OBJECTIVES Successful adaptation of a vein graft to an arterial environment is incompletely understood. We sought to investigate whether early vein graft remodeling is predictive of subsequent patency. METHODS A prospective longitudinal study of 67 patients undergoing lower extremity bypass with autologous vein between February 2004 and April 2008. Preoperative blood samples were drawn for biomarkers. During the bypass operation, a 5 cm index segment of the graft was registered for serial lumen diameter measurements (0, 1, 3, 6, 9, and 12 months) using duplex ultrasound. Patients with at least 2 study ultrasounds were included in this analysis. RESULTS The median age was 70 years (IQR 59-76y) and the median follow-up was 32 months (IQR 15-47mo). Over half (55%) of the subjects were male, 40% had diabetes mellitus, 49% had critical limb ischemia, and most were on a statin (75%) and antiplatelet medication (91%). The median baseline high-sensitivity C-reactive protein level (hsCRP) for the cohort was 3.2mg/L (IQR 1.4-9.7mg/L). The average intraoperative, post-implantation vein lumen diameter was 3.9 ± 1.0mm, increasing to 4.7 ± 1.1mm at 1 month, an average 24 ± 27% change per subject. By 3 months, the average lumen diameter was 5.1 ± 1.6mm, with little subsequent change observed to 12 months. Non-white race, baseline hsCRP ≥5mg/L, statin use and initial lumen diameter were significantly associated with early (0-1 month) vein remodeling in a multivariable regression model. The primary patency rate for the cohort was 60 ±6.3% at 2 years. Initial lumen diameter of the index segment was not associated with primary patency, whereas larger lumen diameter achieved at 1 month (≥5.1mm) was positively associated with primary patency (P=.03, log-rank). Early (30 day) remodeling behavior was used to divide subjects into “poor remodelers” (< −5% lumen diameter change, N=6), “modest remodelers” (−5 to +25% change, N=29) and “robust remodelers” (>+25% change, N=30). Early remodeling category was significantly associated with primary patency rate at 2 years P=.02, log-rank). A multi-variable Cox proportional hazards model showed that modest (HR 3.9, 95% CI 1.02-15, P=.04) and poor (HR 13, 95% CI 1.9-89, P=.008) remodelers had significantly higher hazard ratios for graft failure than robust early remodelers. CONCLUSIONS Early remodeling of the arterialized vein appears to predict mid-term bypass graft patency. In addition to baseline diameter, race, inflammation, CRP, and statin use are associated with early adaptive remodeling, but the mechanism for these observations are not understood.

Purpose The maturation of an arterio-venous fistula (AVF) requires remodeling of the arterial inflow and the venous outflow limbs to sustain flows sufficient to support hemodialysis. However, factors influencing remodeling of AVF are poorly understood. We hypothesized that AVF remodeling was an endothelium-dependent process. Methods This is a prospective cohort study of patients (n=25) undergoing autologous AVF formation. Brachial artery vasoreactivity studies were performed preoperatively to assess endothelium-dependent, flow-mediated vasodilation (FMD). High-resolution ultrasound was used to assess venous and arterial diameters intraoperatively, and at 3 months. Results The mean age was 64.5 ± 13.6 years. Twelve subjects (48%) had diabetes. The mean FMD for the entire cohort was (mean ± SEM) 5.82 ± 0.9%, (range) 0–17.3%. The vein increased in size 3.19 ± .28 to 6.11 ± .41 mm, 108.4 ± 17.9%, p=.0001, while the artery increased from 3.29 ± .14 to 4.48 ± .30 mm, 20.47 ± 10.8%, p=.013. There was a significant positive correlation between the degree of arterial and venous remodeling, r=.52, p=.023. Brachial artery FMD most strongly correlated with the magnitude of arterial remodeling, r=.47, p=.038. Patients with diabetes failed to undergo venous remodeling to the same extent as did those without diabetes, 59.2 ± 24.4% vs. 141.5 ± 25.4%, p=.04. Conclusion Impairment of endothelial function is associated with decreased arterial remodeling and final venous lumen diameter attained at three months. Further investigation is needed to determine whether modulation of endothelial function in this cohort can improve AVF maturation.

Objective A significant portion of patients undergoing lower extremity bypass surgery (LEB) for peripheral arterial disease (PAD) will have cardiovascular or graft-related events. It has been previously demonstrated that systemic inflammation is associated with PAD and its clinical outcomes. We hypothesized that serum biomarkers of insulin resistance and inflammation would identify a sub-group at elevated risk for graft failure, limb loss, and mortality. Methods This was a prospective longitudinal study of patients (N=225) undergoing LEB using autogenous vein. Baseline blood samples were obtained prior to surgery in the fasting state. High-sensitivity C-reactive protein (hsCRP) and the adipokines resistin and high-molecular weight adiponectin (HMWA) were measured by ELISA. Median follow-up was 893 days. The major endpoints of primary patency (PP) and amputation free survival (AFS) were examined using multivariable methods. Endpoints were screened against biomarkers and patient characteristics for univariate associations. Promising explanatory variables (P < 0.1) were included in multivariable Cox proportional hazard models. Results The mean age of subjects was 67.6 years; 71.6% were male and 87.1% were Caucasian. One-hundred and thirty-three (59.1%) subjects underwent bypass for critical limb ischemia (CLI) and 73 (32.4%) had tissue loss. Patients with CLI and diabetes demonstrated elevated resistin and hsCRP levels. HMWA levels correlated with CLI and with a measure of insulin resistance (HOMA-IR) but not with clinical diabetes. Baseline biomarkers were higher in those presenting with tissue loss and in patients with post-operative events (mortality, limb loss). After multivariable analysis (including CLI, diabetes, age, estimated glomerular filtration rate (eGFR), adiponectin, resistin, and CRP), resistin (HR 1.75, 95% CI 1.07 to 2.85, P=0.025) and CRP (HR 2.39, 95% CI 1.30 to 4.39, P=0.005) were independently predictive of reduced AFS. However, only resistin maintained its significance when restricted to the diabetic cohort (HR 2.10, 95% CI 1.10 to 3.99, P=0.025). Higher levels of HMWA were found to be associated with primary graft patency (HR 0.73 for graft failure, 95% CI 0.55 to 0.97, P=0.031) in a multivariable model adjusting for diabetes, CRP, African-American race, CLI, high-risk conduits, and redo bypass procedures. Conclusion These findings suggest that serum biomarkers of insulin resistance and inflammation may be predictive of clinical outcomes following LEB. Improving the systemic milieu of insulin resistance and inflammation in these high-risk patients may lead to reduced morbidity and mortality.

