Christopher D. Owens

Statins are independently associated with reduced mortality in patients undergoing infrainguinal bypass graft surgery for critical limb ischemia

OBJECTIVE Evidence suggesting a beneficial effect of cardioprotective medications in patients with lower extremity atherosclerosis derives largely from secondary prevention studies of heterogeneous populations. Patients with critical limb ischemia (CLI) have a large atherosclerotic burden with related high mortality. The effect of such therapies in this population is largely inferred and unproven. METHODS The Project of Ex-Vivo vein graft Engineering via Transfection III (PREVENT III) cohort comprised 1404 patients with CLI who underwent lower extremity bypass grafting in a multicenter, randomized prospective trial testing the efficacy of edifoligide for the prevention of graft failure. Propensity scores were used to evaluate the influence of statins, beta-blockers, and antiplatelet agents on outcomes while adjusting for demographics, comorbidities, medications, and surgical variables that may influence drug use. Primary outcomes were major adverse cardiovascular events < or =30 days, vein graft patency, and 1-year survival assessed by Kaplan-Meier method. Potential determinants of 1-year survival were modeled using a multivariate Cox regression. RESULTS In this cohort, 636 patients (45%) were taking statins, 835 (59%) were taking beta-blockers, and 1121 (80%) were taking antiplatelet drugs. Perioperative major adverse cardiovascular events (7.8%) and early mortality (2.7%) were not measurably affected by the use of any drug class. Statin use was associated with a significant survival advantage at 1 year of 86% vs 81% (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52-0.98; P = .03) by analysis of both unweighted and propensity score-weighted data. Use of beta-blockers and antiplatelet drugs had no appreciable impact on survival. None of the drug classes were associated with graft patency measures at 1 year. Significant predictors of 1-year mortality by Cox regression modeling were statin use (HR, 0.67; 95% CI, 0.51-0.90; P = .001), age >75 (HR, 2.1; 95% CI, 1.60-2.82; P = .001), coronary artery disease (HR, 1.5; 95% CI, 1.15-2.01; P = .001), chronic kidney disease stages 4 (HR, 2.0; 95% CI, 1.17-3.55; P = .001) and 5 (HR, 3.4; 95% CI, 2.39-4.73; P < .001), and tissue loss (HR, 1.9; 95% CI, 1.23-2.80; P = .003). CONCLUSIONS Statin use is associated with improved survival in CLI patients 1 year after surgical revascularization. Further studies are indicated to determine optimal dosing in this population and to definitively address the question of relationship to graft patency. These data add to the growing literature supporting statin use in patients with advanced peripheral arterial disease.

Adaptive changes in autogenous vein grafts for arterial reconstruction: Clinical Implications

For patients with the most severe manifestations of lower extremity arterial occlusive disease, bypass surgery using autogenous vein has been the most durable reconstruction. However, the incidence of bypass graft stenosis and graft failure remains substantial and wholesale improvements in patency are lacking. One potential explanation is that stenosis arises not only from over exuberant intimal hyperplasia, but also due to insufficient adaptation or remodeling of the vein to the arterial environment. Although in vivo human studies are difficult to conduct, recent advances in imaging technology have made possible a more comprehensive structural examination of vein bypass maturation. This review summarizes recent translational efforts to understand the structural and functional properties of human vein grafts and places it within the context of the rich existing literature of vein graft failure.

Donor postextubation hypotension and age correlate with outcome after donation after cardiac death transplantation.

Background. Compared with standard donors, kidneys recovered from donors after cardiac death (DCD) exhibit higher rates of delayed graft function (DGF), and DCD livers demonstrate higher rates of biliary ischemia, graft loss, and worse patient survival. Current practice limits the use of these organs based on time from donor extubation to asystole, but data to support this is incomplete. We hypothesized that donor postextubation parameters, including duration and severity of hemodynamic instability or hypoxia might be a better predictor of subsequent graft function. Methods. We performed a retrospective examination of the New England Organ Bank DCD database, concentrating on donor factors including vital signs after withdrawal of support. Results. Prolonged, severe hypotension in the postextubation period was a better predictor of subsequent organ function that time from extubation to asystole. For DCD kidneys, this manifested as a trend toward increased DGF. For DCD livers, this manifested as increased rates of poor outcomes. Maximizing the predictive value of this test in the liver cohort suggested that greater than 15 min between the time when the donor systolic blood pressure drops below 50 mm Hg and flush correlates with increased rates of diffuse biliary ischemia, graft loss, or death. Donor age also correlated with worse outcome. Conclusions. Time between profound instability and cold perfusion is a better predictor of outcome than time from extubation to asystole. If validated, this information could be used to predict DGF after DCD renal transplant and improve outcomes after DCD liver transplant.

