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Background: Sedentarism, also termed physical inactivity, is an independent risk factor for cardiovascular diseases. Mechanisms thought to be involved include insulin resistance, dyslipidemia, hypertension, and increased inflammation. It is unknown whether changes in vascular and endothelial function also contribute to this excess risk. We hypothesized that short-term exposure to inactivity would lead to endothelial dysfunction, arterial stiffening, and increased vascular inflammation., Methods: Five healthy subjects (four men and one woman) underwent 5 d of bed rest (BR) to simulate inactivity. Measurements of vascular function (flow-mediated vasodilation to evaluate endothelial function; applanation tonometry to assess arterial resistance), inflammation, and metabolism were made before BR, daily during BR, and 2 d after BR recovery period. Subjects maintained an isocaloric diet throughout., Results: BR led to significant decreases in brachial artery and femoral artery flow-mediated vasodilation (brachial: 11 ± 3% pre-BR versus 9 ± 2% end-BR, P = 0.04; femoral: 4 ± 1% versus 2 ± 1%, P = 0.04). The central augmentation index increased with BR (-4 ± 9% versus 5 ± 11%, P = 0.03). Diastolic blood pressure increased (58 ± 7 mm Hg versus 62 ± 7 mm Hg, P = 0.02), whereas neither systolic blood pressure nor heart rate changed. 15-Hydroxyeicosatetraenoic acid, an arachidonic acid metabolite, increased but the other inflammatory and metabolic biomarkers were unchanged., Conclusions: Our findings show that acute exposure to sedentarism results in decreased endothelial function, arterial stiffening, increased diastolic blood pressure, and an increase in 15-hydroxyeicosatetraenoic acid. We speculate that inactivity promotes a vascular "deconditioning" state characterized by impaired endothelial function, leading to arterial stiffness and increased arterial tone. Although physiologically significant, the underlying mechanisms and clinical relevance of these findings need to be further explored., (Published by Elsevier Inc.)

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.

We have used a multimodality imaging approach to assess the inflammatory component of a growing iliac artery aneurysm in a 53-year-old man who presented with related ureteral obstruction. Research suggests that episodic and heterogeneous inflammatory processes are important for the progression of aneurysms. The combined PET and MRI evaluation of inflammation that we present here is a novel approach to vascular imaging that is well suited for emerging hybrid PET/MRI systems.

Despite current consensus guidelines recommending intensive cardiovascular risk factor management for peripheral artery disease (PAD), patients suffering from PAD continue to experience significant morbidity and mortality. This excess morbid burden is at least partially related to impaired vascular function and systemic inflammation. Interventions bridging this gap are critical. Dietary supplementation of n-3 polyunsaturated fatty acids (n-3 PUFA) has been shown to improve endothelial function and reduce inflammation in different cohorts, as well as to decrease cardiovascular events in secondary prevention trials in patients with coronary artery disease. Their effects in the PAD population are, however, less well understood. The OMEGA-PAD trial is a double-blinded, randomized, placebo-controlled trial that examines the impact of a high-dose, short-duration dietary oral supplementation of n-3 PUFA on vascular function and inflammation in patients with established PAD. The purpose of this article is to provide a detailed description of the design and methods of the OMEGA-PAD trial, and a summary of baseline characteristics of the cohort.

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. [ABSTRACT FROM AUTHOR]

During the past 2 decades, atherosclerosis and its clinical sequelae have increasingly been recognized as an inflammatory disease. Examination of multiple circulating inflammatory biomarkers has shown that they independently predict cardiovascular risk in patients with and without overt cardiovascular disease. Among these, high-sensitivity C-reactive protein has proved to be most robust in adding to global risk prediction models. Statins, a class of drugs that reduce levels of high-sensitivity C-reactive protein and other inflammatory biomarkers, have been the most thoroughly studied anti-inflammatory agents to reduce cardiovascular risk. However, all such trials are necessarily confounded by the ability of statins to markedly reduce cholesterol, a well-known causal risk factor for adverse vascular outcomes. Nevertheless, the provocative results of several key statin trials have provided the scientific basis to test the hypothesis that reducing inflammation will improve cardiovascular outcomes with novel and specific anti-inflammatory agents. These newer drugs promise to reduce inflammatory marker levels without affecting lipids, glucose, or blood pressure. The results of these trials will provide key data to help us understand the relationship between inflammation and vascular risk. [Copyright &y& Elsevier]

Objective: This study was conducted to determine if there are sex-based differences in the inflammatory phenotype of patients undergoing lower extremity bypass (LEB) and if they correlate with clinical outcomes. Methods: This was a retrospective analysis of a prospective cohort of 225 patients (161 men and 64 women) who underwent autogenous vein LEB between February 2004 and May 2008. Fasting baseline blood samples were obtained before LEB, and the inflammatory biomarkers high-sensitivity C-reactive protein (CRP) and fibrinogen were assessed. All patients underwent ultrasound graft surveillance. CRP levels were dichotomized at 5 mg/L and fibrinogen levels at 600 mg/dL. Results: There were no significant differences in age, race, history of hypertension or diabetes mellitus, body mass index, or coronary artery disease between men and women. Men were more likely to be current smokers (P = .02), have a history of hypercholesterolemia (P = .02), and be taking statins (P = .02). Women were more likely to present with critical limb ischemia (P = .03) and had higher median baseline CRP levels (5.15 mg/L; interquartile range [IQR], 1.51-18.62 mg/L) than men (2.70; IQR, 1.24-6.98 mg/L; P = .02). Median follow-up was 893 days (IQR, 539-1315 days). A multivariable Cox proportional hazards model for primary vein graft patency showed a significant interaction between sex and CRP (P = .03) and fibrinogen (P = .02). After adjustment for key covariates, primary vein graft patency was significantly less in women with CRP >5 mg/L compared with women with CRP <5 mg/L (P = .02). No such difference was seen in men (P = .95). Primary graft patency was also decreased in women with fibrinogen >600 mg/dL vs women with fibrinogen <600 mg/dL (P = .002); again, this pattern was not evident in men (P = .19). Conclusions: Women undergoing LEB for advanced peripheral artery disease have a different inflammatory phenotype than men. 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 sex and inflammation in the healing response of vein grafts for LEB. Women with elevated preoperative CRP and fibrinogen levels may benefit from more intensive postoperative graft surveillance protocols. [Copyright &y& Elsevier]

