Peripheral arterial disease is a major health problem and there is a significant need to develop therapies to prevent its progression to claudication and critical limb ischemia. Promising results in rodent models of arterial occlusion have generally failed to predict clinical success and led to questions of their relevance. While sub-optimal models may have contributed to the lack of progress, we suggest that advancement has also been hindered by misconceptions of the human capacity for compensation and the specific vessels which are of primary importance. We present and summarize new and existing data from humans, Ossabaw miniature pigs, and rodents which provide compelling evidence that natural compensation to occlusion of a major artery (i) may completely restore perfusion, (ii) occurs in specific pre-existing small arteries, rather than the distal vasculature, via mechanisms involving flow-mediated dilation and remodeling (iii) is impaired by cardiovascular risk factors which suppress the flow-mediated mechanisms and (iv) can be restored by reversal of endothelial dysfunction. We propose that restoration of the capacity for flow-mediated dilation and remodeling in small arteries represents a largely unexplored potential therapeutic opportunity to enhance compensation for major arterial occlusion and prevent the progression to critical limb ischemia in the peripheral circulation.

arteriogenesis; hindlimb ischemia; necrosis; regeneration; NADPH oxidase 2 IN THE PERIPHERAL CIRCULATION, the dilation and enlargement of preexisting vessels that form collateral pathways subsequent to arterial occlusion are the primary vascular compensations that preserve tissue viability and maintain function. These vessels dilate within seconds (25,39,45,70) and undergo expansion for weeks (20,25,45,69). In various species, the preexisting vessels are the size of the smallest arteries, and they enlarge ϳ100% (14,20,35,45,56). Available clinical studies have indicated that subsequent to arterial occlusion in the peripheral circulation, the primary vessels that enlarge as collaterals are preexisting arteries (4,29,57). The largest of the preexisting vessels are typically those that become the dominant collaterals (35,45,51). Combined anatomic and modeling studies have predicted that hindlimb flow subsequent to femoral artery occlusion is primarily determined by these collaterals (22,56). This is consistent with studies of segmental resistances that demonstrated that compensation in the collateral vessels is of significantly greater hemodynamic importance than adaptations in the distal microvasculature (43,71,75). Nevertheless, few studies investigating the mechanisms of vascular compensation subsequent to arterial occlusion in mice have specifically identified and studied these preexisting vessels that form the primary collateral pathways. Such investigations are needed because angiogenesis and collateral growth are initiated by different stimuli, and differences exist in the molecules and mechanisms that mediate these important processes (7, 11).Leukocytes, especially lymphocytes (63, 74) and macrophages (2,33,37), have been shown to have an important role in vascular compensation to hindlimb ischemia. Recent studies by Tojo et al. (66) and Urao et al. (72) have established that NADPH oxidase 2 (Nox2)-derived ROS from bone marrowderived cells (BMDCs) have an important role in neovascularization in the ischemic mouse hindlimb. The initial report (66) concluded from microsphere data that collateral growth was impaired, but did not specifically identify collateral bypass vessels or measure their diameters.To investigate the hypothesis that Nox2-derived NAD(P)H oxidase mediates primary collateral growth subsequent to arterial occlusion, the present study used Rac2-null (Rac2 Ϫ/Ϫ ) and Nox2-null (Nox2 Ϫ/Ϫ ) mice and a novel method of identifying primary hindlimb collaterals. Rac2 is expressed primarily, if not exclusively, in hematopoietic cells (38, 52) and binds to and activates Nox2-containing NAD(P)H oxidase (24,40). In addition, leukocytes from Rac2 Ϫ/Ϫ and Nox2 Ϫ/Ϫ mice have impaired function related to reduced ROS production (47,66,72). We present a method to identify the dominant or primary collateral that should be the major collateral supplying flow to

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To determine the risk factors in diabetic patients that are associated with increased postcolectomy mortality and anastomotic leak. Design: A prospectively acquired statewide database of patients who underwent colectomy was reviewed. Primary risk factors were diabetes mellitus, hyperglycemia (glucose level Ն140 mg/dL), steroid use, and emergency surgery. Categorical analysis, univariate logistic regression, and multivariate regression were used to evaluate the effects of these risk factors on outcomes. Setting: Participating hospitals within the Michigan Surgical Quality Collaborative. Patients: Database review of patients from hospitals within the Michigan Surgical Quality Collaborative. Main Outcome Measures: Anastomotic leak and 30day mortality rate. Results: Of 5123 patients, 153 (3.0%) had leaks and 153 (3.0%) died. Preoperative hyperglycemia occurred in 15.6% of patients, only 54% of whom were known to have diabetes. Multivariate analysis showed that the risk of leak for patients with and without diabetes increased only by preoperative steroid use (PϽ .05). Mortality among diabetic patients was associated with emergency surgery (P Ͻ.01) and anastomotic leak (PϽ .05); it was not associated with hyperglycemia. Mortality among nondiabetic patients was associated with hyperglycemia (P Ͻ .005). The presence of an anastomotic leak was associated with increased mortality among diabetic patients (26.3% vs 4.5%; P Ͻ .001) compared with nondiabetic patients (6.0% vs 2.5%; PϽ .05). Conclusions: The presence of diabetes did not have an effect on the presence of an anastomotic leak, but diabetic patients who had a leak had more than a 4-fold higher mortality compared with nondiabetic patients. Preoperative steroid use led to increased rates of anastomotic leak in diabetic patients. Mortality was associated with hyperglycemia for nondiabetic patients only. Improved screening may identify high-risk patients who would benefit from perioperative intervention.