Suprarenal aortic cross-clamp position: A reappraisal of its effects on outcomes for open abdominal aortic aneurysm repair

OBJECTIVES With the increasing use of endovascular aneurysm repair, a greater proportion of open aneurysm repairs in the future are expected to be more complex and require suprarenal cross-clamping. We sought to evaluate the effects of suprarenal (SR) vs infrarenal (IR) aortic cross-clamp position in abdominal aortic aneurysm (AAA) repair in an updated single center series. METHODS All elective open AAA repairs performed at our institution between 1990 and 2006 were entered into a prospective database and reviewed retrospectively. Our main stratification variable was SR vs IR. The SR group was further subdivided into those requiring an adjunctive renal revascularization procedure (SR+RRP; n = 54) and those who did not (SR-RRP; n = 117). Univariate and multivariate models were used to analyze the effect of baseline variables and operative variables on our primary endpoint 30-day mortality as well as secondary endpoints such as major adverse events, postoperative decline in renal function (defined as doubling of baseline creatinine to level >2 mg/dL, or new-onset dialysis) and long-term survival. A propensity score model was developed to control for confounding variables associated with the use of an SR cross-clamp. RESULTS A total of 1020 patients underwent elective AAA repair, of which 849 (83.2%) were IR and 171 (16.8%) were SR. Diabetes (14.6% vs 9.1%, P = .027), hypertension (70.2% vs 61.4%, P = .03), and chronic renal failure (14.0% vs 4.7%, P = .001) were more prevalent in the SR group, and mean aneurysm size was larger (6.0 cm vs 5.6 cm, P = .001). Estimated blood loss was higher (1919 mL vs 1257 mL, P = .001) in the SR group, as was mean length of stay (12.6 days vs 10.7 days, P = .047). Perioperative (30-day) mortality rate was 1.8% for the SR group and 1.2% for the IR group (P = .44). Postoperative decline in renal function was 17.0% in SR vs 9.5% in IR (P = .003), however, new-onset dialysis was rare (0.6% SR, 0.8% IR, P = NS). The combination of SR+RRP was associated with an increased risk for postoperative decline in renal function (14.8% SR+RRP, 4.3% SR-RRP, P = .016). Preoperative renal failure was strongly associated with postoperative renal decline (odds ratio [OR] 8.15, 2.92-22.8, P < .0001). Propensity score analysis demonstrated that the use of an SR cross-clamp was associated with an increased risk for postoperative renal decline (OR 2.66, 1.28-5.50, P = .009). Major adverse events were more prevalent in the SR group compared to the IR group (17.0% vs 9.5%, P = .003). Five-year survival was 69.1% + 1.9% for the IR group and 67.7% + 4.3% for the SR group (P = 0.38) by life table analysis. CONCLUSION Suprarenal cross-clamping is associated with low mortality and significant but acceptable morbidity, including postoperative decline in renal function. The results from this series may serve as relevant background data when evaluating emerging branched and fenestrated endograft technologies.

Lower extremity vein graft failure: a translational approach

Abstract Patients with the most severe manifestations of lower extremity arterial occlusive disease often require peripheral bypass surgery for limb salvage and preservation of function. Although good quality saphenous vein offers the most durable conduit for reconstruction, 5-year failure rates are 30–50% and have remained largely unchanged for the past two decades. The majority of these failures occur within the first year of implantation, which is regarded as the most biologically active time during which the vein graft adapts to the arterial environment. Although intimal hyperplasia is generally regarded as the primary culprit of vein graft failure, geometric remodeling of the healing vein graft has recently emerged as a potentially significant contributing factor. While hemodynamic forces, including an increase in shear stress and wall tension, are undoubtedly central to the magnitude and direction of vein graft remodeling, we have determined that these forces alone cannot account for the extent of variability noted in early remodeling patterns. Therefore, we hypothesize that circulating factors, such as mediators of inflammation, may modulate the vein graft response to mechanical forces. This article reviews the definition and diagnosis of vein graft failure and summarizes our current efforts to understand the mechanisms of normal and abnormal vein graft adaptation to the arterial environment.

