Randomized, single-blind, placebo-controlled pilot study of catheter-based myocardial gene transfer for therapeutic angiogenesis using left ventricular electromechanical mapping in patients with chronic myocardial ischemia.

BACKGROUND: Catheter-based myocardial gene transfer (GTx) has not been previously tested in human subjects. Accordingly, we performed a pilot study to investigate the feasibility and safety of catheter-based myocardial GTx of naked plasmid DNA encoding vascular endothelial growth factor-2 (phVEGF-2) in patients with chronic myocardial ischemia. METHODS AND RESULTS: A steerable, deflectable 8F catheter incorporating a 27-guage needle was advanced percutaneously to the left ventricular myocardium of 6 patients with chronic myocardial ischemia. Patients were randomized (1:1) to receive phVEGF-2 (total dose, 200 microgram), which was administered as 6 injections into ischemic myocardium (total, 6.0 mL), or placebo (mock procedure). Injections were guided by NOGA left ventricular electromechanical mapping. Patients initially randomized to placebo became eligible for phVEGF-2 GTx if they had no clinical improvement 90 days after their initial procedure. Catheter injections (n=36) caused no changes in heart rate or blood pressure. No sustained ventricular arrhythmias, ECG evidence of infarction, or ventricular perforations were observed. phVEGF-2-transfected patients experienced reduced angina (before versus after GTx, 36.2+/-2.3 versus 3.5+/-1.2 episodes/week) and reduced nitroglycerin consumption (33.8+/-2.3 versus 4.1+/-1.5 tablets/week) for up to 360 days after GTx; reduced ischemia by electromechanical mapping (mean area of ischemia, 10.2+/-3.5 versus 2.8+/-1.6 cm(2), P=0.04); and improved myocardial perfusion by SPECT-sestamibi scanning for up to 90 days after GTx when compared with images obtained after control procedure. Conclusions-This randomized trial of catheter-based phVEGF-2 myocardial GTx provides preliminary indications regarding the feasibility, safety, and potential efficacy of percutaneous myocardial GTx to human left ventricular myocardium.

Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease: anesthetic management and results.

UNLABELLED: Gene transfer for therapeutic angiogenesis represents a novel treatment for medically intractable angina in patients judged not amenable to further conventional revascularization. We describe the anesthetic management of 30 patients with class 3 or 4 angina, enrolled in a Phase 1 clinical trial to assess the safety and bioactivity of direct myocardial gene transfer of naked DNA-encoding vascular endothelial growth factor (phVEGF(165)), as sole therapy for refractory angina. The phVEGF(165) was injected directly into the myocardium through a mini-thoracotomy. All patients had major clinical predictors for adverse perioperative cardiac complications. Fast-track anesthetic management with remifentanil and desflurane, multimodal analgesia, and aggressive hemodynamic control with nitroglycerin and esmolol were used. All patients tolerated anesthesia and surgery without problems. No perioperative myocardial infarction, hemodynamic instability, or ventricular failure occurred. VEGF injections caused no clinically significant changes in cardiovascular function. Mean hospital stay was 3.8 days. There was one late death (5 months postoperative). Twenty-nine of 30 patients experienced reduced angina (56.2 +/- 4.1 episodes/week preoperatively versus 3.8 +/- 1.6 postoperatively, P < 0.0001) and reduced sublingual nitroglycerin consumption (60.1 +/- 4.4 tablets/week preoperatively versus 2.9 +/- 1.1 postoperatively, P < 0.0001). IMPLICATIONS: Previously revascularized patients now judged "inoperable," continue to present with chronic, recurrent angina. Our study describes the anesthetic considerations and management of such patients treated with a novel approach by using gene therapy to stimulate angiogenesis and improve perfusion to ischemic myocardium.

Left ventricular electromechanical mapping to assess efficacy of phVEGF(165) gene transfer for therapeutic angiogenesis in chronic myocardial ischemia.

BACKGROUND: NOGA left ventricular (LV) electromechanical mapping (EMM) can be used to distinguish among infarcted, ischemic, and normal myocardium. We investigated the use of percutaneous LV EMM to assess the efficacy of myocardial gene transfer (GTx) of naked plasmid DNA encoding for vascular endothelial growth factor (phVEGF(165)), administered during surgery by direct myocardial injection in patients with chronic myocardial ischemia. METHODS AND RESULTS: A total of 13 consecutive patients (8 men, mean age 60.1+/-2. 3 years) with chronic stable angina due to angiographically documented coronary artery disease, all of whom had failed conventional therapy (drugs, PTCA, and/or CABG), were treated with direct myocardial injection of phVEGF(165) via a minithoracotomy. Foci of ischemic myocardium were identified on LV EMM by preserved viability associated with an impairment in linear local shortening. Myocardial viability, defined by mean unipolar and bipolar voltage recordings >/=5 and >/=2 mV, respectively, did not change significantly after GTx. Analysis of linear local shortening in areas of myocardial ischemia, however, disclosed significant improvement after (15.26+/-0.98%) versus before (9.94+/-1.53%, P:=0. 004) phVEGF(165) GTx. The area of ischemic myocardium was consequently reduced from 6.45+/-1.37 cm(2) before GTx to 0.95+/-0. 41 cm(2) after GTx (P:=0.001). These findings corresponded to improved perfusion scores calculated from single-photon emission CT-sestamibi myocardial perfusion scans recorded at rest (7.4+/-2.1 before GTx versus 4.5+/-1.4 after GTx, P:=0.009) and after pharmacological stress (12.8+/-2.7 before GTx versus 8.5+/-1.7 after GTx, P:=0.047). CONCLUSIONS: The results of EMM constitute objective evidence that phVEGF(165) GTx augments perfusion of ischemic myocardium. These findings, together with reduction in the size of the defects documented at rest by serial single-photon emission CT-sestamibi imaging, suggest that phVEGF(165) GTx may successfully rescue foci of hibernating myocardium.

Intraoperative multiplane transesophageal echocardiography for guiding direct myocardial gene transfer of vascular endothelial growth factor in patients with refractory angina pectoris.

Gene transfer for therapeutic angiogenesis represents a novel treatment for patients with chronic angina refractory to standard medical therapy and not amenable to conventional revascularization. We sought to assess the role of intraoperative multiplane transesophageal echocardiography (MPTEE) in guiding injection of naked DNA encoding vascular endothelial growth factor (VEGF) into the left ventricular (LV) myocardium of patients with refractory angina. After exposing the LV myocardium via a limited lateral thoracotomy, each of 17 patients in this series received 4 separate injections of VEGF DNA into different myocardial sites. Initial injections in the first patient produced intracavitary microbubbles, indicating injection of DNA into the LV chamber. Subsequently, each injection was preceded by a test injection of agitated saline. The absence of microbubbles while visualizing the LV cavity during the test injection verified that the ensuing injection of DNA would not be inadvertently squandered in the LV chamber itself. Intracavitary LV microbubbles were observed by MPTEE in 13 of 64 (20.3%) saline test injections and in 8 of 16 (50.0%) patients in which saline test injection was used, leading to adjustments in needle position. MPTEE imaging detected a previously unknown large, apical left ventricular thrombus in one patient, thereby preventing inadvertent injection of VEGF DNA through the myocardium into the thrombus. Imaging during and after injection verified no deleterious impact on LV function. We conclude that MPTEE is a useful tool for ensuring that myocardial gene therapy performed by direct needle injection results in gene transfer to the LV myocardium.

Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia.

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. METHODS AND 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.