Certainly, the clinical problem becomes greater after several years, so that's a good question. Annoyingly, there doesn't seem to have been any long term follow-up with the human patients in the Prevent I & II trials. If there had been, we'd have a little genuine data. So we have to make do with rats and rabbits. Sigh. That would be the second question for management, the first being "how good is angiography for making fine distinctions in luminal diameter?" Raised by rkrw (perhaps you saw my post on the issue on the Valuation thread).
Anyhow, a few references involving the little animals:
>>J Thorac Cardiovasc Surg. 2001 Apr;121(4):714-22.
Long-term stabilization of vein graft wall architecture and prolonged resistance to experimental atherosclerosis after E2F decoy oligonucleotide gene therapy.
Ehsan A, Mann MJ, Dell'Acqua G, Dzau VJ.
Division of Cardiovascular Medicine, Brigham and Women's Hospital/Harvard Medical School, 75 Francis Street, Boston, MA 202115, USA.
OBJECTIVE: We tested the hypothesis that a single intraoperative transfection of rabbit vein grafts with a decoy oligonucleotide that blocks cell-cycle gene transactivation by the transcription factor E2F induces long-term stable adaptation that involves medial hypertrophy and a resistance to neointimal hyperplasia and atherosclerosis. METHODS: Jugular vein to carotid artery interposition vein grafts in hypercholesterolemic rabbits were treated, using pressure-mediated delivery, with either E2F decoy oligonucleotide, scrambled oligonucleotide, or vehicle alone. E2F decoy inhibition of cell-cycle gene expression was determined by measuring proliferating cell nuclear antigen upregulation and bromodeoxyuridine incorporation in vascular smooth muscle cells. Neointimal hyperplasia and atherosclerosis were compared between groups at 6 months after operation. Wall stress was derived from the ratio of luminal radius to wall thickness. Normal rabbits exposed to 6 weeks of diet-induced hypercholesterolemia starting 6 months after operation were analyzed in the same manner. RESULTS: The E2F decoy oligonucleotide, but not scrambled oligonucleotide or vehicle alone, inhibited proliferating cell nuclear antigen expression and smooth muscle cell proliferation. Furthermore, this manipulation of cell-cycle gene expression yielded an inhibition of neointimal hyperplasia and atherosclerotic plaque formation throughout the 6 months of cholesterol feeding. In normocholesterolemic rabbits, vehicle-treated and scrambled oligonucleotide-treated vein grafts remain susceptible to diet-induced atherosclerosis as well, whereas resistance to this disease induction remained stable in genetically engineered grafts. CONCLUSION: A single intraoperative pressure-mediated delivery of E2F decoy effectively provides vein grafts with long-term resistance to neointimal hyperplasia and atherosclerosis. These findings suggest that long-term reduction in human vein graft failure rates may be feasible with this ex vivo gene therapy approach.<<
Does protection during six months of cholesterol feeding extrapolate to five years in a human (based on the assumption that we live about ten times longer)? Beats me. Even iffier extrapolating from rat data. I gather the rat carotid model is not as good as the rabbit model.
pnas.org
pnas.org
These supply some hints that inhibition of the "first wave" of neointimal formation confers long term inhibition because the mechanism for continued neointimal formation is apparently dependent on having something to start with. I gather that process is still being elucidated.
Cheers, Tuck |