Vein graft failure

After the creation of an autogenous lower extremity bypass graft, the vein must undergo a series of dynamic structural changes to stabilize the arterial hemodynamic forces. These changes, which are commonly referred to as remodeling, include an inflammatory response, the development of a neointima, matrix turnover, and cellular proliferation and apoptosis. The sum total of these processes results in dramatic alterations in the physical and biomechanical attributes of the arterialized vein. The most clinically obvious and easily measured of these is lumen remodeling of the graft. However, although somewhat less precise, wall thickness, matrix composition, and endothelial changes can be measured in vivo within the healing vein graft. Recent translational work has demonstrated the clinical relevance of remodeling as it relates to vein graft patency and the systemic factors influencing it. By correlating histologic and molecular changes in the vein, insights into potential therapeutic strategies to prevent bypass failure and areas for future investigation are explored.

Early remodeling of lower extremity vein grafts: Inflammation influences biomechanical adaptation

BACKGROUND The remodeling of vein bypass grafts after arterialization is incompletely understood. We have previously shown that significant outward lumen remodeling occurs during the first month of implantation, but the magnitude of this response is highly variable. We sought to examine the hypothesis that systemic inflammation influences this early remodeling response. METHODS A prospective observational study was done of 75 patients undergoing lower extremity bypass using autogenous vein. Graft remodeling was assessed using a combination of ultrasound imaging and two-dimensional high-resolution magnetic resonance imaging. RESULTS The vein graft lumen diameter change from 0 to 1 month (22.7% median increase) was positively correlated with initial shear stress (P = .016), but this shear-dependent response was disrupted in subjects with an elevated baseline high-sensitivity C-reactive protein (hsCRP) level of >5 mg/L. Despite similar vein diameter and shear stress at implantation, grafts in the elevated hsCRP group demonstrated less positive remodeling from 0 to 1 month (13.5% vs 40.9%, P = .0072). By regression analysis, the natural logarithm of hsCRP was inversely correlated with 0- to 1-month lumen diameter change (P = .018). Statin therapy (beta = 23.1, P = .037), hsCRP (beta = -29.7, P = .006), and initial shear stress (beta = .85, P = .003) were independently correlated with early vein graft remodeling. In contrast, wall thickness at 1 month was not different between hsCRP risk groups. Grafts in the high hsCRP group tended to be stiffer at 1 month, as reflected by a higher calculated elastic modulus (E = 50.4 vs 25.1 Mdynes/cm2, P = .07). CONCLUSIONS Early positive remodeling of vein grafts is a shear-dependent response that is modulated by systemic inflammation. These data suggest that baseline inflammation influences vein graft healing, and therefore, inflammation may be a relevant therapeutic target to improve early vein graft adaptation.

Peripheral artery disease and risk of cardiovascular events in patients with coronary artery disease: Insights from the Heart and Soul Study

Among patients with coronary artery disease (CAD), those with peripheral artery disease (PAD) have a greater vulnerability to cardiovascular (CV) events than those with CAD alone. In a prospective cohort study of patients with CAD, we evaluated potential mechanisms that might explain the adverse CV outcomes associated with PAD. We performed a prospective cohort study of 1018 patients with stable CAD who were recruited from 2000 to 2002. Incident symptomatic PAD events were adjudicated during a follow-up period of 7.2 ± 2.6 years. We used Cox proportional hazards models to evaluate the association between incident symptomatic PAD events and subsequent risk of CV events or death. Models were adjusted for demographics, traditional risk factors, inflammation, insulin resistance and health behaviors. Among the 1018 patients, 50 patients who did not report a history of PAD at baseline suffered incident symptomatic PAD events during the follow-up period. Those patients had a higher risk of subsequent CV events and death compared to those who did not develop PAD. After adjustment for traditional risk factors, symptomatic PAD events remained associated with a 70% increased risk of subsequent CV events (adjusted HR 1.7; 95% CI 1.0, 2.9; p = 0.04) and an 80% increased risk of death (adjusted HR 1.8; 95% CI 1.2, 2.7; p = 0.006). Inflammatory biomarkers were the strongest risk factor contributing to the excess risk. In a contemporary cohort of patients with CAD, incident symptomatic PAD events were associated with an increased risk for subsequent CV events. The increased vulnerability to CV events was partially explained by shared CV risk factors and inflammation.