Background Patients with advanced peripheral artery disease (PAD) have a high prevalence of cardiovascular (CV) risk factors and shortened life expectancy. However, CV risk factors poorly predict midterm (<5 years) mortality in this population. This study was designed to test the hypothesis that baseline biochemical parameters would add clinically meaningful predictive information in patients undergoing lower extremity bypass. Methods This was a prospective cohort study of subjects with clinically advanced PAD undergoing lower extremity bypass surgery. The Cox proportional hazard was used to assess the main outcome of all-cause mortality. A clinical model was constructed with known cardiovascular risk factors and the incremental value of the addition of clinical chemistry, lipid, and a panel of 11 inflammatory parameters were investigated using c-statistic, the integrated discrimination improvement (IDI) index and Akaike information criterion (AIC). Results 225 subjects were followed for a median 893 days; IQR 539–1315 days). In this study 50 (22.22%) subjects died during the follow-up period. By life table analysis (expressed as percent surviving ± standard error), survival at 1, 2, 3, 4, and 5 years respectively was 90.5 ± 1.9%, 83.4 ± 2.5%, 77.5 ± 3.1%, 71.0 ± 3.8%, and 65.3 ± 6.5%. Compared with survivors, decedents were older, diabetic, had extant CAD, and were more likely to present with CLI as their indication for bypass surgery, P<.05. After adjustment for the above, clinical chemistry and inflammatory parameters significant for all cause mortality were albumin, HR .43 (95% CI .26–.71); P=.001, estimated glomerular filtration rate (eGFR), HR .98 (95% CI .97–.99), P=.023, high sensitivity C-reactive protein (hsCRP), HR 3.21 (95% CI 1.21–8.55), P=.019, and soluble vascular cell adhesion molecule (sVCAM), HR 1.74 (1.04–2.91), P=.034. Of all inflammatory molecules investigated, hsCRP proved most robust and representative of the integrated inflammatory response. Albumin, eGFR, and hsCRP improved the c-statistic and IDI beyond that of the clinical model and produced a final c-statistic of .82. Conclusions A risk prediction model including traditional risk factors and parameters of inflammation, renal function and nutrition had excellent discriminatory ability in predicting all cause mortality in patients with clinically advanced PAD undergoing bypass surgery.

Objective To determine if there are gender-based differences in the inflammatory phenotype of patients undergoing lower extremity bypass (LEB), and if they correlate with clinical outcomes. Methods Retrospective analysis of a prospective cohort study of 225 patients (161 men and 64 women) who underwent LEB using autogenous vein between February 2004 and May 2008. Fasting baseline blood samples were obtained prior to surgery and included the inflammatory biomarkers high-sensitivity C-reactive protein (CRP) and fibrinogen. All patients underwent ultrasound graft surveillance. CRP levels were dichotomized at 5mg/L, and fibrinogen levels were dichotomized at 600mg/dL. Results There were no significant differences in age, race, history of hypertension or diabetes mellitus, body mass index, and coronary artery disease between men and women. Men were more likely to be current smokers (p=0.02), have a history of hypercholesterolemia (p=0.02) and taking statins (p=0.02). Women were more likely to present with critical limb ischemia (p=0.03) and had higher baseline CRP levels (median:5.15 mg/L; IQR:1.51-18.62mg/L) compared to men (median:2.70; IQR:1.24-6.98mg/L) (p=0.02). The median follow-up was 893 days (IQR:539-1315 days). In a multivariable Cox proportional hazards model for primary vein graft patency, there was a significant interaction between gender and both CRP (p=0.03) fibrinogen (p=0.02). After adjustment for key covariates, primary vein graft patency was significantly less in women with CRP>5mg/L compared to women with CRP<5mg/L (p=0.02), while there was no such difference seen in men (p=0.95). Primary graft patency was also decreased in women with fibrinogen>600mg/dL compared to women with fibrinogen<600mg/dL (p=0.002), but again, this pattern was not evident in men (p=0.19). Conclusions Women undergoing LEB for advanced peripheral artery disease have a different inflammatory phenotype compared to men, and elevated baseline levels of CRP and fibrinogen are associated with inferior vein graft patency in women, but not in men. These findings indicate an important interaction between gender and inflammation in the healing response of lower extremity vein bypass grafts. Women with elevated pre-operative CRP and fibrinogen levels may benefit from more intensive post-operative graft surveillance protocols.