Losordo D W, Vale P R, Symes J F, Dunnington C H, Esakof D D, Maysky M, Ashare A B, Lathi K, Isner J M
Departments of Medicine, Biomedical Research, Surgery, and Anesthesiology, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass 02135, USA.
Circulation. 1998;98(25):2800-4. doi: 10.1161/01.cir.98.25.2800.
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.
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.
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.
我们开展了一项1期临床研究，以确定血管内皮生长因子（VEGF）直接心肌基因转移作为有症状心肌缺血患者的唯一治疗方法的安全性和生物活性。
对5例（均为男性，年龄53至71岁）常规治疗无效的患者进行VEGF基因转移（GTx）；这些男性患有心绞痛（由血管造影记录的冠状动脉疾病确定）。通过小切口左前开胸术将编码VEGF的裸质粒DNA（phVEGF165）直接注射到缺血心肌中。注射后心率（GTx前=75±15次/分钟，GTx后=80±16次/分钟，P=无显著性差异）、收缩压（114±7与118±7 mmHg，P=无显著性差异）或舒张压（57±2与59±2 mmHg，P=无显著性差异）均无变化。室性心律失常仅限于注射时的单个单灶性早搏。系列心电图显示所有患者均无新的心肌梗死证据。术中失血量为0至50 cm³，胸腔总引流量为110至395 cm³。术后心输出量短暂下降，但在24小时内增加（麻醉前=4.8±0.4与麻醉后=4.1±0.3与术后24小时=6.3±0.8，P=0.02）。关闭后拔管时间为18.4±1.4分钟；术后平均住院时间为3.8天。所有患者心绞痛均显著减轻（GTx前硝酸甘油[NTG]使用量=53.9±10.0/周，GTx后=9.8±6.9/周，P<0.03）。术后左心室射血分数（LVEF）要么无变化（n=3），要么改善（n=2，LVEF平均增加5%）。所有患者均使用多巴酚丁胺单光子发射计算机断层扫描（SPECT）-锝[99mTc]甲氧基异丁基异腈显像记录到缺血减轻的客观证据。冠状动脉造影显示5例患者中有5例的Rentrop评分改善。
这种将裸基因转移作为心肌缺血唯一治疗方法的初步经验表明，通过微创胸壁切口直接心肌注射裸质粒DNA是安全的，可能会使部分慢性心肌缺血患者的症状减轻，心肌灌注改善。