Chemical Mediators of Inflammation and Resolution in Post-Operative Abdominal Aortic Aneurysm Patients

Temporal–metabolomic studies of local mediators during inflammation and its resolution uncovered novel pathways and mediators, e.g., lipoxins, resolvins, and protectins that stimulate key resolution responses. Since these studies were carried out with isolated human cells and in animal models, it is important to determine in humans whether temporal profiles between pro-inflammatory mediators and pro-resolving mediators are demonstrable in vivo. To this end, we examined patients undergoing abdominal aortic aneurysm (AAA) surgery. Profiles of mediators including eicosanoids were assessed in addition to pro-resolving mediators. The results demonstrate temporal relationships for local-acting peptides (e.g., VEGF, IL-10, TGFβ) and lipid mediators (leukotrienes and resolvins). In addition, profiles obtained for AAA patients divided into two groups based on their temporal profile: one group consistent with a pro-inflammatory and another with a resolving profile. Together, these translational metabolomic profiles demonstrate for the first time the temporal relationships between local mediators in humans relevant in inflammation resolution.

Inferior outcomes of autogenous infrainguinal bypass in Hispanics: an analysis of ethnicity, graft function, and limb salvage.

INTRODUCTION Recent evidence suggests disparities exist among racial groups with peripheral arterial disease (PAD). Hispanics (HI) are the fastest growing demographic in the United States, but little outcome data is available for this population. Therefore, we undertook this study to compare the results of autogenous infrainguinal bypass grafting in HI to Caucasians (CA) and African Americans (AA). METHODS This was a comparative cohort study of prospectively collected registry data of infrainguinal bypass performed at a tertiary center. Patient demographics and comorbidities, operative indications, bypass graft characteristics, and postoperative courses were analyzed. Cumulative patency rates, limb salvage, mortality, and factors associated with these outcomes were determined using Kaplan-Meier analysis and Cox proportional hazards models. RESULTS From January 1, 1985, through December 31, 2007, 1646 consecutive patients (1408 CA, 57 HI, and 181 AA) underwent 1646 autogenous infrainguinal reconstructions. HI and AA were younger and more often diabetic than CA but HI had less chronic renal insufficiency (CRI) and dialysis-dependence than AA. AA, but not HI, more commonly underwent bypass for critical limb ischemia (CLI) in comparison to CA (AA 90% vs CA 80%, P < .0001; HI 86%). HI and AA bypass grafts had inflow and outflow distal to that in CA. Perioperative mortality (2.3%) and morbidity were similar between groups. Five-year primary patency (+/- standard error [SE]) was significantly lower in HI compared to CA and similar to that in AA (HI 54% +/- 7% vs CA 69% +/- 1%, P = .02; AA 58% +/- 4%). Cox proportional hazard modeling showed high-risk conduit, age <65, CLI, female gender, and AA race were risk factors for failure of primary patency. Secondary patency of HI grafts, unlike AA, was not different than that in CA. Five-year limb salvage (+/- SE) was significantly lower in HI compared to CA and similar to that in AA (HI 80% +/- 6% vs CA 91% +/- 1%, P = .004; AA 83% +/- 3%). Hispanic ethnicity, CLI, high-risk conduit, age <65, CRI, female gender, and diabetes were significant predictors of limb loss. CONCLUSION Autogenous infrainguinal bypass surgery in HI is associated with primary patency and limb salvage inferior to that of CA and similar to that of AA, despite HI rates of CLI equivalent to CA and HI comorbidities less severe than AA. HI ethnicity was an independent predictor of limb loss. Our data provides evidence of outcome disparities in HI treated aggressively for their PAD. Further investigation with regard to biologic and social factors is required to delineate the reasons for these inferior outcomes in HI patients.