Lower-extremity vein graft failure causes significant morbidity, increases health care costs, and negatively impacts patient quality of life. Identification of risk factors is essential for patient selection, risk factor modification, and identifying individuals who would benefit from more stringent surveillance protocols. Risk factors can be considered as either patient-related or technical. Here we discuss the patient-related risk factors for vein graft failure. Nontechnical factors related to the indication for operation include operation after a previously failed graft, or redo bypass, critical limb ischemia, and infection. Risk factors for vein graft failure are distinct from the risk factors for cardiovascular events. Young age and African American and Hispanic race are risk factors for lower-extremity vein graft failure. Hypercoaguable and inflammatory states also increase risk for vein graft failure. Therapy with statins is indicated in patients with peripheral atherosclerosis and may have beneficial effects on vein graft function, although further studies are needed in this area. [Copyright &y& Elsevier]

Objectives: Inflammatory markers such as high-sensitivity C-reactive protein (hsCRP) are associated with an increased risk of cardiovascular events and with the severity of peripheral arterial disease. The effects of inflammation on the development of vein graft disease remain speculative. We hypothesized that high levels of inflammatory markers would identify patients at increased risk for adverse events (graft failure, major cardiovascular events) after lower extremity bypass surgery. Methods: Patients (n = 91) scheduled to undergo lower extremity bypass using autogenous vein were enrolled into a prospective study at two institutions. Exclusion criteria included the presence of major infection. A baseline plasma sample was obtained on the morning of lower extremity bypass. Biomarkers for inflammation included hsCRP, fibrinogen, and serum amyloid A (SAA). Values between patients with and without critical limb ischemia were compared. Proportions of events among dichotomized populations (upper limit of normal of each laboratory assay) were compared by log-rank test. Results: Of the patients undergoing lower extremity bypass, 69% were men, 53% were diabetic, 81% were smokers, and their mean ankle-brachial index was 0.51 ± 0.19. The indication for lower extremity bypass was critical limb ischemia in 55%. There were no perioperative deaths and two early graft occlusions. During a mean follow-up of 342 days (range, 36-694 days) there were four deaths, 27 graft-related events, and 10 other cardiovascular events. No relationships were found between events and demographics, comorbidities, baseline ankle-brachial index, or statin use. High-sensitivity CRP (P = .005), fibrinogen (P < .001), and SAA (P = .0001) levels were associated with critical limb ischemia at presentation. Among patients with an elevated hsCRP (>5 mg/L) immediately before surgery, major postoperative vascular events occurred in 60% (21/35), compared with a 32% (18/56) rate in those with a baseline CRP <5 mg/L (P = .004, log-rank test). On multivariable analysis, only elevated hsCRP correlated with adverse graft-related or cardiovascular events (P = .018). Conclusions: The inflammatory biomarkers of hsCRP, fibrinogen, and SAA correlate with peripheral arterial disease severity at presentation in patients undergoing lower extremity bypass. Patients with elevated hsCRP are at increased risk for postoperative vascular events, most of which are related to the vein graft. These findings suggest a potential relationship between inflammation and outcomes after lower extremity vein bypass surgery. [Copyright &y& Elsevier]

Abstract: Background: Diet is known to have an important impact on cardiovascular health. n-3 Fatty acids (FAs), found in high quantity in fish oil, have demonstrated beneficial effects in patients with coronary artery disease. The role of n-6 FAs remains more controversial. The objective of this study was to examine the effect of arachidonic acid (AA), an n-6 FA, and eicosapentanoic acid (EPA), an n-3 FA, on the interaction between monocytes and endothelial cells (ECs). Design: We used a cellular model of ECs (EA.hy.926) and monocytes (human leukemic myelomonocytic U937). Confluent ECs were treated with AA or EPA, in the presence of tumor necrosis factor-alpha (TNF-α) or vehicle alone for either 4 or 24h. Adhesion of monocytes to the endothelial monolayer was performed. For gene expression, reverse transcription, followed by real-time quantitative polymerase chain reaction, was performed. Results: There was a significant increase in adhesion of monocytes to the endothelial monolayer in the presence of n-6 FAs, both in the presence and in the absence of TNF-α at 4 and 24h. The adhesion of monocytes to the endothelial monolayer was decreased with n-3 FAs at 24h. Intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E-Selectin, Interleukin 6, and TNF-α were significantly increased in ECs treated with n-6 FAs. Conclusions: We conclude that AA increases inflammation and enhances the ability of ECs to bind monocytes in vitro. EPA leads to a decrease in the ability of EA.hy.926 to bind monocytes, although the effect appears more modest. Taken together, these data indicate that the n-6 FA AA could potentiate inflammation and early events of atherosclerosis. [Copyright &y& Elsevier]