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Abstract & Commentary
Synopsis: Direct myocardial instillation of vascular endothelial growth factor (VEGF) via thoracotomy shows clinical benefit.
Source: Losordo DW, et al. Circulation 1998;98:2800-2804.
Gene therapy using a variety of vectors and growth factors is a promising new approach to the therapy of myocardial ischemia. Losordo and colleagues at St. Elizabeth’s Medical Center in Boston are among the world pioneers and have previously reported on the successful use of an adenoviral vector expressing vascular endothelial growth factor (VEGF) for severe limb ischemia in humans. A new study, the first use of direct intramyocardial instillation of naked plasma DNA that encodes VEGF, is reported in five male subjects with refractory angina, all of whom had had between two and three prior revascularization procedures and were deemed to be inoperable. The results, while preliminary and short term in a small cohort, are dramatically positive.
The gene therapy was initiated through a small thoracotomy, with injections of a vector encoding the 165-amino acid isoform of the human VEGF gene, using plasmid DNA administered in four aliquots via direct myocardial injection into the LV anterolateral free wall. Mean operative time was less than two hours and all patients were discharged within 3-4 days without complications or evidence of myocardial necrosis. Serial studies, evaluated by blinded investigators, were carried out and included a dobutamine SPECT-sestamibibi perfusion study at baseline and at 30 and 60 days; coronary angiography with explicit attention to collateral status at baseline and 60 days; and assessment of clinical status (angina frequency and severity NTG consumption). The patient population consisted of five men with class IV angina pectoris, age 53-71; two were diabetic. All were on polypharmacy for angina and were severely limited. Approximately three weeks following the VEGF administration in the operating room, all patients began to notice clinical improvement, and by 60 days represented a major decrease in angina rates compared to preoperatively. The ability to perform physical activity increased substantially, and NTG use decreased. Objective evidence for improvement in ischemia and collateralization was obtained in each individual. Perfusion imaging with dobutamine demonstrated an increase in the number of normally perfused segments per patient from 6.0 ± 1.1 to 8.0 ± 0.7 (p < 0.05 at 60 days) and a decrease in the number of irreversible defects from 2.4 ± 0.2 to 1.2 ± 0.4 (p = < 0.05). This is suggestive of improvement in hibernating myocardium.
Coronary artery angiography performed before and two months after gene transfer indicated improved collateral flow to the ischemic areas in all five patients. New collateral vessels were suggested by improvement in filling of previously identified collaterals as well as new collateral vessel development. Losordo and colleagues conclude that "the present study provides the first evidence for favorable clinical effect of direct myocardial injection of naked plasmid DNA encoded VEGF." They comment that the ideal number of injections is unknown, as is the optimal anatomic site for placement of the DNA. They note that the vectors and formulations incorporating VEGF are subjects for future research. Losordo et al comment that groups have used VEGF protein with preliminary success in the treatment of limb and myocardial ischemia in animals. Some investigators are exploring catheter-based systems, as well as direct myocardial instillation of fibroblast growth factor (FGF) at the time of coronary bypass surgery. FGF variants in gene or protein formulation are the focus of ongoing and future clinical trials.
Comment by Jonathan Abrams, MD
This report is of enormous interest, as it suggests that gene transfer may enhance perfusion in the human heart with coronary atherosclerosis, presumably through the induction of a more robust and extensive collateral system. Losordo et al have previously shown this approach works in the treatment of severe limb ischemia. Several reports presented at the recent American Heart Association meetings in Dallas in November 1998 confirmed that many groups are working on a variety of techniques to provide VEGF, human growth factor, FGF, and other moieties with a variety of delivery systems in animal models. The Germans have previously reported similar but favorable results of FGF in conjunction with bypass surgery (Schumacher B, et al. Circulation 1998;97:645). This field is moving rapidly and clinicians are alerted to keep abreast of these developments. Protocols are now available in the United States from a variety of centers to enroll patients with refractory angina in randomized trials incorporating theracotomy for direct myocardial injection of gene products, catheter-based systems, as well as gene therapy in association with concomitant coronary bypass surgery.
Assuming that minimally invasive or noninvasive techniques are effective in enhancing collateral circulation (or in preventing or attenuating restenosis following coronary angioplasty), the future is bright indeed. Many biotech companies are involved in this rapidly expanding field. The New York Times published a comprehensive article on this subject (New York Times. December 22, 1998). The molecular biology technology is sophisticated and advances are moving rapidly. Losordo et al are to be congratulated for pursuing research that initially seems to be truly revolutionary, but that may result in commonplace therapy within the next decade. While caution is advisable until long-term results in larger groups of patients are obtained, this is an exciting area of investigation.