Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease.

BACKGROUND: Therapeutic angiogenesis, a new experimental strategy for the treatment of vascular insufficiency, uses the administration of mediators known to induce vascular development in embryogenesis to induce neovascularization of ischemic adult tissues. This report summarizes a phase I clinical experience with a gene-therapy strategy that used an E1(-)E3(-) adenovirus (Ad) gene-transfer vector expressing human vascular endothelial growth factor (VEGF) 121 cDNA (Ad(GV)VEGF121.10) to induce therapeutic angiogenesis in the myocardium of individuals with clinically significant coronary artery disease. METHODS AND RESULTS: Ad(GV)VEGF121.10 was administered to 21 individuals by direct myocardial injection into an area of reversible ischemia either as an adjunct to conventional coronary artery bypass grafting (group A, n=15) or as sole therapy via a minithoracotomy (group B, n=6). There was no evidence of systemic or cardiac-related adverse events related to vector administration. In both groups, coronary angiography and stress sestamibi scan assessment of wall motion 30 days after therapy suggested improvement in the area of vector administration. All patients reported improvement in angina class after therapy. In group B, in which gene transfer was the only therapy, treadmill exercise assessment suggested improvement in most individuals. CONCLUSIONS: The data are consistent with the concept that direct myocardial administration of Ad(GV)VEGF121.10 to individuals with clinically significant coronary artery disease appears to be well tolerated, and initiation of phase II evaluation of this therapy is warranted.

Perioperative myocardial infarction associated with coronary artery bypass graft surgery: improved sensitivity in the diagnosis within 6 hours after operation with 99mTc-glucoheptonate myocardial imaging and myocardial-specific isoenzymes.

The present study was performed to evaluate scintigraphic imaging with technetium 99m-labeled glucoheptonate and serum enzyme levels of creatine phosphokinase isoenzyme (MB-CPK) in the early diagnosis of perioperative acute myocardial infarction associated with saphenous vein bypass graft operations. Myocardial imaging was done in 27 patients (50% of whom were considered high-risk) before operation and again 5 hours after operation. Four of these patients (15%) had both electrocardiographic and serum MB-CPK evidence of acute myocardial infarction, and all 4 had developed positive postoperative scintigrams. Four other patients had only elevated serum MB-CPK, and scintigrams became positive after operation in 3 of them. In addition, serum MB-CPK 6 hours after operation was 83 +/- 21 mIU/ml (mean +/- standard error of the mean) in patients with positive postoperative scans compared with 24 +/- 5 mIU/ml in those patients with negative postoperative scintigrams (p less than 0.001). Myocardial imaging with 99mTc-glucoheptonate in the perioperative period is rapid, safe, and atraumatic. Furthermore, our results suggest that it is a sensitive method for the early diagnosis of perioperative acute myocardial infarction, and, when imaging is combined with serum MB-CPK isoenzyme analysis, the reliability of the diagnosis of acute myocardial infarction is enhanced even further. Only 1 of the patients who showed perioperative myocardial damage had acute hemodynamic compromise or obvious impairment of recovery in the immediate postoperative period, and the 30-day mortality of the total group was 4% (1 of 27).

Role of delayed intraaortic balloon pumping in treatment of experimental myocardial infarction.

Intraaortic balloon pumping improves coronary blood flow characteristics while simultaneously reducing myocardial oxygen demands by reducing aortic systolic pressure. Clinical application of intraaortic balloon pumping has largely been in the "high risk" patient (cardiogenic shock, postinfarction angina, left main coronary artery disease and unstable angina) for support during diagnostic studies or cardiac surgery, or both. In addition, there is some evidence that balloon pumping immediately after coronary occlusion reduces the size of experimentally induced myocardial infarcts. In this study, myocardial infarcts were produced by ligation of the left anterior descending coronary artery in 12 dogs, 6 of which were treated with balloon counterpulsation beginning 3 hours after coronary occlusion. All dogs were killed 8 hours after coronary ligation. Intraaortic balloon pumping resulted in the expected hemodynamic changes (decreased aortic systolic pressure, left ventricular end-diastolic pressure and heart rate and increased aortic peak diastolic pressure). In addition, there was a significant reduction in infarct size in the group with balloon pumping as determined with epicardial S-T segment mapping, myocardial imaging with technetium-99m-glucoheptonate and histochemical staining with nitroblue tetrazolium. These results suggest that even when instituted as long as 3 hours after coronary occlusion, intraaortic balloon pumping results in significant reduction in infarct size and, it might be speculated, the mortality and morbidity associated with acute myocardial infarction may also be decreased.

Early diagnosis of myocardial infarction in the dog with 99mTc-glucoheptonate.

Early gamma imaging of acute experimental myocardial infarcts was evaluated in mongrel dogs with 99mTc-glucoheptonate. From 15 to 20 mCi were injected between 1 and 27 hr after coronary artery occlusion. Nine dogs imaged 3 hr after injection (4 hr after occlusion) showed unequivocal uptake in the region of the infarct. Fifteen dogs imaged 5-7 hr after injection (6-8 hr after occlusion) showed sufficiently well-defined regions of abnormal uptake so that planimetry could be performed reliably. Five animals imaged serially showed improvement of the image only up to about 5-7 hr after injection. Infarct-to-normal myocardium and infarct-to-blood ratios were slightly higher in dogs injected 15-27 hr after infarction than in those injected 1 hr after infarction, implying that equally good results can be obtained with injection and imaging of 99mTc-glucoheptonate at any time within the first day. No other infarct-labeling radiopharmaceutical shares this capability for the early detection a delineation of acute infarcts.