On the horizon: Therapeutic angiogenesis
Patients grow their own bypasses
Two phase I trials offer a glimmer of hope for pain relief for patients with coronary artery disease. One dose of either of two experimental drugs injected directly into the heart seems to encourage the growth of new blood vessels that bypass clogged arteries. Research is preliminary and on limited samples; it may be years before the therapies are available, but its progress is worth following because such treatment could mean substantial savings in the cost of cardiac care.
One treatment is gene therapy to produce a pro-tein called VegF (vascular endothelial growth fac-tor).1 VegF is the body’s signal to grow new blood vessels. The other involves the injection of a protein called FGF-1 (fibroblast growth factor). In each case, the factor is given in a single injection through a chest incision under general anesthesia, and the goal is to allow patients to grow their own by-passes by sprouting thin collateral blood vessels.
Following the VegF procedure, participants reported pain relief about three weeks after the injection procedures. The procedure took about an hour in the OR, and hospital stays averaged four days. Patients reported using substantially fewer nitroglycerine pills to relieve angina —9.8/patient/week as opposed to a previous aver-age of 53.9.
Jonathan D. Marmur, MD, a cardiologist at Mount Sinai Hospital in New York City, states he was optimistic the therapy could one day be administered less invasively through catheterization.
Results of the trials on VegF were reported during the 71st annual scientific sessions of the American Heart Association in Dallas.
Jeffrey M. Isner, MD, of Tufts University in Boston and colleagues administered the gene as sole therapy to 16 patients with myocardial ischemia refractory to other treatment options. Patients had a history of, on average, three heart attacks and two bypass surgeries. All 16 were in functional heart class IV before treatment. The VegF plasmid was injected directly into the myocardium via minithoracotomy. No adverse effects were seen, including no funduscopic changes during assessment of retinopathy.
Coronary angiography shows improved filling, and nuclear perfusion tests show "a highly statis-tical increase in the number of segments of the left ventricle being perfused," Isner reports.
Another investigator, Ronald G. Crystal, MD, of New York Hospital-Cornell Medical Center in New York City reports similar results using VegF. Crystal’s team administered the gene to 21 patients during bypass procedures at location on vessels that were not being bypassed. Crystal cautions that this was a phase I trial and was not designed to assess clinical endpoints, however, "all of the patients report improvement" and show increased exercise tolerance without side effects.
Isner and Crystal concur that persistent gene expression is a problem among all of the trials: "The duration of expression is pretty well exhausted after two to three weeks."
VegF has its drawbacks
Aserious caveat accompanies that research: A related study shows that VegF might promote heart disease as well as treat it. The factor might also have a pathophysiologic role in the progression of coronary atherosclerosis, according to the results of the first study to investigate this possibility.2
Hiroshi Itoh, MD, of Kyoto University in Japan, writes a word of caution: "Our observa-tions also suggest that VegF itself may promote the process of atherogenesis."
Itoh’s team investigated the expression of VegF in coronary artery segments from 15 patients. Twelve segments were normal except for diffuse intimal thickening, seven contained early atherosclerotic lesions, and 19 contained advanced lesions, including four that were totally occlusive.
The research team determined that expression of VegF was significantly higher in the macrophages, endothelial cells, and smooth muscle cells of atherosclerotic lesions than in healthy arteries. "Considering the multipotent actions of VegF . . .," the authors write, "our findings suggest that VegF may have some role in the progression of human coronary atherosclerosis, as well as in recanaliza-tion processes in obstructive coronary diseases."
References
1. Losordo DW, Vale PR, Symes JF, et al. Initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation 1998; 98:2,800-2,804.
2. Inoue M, Itoh H, Ueda M, et al. Vascular endothelial growth factor (VegF) expression in human coronary atherosclerotic lesions: Possible pathophysiological signifi-cance of VegF in progression of atherosclerosis. Circulation 1998; 98:2,108-2,116.
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