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Vein grafts respond to low flow and shear stress (tau(w)) by generating thicker walls and smaller lumens through the processes of neointimal hyperplasia and remodeling. Clinically, however, vein grafts with obviously low tau(w), such as those distal to high-grade proximal obstructions, are not infrequently found to be widely patent and pliable. One possible explanation for this phenomenon may be that vein grafts remodel more favorably in response to changes in shear that occur gradually over time compared to abruptly. This hypothesis was tested in an experimental animal model in this report. Two separate models of experimental vein graft failure were created, causing either immediate exposure to ultralow tau(w) (<1 dyne/cm2) or delayed exposure to ultralow tau(w). Under general anesthesia and using a sterile technique, the right external jugular (EJ) veins of 28 New Zealand white rabbits were surgically exposed and isolated. An end-to-side distal EJ/common carotid artery anastomosis was created, resulting in a widely patent arteriovenous fistula. For the immediate exposure group (n = 5), the EJ was suture-ligated just proximal to the thoracic inlet, distal to a small 10-50 microm venous tributary. This created a reversed vein segment immediately and abruptly exposed to high wall tension (2.0 +/- 0.3 x 10(4) dyne/cm) and ultralow tau(w) (0.15 +/- 0.08 dyne/cm2). For the delayed exposure group (n = 22), the EJ was ligated over a 0.035 guidewire, leaving a small aperture to sustain some measure of blood flow and tau(w). This predictably resulted in slightly less wall tension (1.4 +/- 0.2 x 10(4) dyne/cm) and higher tau(w) (0.68 +/- 0.21 dyne/cm2) than the immediate exposure group. During the first week, the small outflow aperture in the delayed exposure grafts thrombosed, eventually exposing them to the same low level of tau(w) as the immediate exposure grafts. Thus, the only difference in the two models was that delayed exposure grafts enjoyed a slower decline in tau(w) than immediate exposure grafts. Fourteen rabbits in the delayed exposure group were harvested over the first 7 days to define the patency curve of the restricted outflow channel. As expected, the small aperture had thrombosed in all animals by 7 days. The remaining 14 grafts were harvested after 4 weeks, and 13/14 remained patent. Examination of the hemodynamic parameters at the time of death confirmed that wall tension and tau(w) had equalized (wall tension 0.9 +/- 0.1 vs. 1.1 +/- 0.1 x 10(4) dyne/cm, tau(w) 0.45 +/- 0.12 vs. 0.30 +/- 0.08 dyne/cm2). Histological examination revealed less neointimal hyperplasia in the delayed exposure group compared to the immediate exposure group (wall thickness 266 +/- 16 vs. 180 +/- 24 microm, p = 0.025) as well as a slightly greater luminal diameter (0.30 +/- 0.02 vs. 0.40 +/- 0.02 cm, p = 0.038). The results of this experiment suggest that slow exposure to reduced tau(w) results in more favorable remodeling (less thickening) than abrupt exposure. This finding may explain the occasional clinical observation of a widely patent vein graft even in the face of proximal arterial obstruction and very low flow; the change in tau(w) presumably occurred slowly mitigating the remodeling response.

Objective: The purpose of this study was to examine the outcome of patients in whom an infrainguinal bypass graft failed., Methods: This was a retrospective analysis of consecutive patients undergoing infrainguinal bypass grafting in a single institution over 8 years., Results: Six hundred thirty-one infrainguinal bypass grafts were placed in 578 limbs in 503 patients during the study period. The indication for surgery was limb-threatening ischemia in 533 patients (85%); nonautologous conduits were used in 259 patients (41%), and 144 (23%) were repeat operations. After a mean follow-up of 28 +/- 1 months (median, 23 months; range, 0-99 months), 167 grafts (26%) had failed secondarily. The rate of limb salvage in patients with graft failure was poor, only 50% +/- 5% at 2 years after failure. The 2-year limb salvage rate depended on the initial indication for bypass grafting: 100% in patients with claudication (n = 16), 55% +/- 8% in patients with rest pain (n = 49), and 34% +/- 6% in patients with tissue loss (n = 73; P <.001). The prospect for limb salvage also depended on the duration that the graft remained patent. Early graft failure (<30 days; n = 25) carried a poor prognosis, with 2-year limb salvage of only 25% +/- 10%; limb salvage was 53% +/- 5% after intermediate graft failure (<2 years, n = 110) and 79% +/- 10% after late failure (>2 years, n = 15; P =.04). Multivariate analysis revealed shorter patency interval before failure (P =.006), use of warfarin sodium (Coumadin) postoperatively (P =.006), and infrapopliteal distal anastomosis (P =.01) as significant predictors for ultimate limb loss., Conclusion: The overall prognosis for limb salvage in patients with failed infrainguinal bypass grafts is poor, particularly in patients with grafts placed because of tissue loss and those with early graft failure.

Neointimal hyperplasia resulting from vascular smooth muscle cell (SMC) proliferation and luminal migration is the major cause of autologous vein graft failure following vascular coronary or peripheral bypass surgery. Strategies to attenuate SMC proliferation by the delivery of oligonucleotides or genes controlling cell division rely on the use of high concentrations of vectors, and require pre-emptive disruption of the endothelial cell layer. We report a genetically engineered herpes simplex virus (HSV-1) mutant that, in an in vivo rabbit model system, infects all vascular layers without prior injury to the endothelium; expresses a reporter gene driven by a viral promoter with high efficiency for at least 4 weeks; exhibits no systemic toxicity; can be eliminated at will by administration of the antiviral drug acyclovir; and significantly reduces SMC proliferation and restenosis in vein grafts in immunocompetent hosts.