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000628:therapy*; D018919:Neovascularization, Physiologic; D010957:Plasmids / Q000235:genetics; D013908:Thoracotomy / Q000379:methods; D015899:Tomography, Emission-Computed, Single-Photon; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors