Implications and Late Outcomes of Type II Endoleaks After Endovascular Aneurysm Repair.

OBJECTIVE: Type II endoleaks (T2EL) are the most common cause of reintervention after endovascular aneurysm repair (EVAR). While most resolve spontaneously, the long-term implications of T2EL remain elusive. We aim to evaluate the impact of persistent and late T2EL on clinical outcomes after EVAR. METHODS: Single institution retrospective review of patients who underwent EVAR for degenerative infrarenal abdominal aortic aneurysm between January 2010 and June 2022 with no Type I (T1EL) or III (T3EL) endoleak seen at EVAR completion. Patients were categorized based on T2EL status. Group 1 included patients with never detected or transient T2EL (detected at EVAR completion but not after). Group 2 encompassed persistent T2EL (seen at EVAR completion and again during follow-up) and late T2EL (detected for the first time at any point during follow-up). Time-to-event analysis was conducted using a time-dependent approach to T2EL status. Primary outcomes included freedom from sac enlargement (SE), aneurysm-related reinterventions, and overall survival. RESULTS: 803 patients met inclusion criteria. Group 1 included 418 patients (52%), of which 85% had no T2EL and 15% had transient T2EL. Group 2 had 385 patients; 23% had persistent T2EL, and 77% developed a new T2EL. Patients in group 1 had a higher prevalence of smoking (88% vs. 83%; p<0.001), COPD (33% vs. 25%; p=0.008), chronic kidney disease (13% vs. 8%; p=0.021) and a higher mean SVS score (7 vs. 6 points; p=0.049). No differences were found in aneurysm diameter or morphology. Mean follow-up was 5 years for the entire cohort. In Group 2, 58 patients (15%) underwent T2EL treatment, most commonly transarterial embolization. At 10 years after EVAR, Group 2 was associated with lower freedom from SE (p<0.001) and AAA-related reinterventions (p<0.001) and comparable overall survival (p=0.42). More T1EL were detected during follow-up in Group 2 (6 [1%] vs. 20 [5%]; p=0.004), with 15 (75%) of these detected at a median of 3 years after the T2EL. No difference between groups was observed in explant (0.7% vs. 2.1%; p=0.130) or aneurysm rupture (0.5% vs. 1.3%; p=0.269) rates. CONCLUSION: One-half of patients treated with infrarenal EVAR developed persistent/late T2ELs, which are associated with a higher risk of sac enlargement and reinterventions. No difference in overall survival or aneurysm rupture risk was seen at 10 years, based on T2EL status or T2EL intervention. A conservative approach to T2EL may be appropriate for most patients with absent T1EL or T3EL.

Outcomes of lower extremity arterial bypass using the Human Acellular Vessel in patients with chronic limb-threatening ischemia.

OBJECTIVE: Patients with chronic limb-threatening ischemia (CLTI) and no great saphenous vein to use as a conduit for arterial bypass have a high risk for amputation despite advances in medical and endovascular therapies. This report presents findings from a U.S. Food and Drug Administration (FDA) supported study of the Human Acellular Vessel (HAV) (Humacyte Inc.) used as a conduit for arterial bypass in patients with CLTI and inadequate or absent autologous conduit. METHODS: The HAV is a 6-mm, 40-cm vessel created from human vascular smooth muscle cells seeded onto a polyglycolic acid scaffold pulsed in a bioreactor for 8 weeks as cells proliferate and the scaffold dissolves. The resultant vessel is decellularized, creating a nonimmunogenic conduit composed of collagen, elastin, and extracellular matrix. The FDA issued an Investigational New Drug for an intermediate-sized, single-center study of the HAV under the agency's Expanded Access Program in patients with advanced CLTI and inadequate or absent autologous conduit. Technical results and clinical outcomes were analyzed and reported. RESULTS: Between March 2021 and July 2023, 29 patients (20 males; mean age, 71 ± 11 years) underwent limb salvage operation using the HAV as a bypass conduit. Most patients had advanced CLTI (Rutherford class 5/6 in 72%; wound, ischemia, and foot infection stage 3/4 in 83%), and 97% had previously failed revascularization(s) of the extremity. Two HAVs were sewn together to attain the needed bypass length in 24 patients (83%). Bypasses were to tibial arteries in 23 patients (79%) and to the popliteal artery in 6 (21%). Technical success was 100%, and the 30-day mortality rate was 7% (2 patients). With 100% follow-up (median, 9.3 months), the limb salvage rate was 86% (25/29 patients). There were 16 reinterventions to restore secondary patency, of which 15 (94%) were successful. Primary and secondary patency of the HAV at 9 months were 59% and 71%, respectively. CONCLUSIONS: The HAV has demonstrated short- to intermediate-term safety and efficacy as an arterial bypass conduit in a complex cohort of patients with limb-threatening ischemia and no autologous options. This experience using the FDA's Expanded Access Program provides real-world data to inform regulatory deliberations and future trials of the HAV, including the study of the vessel as a first-line bypass conduit in less severe cases of chronic limb ischemia.

Cryopreserved arterial allografts vs autologous vein for arterial reconstruction in infected fields.

OBJECTIVE: Peripheral arterial infections are rare and difficult to treat when an in situ reconstruction is required. Autologous vein (AV) is the conduit of choice in many scenarios. However, cryopreserved arterial allografts (CAAs) are an alternative. We aimed to assess our experience with CAAs and AVs for reconstruction in primary and secondary peripheral arterial infections. METHODS: Data from patients with peripheral arterial infections undergoing reconstruction with CAA or AV from January 2002 through August 2022 were retrospectively analyzed. Patients with aortic- or iliac-based infections were excluded. RESULTS: A total of 42 patients (28 CAA, 14 AV) with a mean age of 65 and 69 years, respectively, were identified. Infections were secondary in 31 patients (74%) and primary in 11 (26%). Secondary infections included 10 femoral-femoral grafts, 10 femoropopliteal or femoral-distal grafts, five femoral patches, four carotid-subclavian grafts, one carotid-carotid graft, and one infected carotid patch. Primary infection locations included six femoral, three popliteal, and two subclavian arteries. In patients with lower extremity infections, associated groin infections were present in 19 (56%). Preoperative blood cultures were positive in 17 patients (41%). AVs included saphenous vein in eight and femoral vein in six. Intraoperative cultures were negative in nine patients (23%), polymicrobial in eight (21%), and monomicrobial in 22 (56%). Thirty-day mortality occurred in four patients (10%), two due to multisystem organ failure, one due to graft rupture causing acute blood loss and myocardial infarction, and one due to an unknown cause post-discharge. Median follow-up was 20 months and 46 months in the CAA and AV group, respectively. Graft-related reintervention was performed in six patients in the CAA group (21%) and one patient in the AV group (7%). Freedom from graft-related reintervention rates at 3 years were 82% and 92% in the CAA and AV group, respectively (P = .12). Survival rates at 1 and 3 years were 85% and 65% in the CAA group and 92% and 84% in the AV group (P = .13). Freedom from loss of primary patency was similar with 3-year rates of 77% and 83% in the CAA and AV group, respectively (P = .25). No patients in either group were diagnosed with reinfection. CONCLUSIONS: CAAs are an alternative conduit for peripheral arterial reconstructions when AV is not available. Although there was a trend towards higher graft-related reintervention rates in the CAA group, patency is similar and reinfection is rare.

Cryopreserved Arterial Allografts Versus Rifampin-Soaked Dacron for the Treatment of Infected Aortic and Iliac Aneurysms.

BACKGROUND: Infected aortic and iliac artery aneurysms are challenging to treat. Cryopreserved arterial allografts (CAAs) or rifampin-soaked Dacron (RSD) are standard options for in situ reconstruction. Our aim was to compare the safety and effectiveness of CAA versus RSD for these complex pathologies. METHODS: This is a retrospective review of infected iliac, abdominal, and thoracoabdominal aortic aneurysms treated with either CAAs or RSD between 2002 and 2022 at our institution. The diagnosis was confirmed by intraoperative, radiologic, or microbiological evidence of aortic infection. Perioperative events, 30-day and long-term mortality, reinfection, and reintervention were analyzed. RESULTS: Thirty patients (17 CAA, 13 RSD) with a mean age of 61 and 68 years, respectively, were identified. The infected aneurysm was most commonly suprarenal or infrarenal. Culture-negative infections were present in 47% of the CAA group and 54% in the RSD group. Early major morbidity was 57% and 54% for the CAA and RSD, respectively. Thirty-day mortality was similar between groups (18% vs. 23% CAA vs. RSD, P ≥ 0.99). Median follow-up was longer in the RSD group (14.5 months vs. 13 months). Overall survival at 1 and 5 years was 80.8% and 64.8% in the CAA group and 69.2% and 57.7% in the RSD group. Reinterventions only occurred with CAA repairs and indications included graft occlusion (2), multiple pseudoaneurysms and reinfection (1), and hemorrhagic shock caused by graft rupture (1). Freedom from reintervention at 1 and 3 years was 87.5% and 79.5% (CAA group) versus 100% and 100% (RSD, P = 0.06). Freedom from reinfection at 1 year was 100% in both groups, while at 3 years it was 90.9% for the CAA group and 100% for the RSD group (P = 0.39). CONCLUSIONS: Infected aortic and iliac aneurysms have high early morbidity and mortality. CAA and RSD had similar outcomes in our series; CAA trended toward higher reintervention rates. Both remain viable options for complex scenarios but require close surveillance.

The association between diabetes mellitus and its management with outcomes following endovascular repair for descending thoracic aortic aneurysm.

OBJECTIVE: Prior literature is conflicted regarding the effect of diabetes mellitus (DM) on outcomes after endovascular repair of aortic aneurysms. In this study, we aimed to examine the association between DM and outcomes after thoracic endovascular aneurysm repair (TEVAR) for thoracic aortic aneurysm (TAA). METHODS: We identified patients who underwent TEVAR for TAA of the descending thoracic aorta in the Vascular Quality Initiative between 2014 and 2022. We created two cohorts, DM and nonDM, based on the patient's preoperative DM status, and secondarily substratified patients with DM by management strategy: dietary management, noninsulin medications, and insulin therapy cohorts. Outcomes included perioperative and 5-year mortality, in-hospital complications, indications for repair, and 1-year sac dynamics, which were analyzed with multivariable cox regression, multivariable logistic regression, and χ2 tests, respectively. RESULTS: We identified 2637 patients, of which 473 (18%) had DM preoperatively. Among patients with DM, 25% were diet controlled, 54% noninsulin medications, and 21% insulin therapy. Within patients who underwent TEVAR for TAA, the proportions of ruptured presentation were higher in the dietary-managed (11.1%) and insulin-managed (14.3%) cohorts relative to noninsulin therapy (6.6%) and those without DM (6.9%). After multivariable regression analysis, we found that DM was associated with similar perioperative mortality (odds ratio, 1.14; 95% confidence interval [CI], 0.70-1.81) and 5-year mortality compared with patients without DM (hazard ratio, 1.15; 95% CI, 0.91-1.48). Furthermore, all in-hospital complications were comparable between patients with DM and patients without DM. Compared with patients without DM, dietary management of DM was significantly associated with higher adjusted perioperative mortality (OR, 2.16; 95% CI, 1.03-4.19) and higher 5-year mortality (hazad ratio, 1.50; 95% CI, 1.03-2.20), although this was not the case for other DM subgroups. All cohorts displayed similar 1-year sac dynamics, with sac regression occurring in 47% of patients without DM vs 46% of patients with DM (P = .27). CONCLUSIONS: Preoperatively, patients with DM who underwent TEVAR had a higher proportion of ruptured presentation when treated with diet or insulin medications than when treated with noninsulin medications. After TEVAR for descending TAA, DM was associated with a similar risk of perioperative and 5-year mortality as nonDM. In contrast, dietary therapy for DM was associated with significantly higher perioperative mortality and 5-year mortality.

Treatment With a Marine Oil Supplement Alters Lipid Mediators and Leukocyte Phenotype in Healthy Patients and Those With Peripheral Artery Disease.

Background Peripheral artery disease (PAD) is an advanced form of atherosclerosis characterized by chronic inflammation. Resolution of inflammation is a highly coordinated process driven by specialized pro-resolving lipid mediators endogenously derived from omega-3 fatty acids. We investigated the impact of a short-course, oral, enriched marine oil supplement on leukocyte phenotype and biochemical mediators in patients with symptomatic PAD and healthy volunteers. Methods and Results This was a prospective, open-label study of 5-day oral administration of an enriched marine oil supplement, assessing 3 escalating doses in 10 healthy volunteers and 10 patients with PAD. Over the course of the study, there was a significant increase in the plasma level of several lipid mediator families, total specialized pro-resolving lipid mediators, and specialized pro-resolving lipid mediator:prostaglandin ratio. Supplementation was associated with an increase in phagocytic activity of peripheral blood monocytes and neutrophils. Circulating monocyte phenotyping demonstrated reduced expression of multiple proinflammatory markers (cluster of differentiation 18, 163, 54, and 36, and chemokine receptor 2). Similarly, transcriptional profiling of monocyte-derived macrophages displayed polarization toward a reparative phenotype postsupplementation. The most notable cellular and biochemical changes over the study occurred in patients with PAD. There were strong correlations between integrated biochemical measures of lipid mediators (specialized pro-resolving lipid mediators:prostaglandin ratio) and phenotypic changes in circulating leukocytes in both healthy individuals and patients with PAD. Conclusions These data suggest that short-term enriched marine oil supplementation dramatically remodels downstream lipid mediator pathways and induces a less inflammatory and more pro-resolution phenotype in circulating leukocytes and monocyte-derived macrophages. Further studies are required to determine the potential clinical relevance of these findings in patients with PAD. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02719665.

Circulating exosomes from patients with peripheral artery disease influence vascular cell migration and contain distinct microRNA cargo.

OBJECTIVE: Peripheral artery disease (PAD) is a chronic condition characterized by inflammation. Emerging literature suggests that circulating exosomes and their microRNA (miRNA) contents may influence atherosclerosis and vascular remodeling. We hypothesize that circulating exosomes in patients with PAD directly modulate vascular cell phenotype and contain proinflammatory miRNAs. METHODS: Exosomes (particle size, 30-150 nm) were isolated from plasma of healthy individuals (n = 6), patients with mild PAD (mPAD; median Rutherford class, 2.5; n = 6), and patients with severe PAD (sPAD; median Rutherford class, 4; n = 5). Exosome identity, size, and concentration were determined by Western blot and nanoparticle tracking analysis. Human vascular smooth muscle cell (VSMC) and endothelial cell (EC) migration was assessed by a standard wound closure assay after exposure to exosome preparations. Monocyte-derived macrophages isolated from healthy volunteers were exposed to exosome preparations, and targeted gene expression was analyzed using quantitative polymerase chain reaction. Exosome miRNA cargos were isolated, and a panel of defined, vascular-active miRNAs was assessed by quantitative polymerase chain reaction. RESULTS: There was no difference in overall exosome particle concentration or size between the three groups (one-way analysis of variance [ANOVA], P > .05). Compared with exosomes from healthy individuals, exosomes from mPAD and sPAD patients increased VSMC migration (1.0 ± 0.09-fold vs 1.5 ± 0.09-fold vs 2.0 ± 0.12-fold wound closure; ANOVA, P < .0001) and inhibited EC migration (1.8 ± 0.07-fold vs 1.5 ± 0.04-fold vs 1.3 ± 0.02-fold wound closure; ANOVA, P < .01) in a stepwise fashion. Exosomes also induced changes in monocyte-derived macrophage gene expression that did not appear PAD specific. Hierarchical analysis of exosome miRNA revealed distinct clustering of vascular-active miRNAs between the three groups. Several miRNAs that promote inflammatory pathways in vascular cells were expressed at higher levels in exosomes from sPAD patients. CONCLUSIONS: Circulating exosomes from individuals with PAD exert in vitro functional effects on VSMCs and ECs that may promote adverse vessel remodeling. Exosomes from healthy individuals, mPAD patients, and sPAD patients contain distinct signatures of immune-regulatory miRNA. Together these data suggest that the proinflammatory cargo of circulating exosomes correlates with atherosclerosis severity in PAD patients and could influence vascular injury and repair. (JVS: Vascular Science 2020;1:28-41.). CLINICAL RELEVANCE: Exosomes and their cargo have been implicated in several vascular remodeling processes including atherosclerosis, angiogenesis, and neointimal hyperplasia. In this study, we demonstrate that circulating exosomes from individuals with peripheral artery disease exert in vitro effects on vascular cells that may adversely affect vessel remodeling. Moreover, these exosomes contain elevated levels of vascular-active microRNA. Our results suggest that exosomes may serve as both biomarkers and effectors of vascular disease in patients with peripheral artery disease and motivate further investigation into the role of exosomes and their contents in aberrant remodeling in vascular diseases.

Oral Resolvin D1 attenuates early inflammation but not intimal hyperplasia in a rat carotid angioplasty model.

Inflammation ensuing from vascular injury promotes intimal hyperplasia (IH) and restenosis. Resolvin D1 (RvD1) is a lipid mediator that attenuates IH in vivo when delivered locally to the vessel wall in animal models. We tested the hypothesis that peri-procedural oral administration of RvD1 could blunt the local inflammatory response to angioplasty, and attenuate downstream IH. Carotid angioplasty was performed on rats fed with either RvD1 or vehicle through oral gavage, starting one day prior to injury until post-operative day (POD) 3 or 14 when arteries were harvested. To study pharmacokinetics and bioactivity of oral RvD1, we measured plasma RvD1 by ELISA, whole blood phagocytosis activity using flow cytometry, and cAMP levels in the thoracic aorta by ELISA. Carotid arteries were harvested on POD3 for staining (anti-CD45, anti-Myeloperoxidase (MPO), anti-Ki67 or dihydroethidium (DHE) for reactive oxygen species), mRNA expression of target genes (quantitative RT-PCR), or on POD14 for morphometry (elastin stain). RvD1 plasma concentration peaked 3 h after gavage in rats, at which point we concurrently observed an increase in circulating monocyte phagocytosis activity and aortic cAMP levels in RvD1-treated rats vs. vehicle. Oral RvD1 attenuated local arterial inflammation after angioplasty by reducing CD45+, MPO+, Ki67+ cells, and DHE staining intensity. Oral RvD1 also reduced the expression of several pro-inflammatory genes within the injured vessels. However, oral RvD1 did not significantly reduce IH. Oral RvD1 attenuated acute inflammation within the arterial wall after angioplasty in rats, but did not significantly affect IH.

Late graft failure is rare after endovascular aneurysm repair using the Zenith stent graft in a cohort of high-risk patients.

OBJECTIVE: Device-specific data on the long-term efficacy of endovascular aneurysm repair (EVAR) are limited by the constant evolution of stent graft design. Whereas some modifications, such as barb-mediated fixation, probably enhance durability, others, such as thin-walled fabric, are of less certain benefit. The purpose of this study was to examine 15 years of a single-center experience of EVAR using the Zenith stent graft (Cook Medical, Bloomington, Ind). METHODS: Retrospective analysis was conducted of 325 high-risk patients who underwent elective EVAR with Zenith stent grafts between October 1998 and December 2005 under a physician-sponsored investigational device exemption. Patients' charts and death registries were reviewed to identify late stent graft failures and causes of death. Late stent graft failures were defined as type I or type III endoleaks; enlarging aneurysm sac requiring revision; and limb kinking or occlusion, stent graft infection, renal artery occlusion, or aneurysm rupture occurring >30 days after the index procedure. RESULTS: The mean age at treatment was 75.9 ± 7.4 years, and 300 of 325 (92%) were men. The mean aneurysm diameter was 60 ± 9 mm, and the median main body stent graft diameter was 28 mm (range, 22-32 mm). During a median follow-up time of 5.6 years (interquartile range, 2.6-8.7 years), there were six (2%) aneurysm-related deaths caused by the following: one stent graft infection, one infection of a femoral-femoral bypass graft placed after limb occlusion, one infection of a stent graft placed to treat a type IB endoleak, and three aneurysm ruptures. There were 19 (6%) late stent graft failures occurring at a median time of 4.0 years (range, 39 days-14.6 years) after the procedure. Patients with late stent graft failure were more likely to have had impaired renal function (creatinine concentration ≥2 mg/dL; 21% vs 6%; P = .03) and less likely to have had cardiac disease (42% vs 67%; P = .04) at the time of the index procedure. There was no significant association between late stent graft failure and age, sex, aneurysm size, stent graft diameter, diabetes, smoking, or lung disease. Kaplan-Meier estimated overall survival was 60% at 5 years, 29% at 10 years, and 12% at 15 years. Kaplan-Meier estimated freedom from aneurysm-related mortality was 98% at 5 years, 97% at 10 years, and 97% at 15 years. CONCLUSIONS: Late-occurring stent graft failures and aneurysm-related death are rare after EVAR using the Zenith stent graft, especially in high-risk patients whose comorbidities diminish life expectancy.

Radial Artery Tonometry is Associated With Major Adverse Cardiac Events in Patients With Peripheral Artery Disease.

BACKGROUND: Peripheral artery disease (PAD) is associated with increased arterial stiffness, as measured by an increasing radial artery augmentation index (AIX). However, it has not yet been clearly demonstrated whether AIX is associated with adverse cardiovascular outcomes in a PAD population. MATERIALS AND METHODS: Seventy-two patients with PAD were recruited between 2011 and 2016. Radial artery applanation tonometry was performed at a baseline visit, and the central AIX, normalized to 75 beats/min, and the peripheral AIX were calculated using pulse wave analysis. Incident major adverse cardiac events (MACEs) were identified by subsequent chart review. RESULTS: Study subjects had comorbidities commonly associated with PAD including a high prevalence of hypertension (93%), hyperlipidemia (85%), coronary artery disease (39%), and diabetes mellitus (39%). During a median follow-up period of 34 mo (interquartile range 29-38), 14 patients experienced a MACE. In a univariate Cox proportional hazards model, a 10-unit increase in the peripheral AIX was significantly associated with a 54% increased rate of MACE (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.06-2.22, P = 0.02), but central AIX, normalized to 75 beats/min, was not (HR 1.33, 95% CI 0.71-2.47, P = 0.37). In a multivariable model adjusted for coronary artery disease, age, and Rutherford category the peripheral AIX remained significantly associated with MACE (HR 1.70, 95% CI 1.10-2.62, P = 0.02). CONCLUSIONS: Increased arterial stiffness, as measured by the peripheral AIX, was independently associated with an increased rate of MACE in patients with PAD. The use of radial artery tonometry should be contemplated as a tool for risk stratification in patients with PAD.

Serum resistin is associated with impaired endothelial function and a higher rate of adverse cardiac events in patients with peripheral artery disease.

OBJECTIVE: Resistin is a hormone that has been associated with metabolic syndrome and cardiovascular disease. The role of resistin in patients with peripheral artery disease (PAD) has not been fully explored. This study seeks to understand the relationship between serum resistin, vascular function, and cardiovascular outcomes in patients with PAD. METHODS: There were 106 patients with PAD who were recruited between 2011 and 2016. Patients attended a baseline visit during which a comprehensive vascular physiology assessment including medical and surgical history, radial artery tonometry, and flow mediated-vasodilation (FMD) was completed. A blood sample was drawn, and serum resistin was assayed using enzyme-linked immunosorbent assay kits. Using the time of study enrollment as the time of origin, incident major adverse cardiac events (MACEs) were identified by subsequent chart review and defined as a composite end point of myocardial infarction, coronary revascularization, transient ischemic attack, stroke, or death from a cardiac cause. RESULTS: Patients had a mean age of 68 ± 8 years, were largely white (75%), and had comorbidities commonly associated with PAD including hypertension (92%), hyperlipidemia (87%), coronary artery disease (37%), and diabetes mellitus (38%). After stratification by resistin quartile, higher resistin quartiles were significantly associated with an older age, a greater number of pack-years smoked, and a lower estimated glomerular filtration rate. Despite similar comorbidities and medication use, endothelial function, as measured by FMD, was significantly lower with increasing resistin quartile (I, 9.1% ± 3.3%; II, 7.1% ± 3.5%; III, 5.8% ± 4.0%; IV, 5.6% ± 3.5%; P = .002). In multivariable linear regression, higher resistin quartiles (III and IV) were associated with lower FMD relative to quartile I after adjusting for several patient characteristics, medications, and comorbidities (III, -2.26 [95% confidence interval (CI), -4.51 to -0.01; P = .05]; IV, -2.53 [95% CI, -4.87 to -0.20; P = .03]). During a median follow-up period of 36 months (interquartile range, 29-45 months), 21 patients experienced the primary end point. In a Cox proportional hazards model adjusted for smoking status, coronary artery disease, and age, each 1 ng/mL increase in resistin was associated with a 10% increased risk of MACEs (hazard ratio, 1.10; 95% CI, 1.00-1.20; P = .04). CONCLUSIONS: In patients with PAD, higher levels of resistin were associated with impaired endothelial function and an increased rate of MACEs. These results suggest that resistin may be a marker or effector of impaired vascular physiology and adverse cardiac outcomes in patients with PAD. Further research is needed to determine the potential mechanisms by which resistin may impair endothelial function and increase MACEs in this population.

Characterizing the relationship between flow-mediated vasodilation and radial artery tonometry in peripheral artery disease.

BACKGROUND: Arterial stiffness, measured by the augmentation index (AIX) from radial artery tonometry, and endothelial dysfunction, measured by brachial-artery flow-mediated vasodilation (FMD), have each been associated with increased risk of cardiovascular events. However, their interrelationship in peripheral artery disease (PAD) patients is poorly understood. MATERIALS AND METHODS: In a cross-sectional analysis of 123 vascular surgery outpatients, the association between FMD and AIX was examined in controls with atherosclerotic risk factors (n = 32) and patients with PAD (n = 91). PAD was defined as claudication symptoms with an ankle-brachial index of <0.9 or a history of revascularization for symptomatic PAD. Controls had an ankle-brachial index ≥0.9 and no history of atherosclerotic vascular disease. RESULTS: Compared to controls, patients with PAD had lower FMD (6.3 ± 3.8 versus 8.4 ± 3.7, P = 0.008), while central AIX normalized to 75 beats per minute (25.5 ± 9.0 versus 19.3 ± 8.6, P = 0.001) and peripheral AIX (91.3 ± 14.5 versus 81.3 ± 11.4, P = 0.001) were higher. FMD was not significantly correlated with either central or peripheral AIX (central AIX: P = 0.58; peripheral AIX: P = 0.89) across the entire cohort, or in either the patients with PAD (central AIX: P = 0.48; peripheral AIX: P = 0.23) or controls (central AIX: P = 0.43; peripheral AIX: P = 0.92). In a multivariate model including FMD, higher AIX remained independently associated with PAD. CONCLUSIONS: In an analysis of vascular surgery outpatients, no correlation between FMD and AIX was detected. Larger prospective studies are needed to determine whether the inclusion of both parameters improves predictive models for the early identification and potential risk stratification of PAD patients.

Frailty Is Associated with an Increased Risk of Major Adverse Cardiac Events in Patients with Stable Claudication.

BACKGROUND: Frailty, a syndrome characterized by decreased physiologic reserves and resistance to stressors, is associated with disability, poor surgical outcomes, and mortality. We evaluated the impact of frailty on cardiovascular disease (CVD) events in peripheral arterial disease (PAD) patients with intermittent claudication. METHODS: We conducted a retrospective review of patients with stable intermittent claudication enrolled in the OMEGA-PAD study between 2010 and 2015. The modified frailty index (mFI) is a retrospectively validated index of frailty derived from the Canadian Study of Health and Aging and was used in this study to categorize frailty as low, medium, or high. Our outcome was time to occurrence of a major adverse cardiac event (MACE), defined as a composite endpoint of myocardial infarction, coronary revascularization, stroke, or CVD-related death. Cox proportional hazards models were used to calculate relative hazards ratio. RESULTS: There were 129 subjects with a mean age of 67 years, 97% were men, 36% were diabetic, and 33% had known coronary heart disease. When the mFI criteria were applied, 38 subjects were "low" frailty, 72 were "medium" frailty, and 19 were "high" frailty. During the median follow-up period of 34 months (interquartile range: 25-43), 29 subjects experienced a MACE. When compared to the lowest mFI, patients with medium frailty were 2.8 times more likely to have an event (95% confidence interval [CI]: 0.95-8.46, P = 0.06), whereas patients with a high mFI were 4.8 times as likely (95% CI: 1.43-15.8, P = 0.01). In a model adjusted for age, smoking status, and presence of diabetes, those with a medium mFI were 4.3 times more likely to have an event (95% CI: 1.37-13.7, P = 0.01) and those with a high mFI were 9.2 times as likely (95% CI: 2.6-32.4, P = 0.001). CONCLUSIONS: Higher mFI category is associated with a significantly increased risk of MACE in PAD patients with stable claudication. Frailty may serve as a useful adjunct for assessment of overall cardiac risk, particularly as treatment options are being contemplated.

Relationship between the omega-3 index and specialized pro-resolving lipid mediators in patients with peripheral arterial disease taking fish oil supplements.

BACKGROUND: Oral supplementation with n-3 polyunsaturated fatty acids (PUFA) increases the omega-3 index, a biomarker of red blood cell eicosapentaenoic acid and docosahexaenoic acid, and plasma levels of biosynthesis pathway markers and potent lipid mediators involved in the resolution of inflammation among patients with peripheral arterial disease (PAD). OBJECTIVE: We aimed to quantify the association between an upstream change in the omega-3 index and downstream changes in lipid mediator production. METHODS: We conducted a secondary analysis of the OMEGA-PAD I Trial, a randomized, placebo controlled trial investigating high-dose n-3 PUFA oral supplementation in PAD patients. Eighty subjects were randomized to either 4.4 g of fish oil or placebo for 1 month. Regression analyses using generalized estimating equation techniques were used to investigate the relationship between changes in the omega-3 index and changes in lipid mediators, pre- and post-intervention. RESULTS: In the fish oil group, there was a significant increase in the omega-3 index (5 ± 1% to 9 ± 2%, P < .001) as well as in the plasma levels of several downstream lipid mediator pathway markers of resolution, which are involved with the regulation of leukocyte effector function and host defense. A doubling of the omega-3 index correlated with increases of 2.3-fold in 18-hydroxy-eicosapentaenoic acid (HEPE; P < .0001), 1.7-fold in 15-HEPE (P = .03), 1.9-fold in 5-HEPE (P = .04), and 3.6-fold in 4-hydroxy-docosahexaenoic acid (P < .001). CONCLUSION: Among subjects with symptomatic PAD who took oral fish oil supplements for 1 month, observed changes in the omega-3 index were strongly associated with increases in downstream mediators in the biochemical pathways of resolution.

Association between arterial stiffness and peripheral artery disease as measured by radial artery tonometry.

OBJECTIVE: Arterial stiffness and peripheral artery disease (PAD) are both associated with an elevated risk of major adverse cardiac events; however, the association between arterial stiffness and PAD is less well characterized. The goal of this study was to examine the association between parameters of radial artery tonometry, a noninvasive measure of arterial stiffness, and PAD. METHODS: We conducted a cross-sectional study of 134 vascular surgery outpatients (controls, 33; PAD, 101) using arterial applanation tonometry. Central augmentation index (AIX) normalized to 75 beats/min and peripheral AIX were measured using radial artery pulse wave analysis. Pulse wave velocity was recorded at the carotid and femoral arteries. PAD was defined as symptomatic claudication with an ankle-brachial index of <0.9 or a history of peripheral revascularization. Controls had no history of atherosclerotic vascular disease and an ankle-brachial index ≥0.9. RESULTS: Among the 126 participants with high-quality tonometry data, compared with controls (n = 33), patients with PAD (n = 93) were older, with higher rates of hypertension, hyperlipidemia, diabetes, and smoking (P < .05). Patients with PAD also had greater arterial stiffness as measured by central AIX, peripheral AIX, and pulse wave velocity (P < .05). In a multivariable model, a significantly increased odds of PAD was associated with each 10-unit increase in central AIX (odds ratio, 2.1; 95% confidence interval, 1.1-3.9; P = .03) and peripheral AIX (odds ratio, 1.9; 95% confidence interval, 1.2-3.2; P = .01). In addition, central and peripheral AIX were highly correlated (r120 = 0.76; P < .001). CONCLUSIONS: In a cross-sectional analysis, arterial stiffness as measured by the AIX is independently associated with PAD, even when adjusting for several atherosclerotic risk factors. Further prospective data are needed to establish whether radial artery tonometry could be a tool for risk stratification in the PAD population.

Predictors of change in omega-3 index with fish oil supplementation in peripheral artery disease.

BACKGROUND: The omega-3 index represents the red blood cell (RBC) content of two major long-chain n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid, and docosahexaenoic acid. We sought to determine factors associated with a favorable response to fish oil treatment and to characterize changes in RBC PUFAs associated with fish oil supplementation. METHODS: This study was a secondary analysis of the OMEGA-PAD I trial, a randomized, double-blinded, placebo-controlled trial investigating short-duration, high-dose n-3 PUFA oral supplementation on endothelial function and inflammation in subjects with peripheral arterial disease. Patients with mild to severe claudication received either 4.4 g of fish oil providing 2.6 g of eicosapentaenoic acid and 1.8 g of docosahexaenoic acid daily (n = 40) or placebo capsules (n = 40) for 1 mo. The RBC fatty acid content was measured by gas chromatography and expressed as a percent of total fatty acids. The change in omega-3 index was calculated as the difference between pre- and post-supplementation in the fish oil and placebo groups. Univariate analysis identified predictors of change in omega-3 index, with these variables included in our multivariable model. RESULTS: In the fish oil group, there was an increase in the omega-3 index (5.1± 1.3% to 9.0± 1.8%; P < 0.0001), whereas there was no change in the control group. Factors associated with a favorable response (i.e., greater than the median change of 4.06%) included a lower body mass index and higher concentrations of low-density lipoproteins. Other demographic and/or lifestyle factors such as age, race, or smoking status were unrelated to the response. Oral n-3 PUFA supplementation also decreased the n-6 PUFA content in RBCs. CONCLUSIONS: Short-term, high-dose n-3 PUFA supplementation increases the omega-3 index to a greater extent in patients with a lower body mass index and higher total and low-density lipoprotein cholesterol levels.

Surface complexation modeling of Cd(II) adsorption on mixtures of hydrous ferric oxide, quartz and kaolinite.

Cadmium adsorption was measured as a function of ionic strength (0.001-0.1M NaNO(3)), and spanning a range of sorbate/sorbent ratios, on pure hydrous ferric oxide (HFO), kaolinite, and quartz and also on binary and ternary mixtures of the three solids. Diffuse- layer surface complexation models (DLMs) were parameterized to fit Cd sorption data for the pure kaolinite and quartz systems. Cd adsorption on kaolinite was modeled using a two-site DLM, with formation of a monodentate Cd complex on a variable charge site and Cd binding to a permanent exchange site; Cd adsorption on quartz was described using a one-site DLM with formation of a mondentate Cd complex on a variable charge site. These DLMs, together with the Dzombak and Morel DLM for HFO, were used to predict Cd adsorption on the binary and ternary mineral mixtures using a simple component additivity approach. In general, the predicted adsorption edges were in good agreement with measured data, with statistically similar goodness of fit compared to that obtained for the pure mineral systems. However, in some cases the model overpredicted Cd sorption, possibly indicating that interaction of the solids may prevent Cd from accessing all of the sorption sites.

Surface complexation modeling of Cu(II) adsorption on mixtures of hydrous ferric oxide and kaolinite.

BACKGROUND: The application of surface complexation models (SCMs) to natural sediments and soils is hindered by a lack of consistent models and data for large suites of metals and minerals of interest. Furthermore, the surface complexation approach has mostly been developed and tested for single solid systems. Few studies have extended the SCM approach to systems containing multiple solids. RESULTS: Cu adsorption was measured on pure hydrous ferric oxide (HFO), pure kaolinite (from two sources) and in systems containing mixtures of HFO and kaolinite over a wide range of pH, ionic strength, sorbate/sorbent ratios and, for the mixed solid systems, using a range of kaolinite/HFO ratios. Cu adsorption data measured for the HFO and kaolinite systems was used to derive diffuse layer surface complexation models (DLMs) describing Cu adsorption. Cu adsorption on HFO is reasonably well described using a 1-site or 2-site DLM. Adsorption of Cu on kaolinite could be described using a simple 1-site DLM with formation of a monodentate Cu complex on a variable charge surface site. However, for consistency with models derived for weaker sorbing cations, a 2-site DLM with a variable charge and a permanent charge site was also developed. CONCLUSION: Component additivity predictions of speciation in mixed mineral systems based on DLM parameters derived for the pure mineral systems were in good agreement with measured data. Discrepancies between the model predictions and measured data were similar to those observed for the calibrated pure mineral systems. The results suggest that quantifying specific interactions between HFO and kaolinite in speciation models may not be necessary. However, before the component additivity approach can be applied to natural sediments and soils, the effects of aging must be further studied and methods must be developed to estimate reactive surface areas of solid constituents in natural samples.