Objective

Peripheral arterial disease (PAD) is a burdensome cardiovascular condition that results from chronic inflammatory insults to the arterial vasculature. Key risk factors include age, gender, type 2 diabetes mellitus, hypertension, hypercholesterolemia, hyperhomocysteinemia, smoking, lack of physical fitness, and poor diet, the latter three being modifiable in the development and progression of PAD. A growing body of evidence indicates that imbalanced nutrient intake may contribute to the development and progression of PAD. The purpose of this review is to summarize current knowledge about nutritional patterns among patients with PAD and to ascertain whether certain health-promoting foods and nutrients could benefit patients with this condition.

Methods

We conducted a comprehensive literature review to examine primary source evidence for or against the nutrients that are commonly associated with PAD and their potential utility as therapies.

Results

We summarized nine categories of nutrients, as well as four diets endorsed by the American Heart Association that may be prescribed to patients with or at risk for PAD. The nutrients reviewed included omega-3 polyunsaturated fatty acids (n-3 PUFAs), folate and B-series vitamins, and antioxidants. The diet plans described include the Dietary Approaches to Stop Hypertension (DASH) diet, Mediterranean diet, low-fat diet, low carbohydrate diet, Dr Dean Ornish's Spectrum Diet and Dr Andrew Weil's Anti-Inflammatory Diet.

Conclusions

PAD is a chronic inflammatory condition that is associated with longstanding poor nutrition habits. We advocate for an intensified use of diet in PAD therapy, and we specifically recommend following eating patterns that are rich in nutrients with anti-inflammatory and antioxidant properties.

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.

Background

Despite the high prevalence of peripheral arterial disease (PAD) in women, risk factors for PAD in women are not well understood.

Methods

Gender-specific risk factors for PAD were examined in a prospective cohort study of 1024 patients (184 women and 840 men) with stable coronary artery disease who were recruited between 2000 and 2002. Logistic regression models were used to evaluate associations between traditional and nontraditional risk factors and PAD in men and women.

Results

PAD was found in 11% of women and in 13% of men. Women with PAD had a similar prevalence of traditional risk factors (hypertension, hyperlipidemia, and smoking) compared with women without PAD and were significantly more likely to suffer from depression than women without PAD. Men with PAD were more likely to have hypertension, diabetes mellitus, a history of smoking, a worse lipid profile, and higher levels of inflammatory biomarkers than men without PAD. A multivariate model showed depression was the strongest independent factor associated with PAD in women, whereas smoking and elevated fibrinogen were independently associated with PAD in men.

Conclusions

The current findings suggest there are gender differences in risk factors for the development of PAD. Further research is needed to understand the role of depression in PAD.

The health risks of a dysregulated immune response during spaceflight are important to understand as plans emerge for humans to embark on long-term space travel to Mars. In this first-of-its-kind study, we used adoptive transfer of T-cell receptor transgenic OT-II CD4 T cells to track an in vivo antigen-specific immune response that was induced during the course of spaceflight. Experimental mice destined for spaceflight and mice that remained on the ground received transferred OT-II cells and cognate peptide stimulation with ovalbumin (OVA) 323-339 plus the inflammatory adjuvant, monophosphoryl lipid A. Control mice in both flight and ground cohorts received monophosphoryl lipid A alone without additional OVA stimulation. Numbers of OT-II cells in flight mice treated with OVA were significantly increased by 2-fold compared with ground mice treated with OVA, suggesting that tolerance induction was impaired by spaceflight. Production of proinflammatory cytokines were significantly increased in flight compared with ground mice, including a 5-fold increase in IFN-γ and a 10-fold increase in IL-17. This study is the first to show that immune tolerance may be impaired in spaceflight, leading to excessive inflammatory responses.

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.

Objective

Patients with peripheral artery disease (PAD) have varying degrees of walking disability that do not completely correlate with ankle-brachial index (ABI) or angiographic anatomy. We hypothesized that endothelial function (EF) is an independent predictor of symptom severity in PAD patients.

Methods

This was a cross-sectional study of 100 PAD patients presenting to a vascular surgery clinic. All patients received ABI testing and brachial artery flow-mediated, endothelium-dependent vasodilation (FMD) to assess arterial EF. Symptom severity and walking disability reported by Rutherford category was based on the patient's self-report during the clinic visit and recorded by the investigator-vascular surgeons. Demographic, biochemical, and physiologic parameters were entered into regression equations to determine association with symptom severity.

Results

Patients were a mean age of 66 ± 8 years, and 43% had diabetes. Mean FMD was 7.4%, indicating impaired EF. EF progressively declined as Rutherford category increased (P = .01). Brachial artery FMD, ABI, systolic blood pressure, C-reactive protein, low-density lipoprotein, high-density lipoprotein, β-blocker use, and a history of diabetes or coronary artery disease were all associated with Rutherford category (all P < .05). Multivariable regression showed EF (P < .02) and ABI (P < .0001) were independently associated with walking disability. When the cohort was restricted to claudicant patients (n = 73), EF remained associated with walking disability after adjustment for other covariates (P = .0001).

Conclusions

Symptom severity in PAD is multifactorial, reflecting impaired hemodynamics and vascular dysfunction. This is the first report demonstrating that walking disability in PAD is associated with arterial EF. The mechanistic link underlying these observations remains to be defined.

Objective

The n-3 polyunsaturated fatty acids are dietary components derived from fish oil with beneficial cardiovascular effects that may relate in part to anti-inflammatory properties. Peripheral artery disease (PAD) is characterized by a marked proinflammatory state. We hypothesized that the n-3 polyunsaturated fatty acids content of red blood cells (omega-3 index) would be correlated with biomarkers of inflammation and vascular function in a PAD cohort.

Methods

This was a cross-sectional study of subjects who presented to an outpatient vascular surgery clinic for evaluation of PAD. We used linear regression to evaluate the independent association between the omega-3 index, inflammatory biomarkers (C-reactive protein [CRP], intercellular adhesion molecule-1, interleukin-6, and tumor-necrosis-factor-α) and endothelial function (brachial artery flow mediated dilation).

Results

64 subjects (61 claudicants and three with critical limb ischemia) were recruited for the study. The mean CRP level was 5.0 ± 5.0 mg/L, and the mean omega-3 index was 5.0% ± 1.8%. In an unadjusted model, the omega-3 index was negatively associated with CRP (38% increase in CRP for one standard deviation decrease in the omega-3 index; P = .007), which remained significant after adjustment for age, body mass index, smoking, ankle-brachial index, and high-density lipoprotein (33%; P = .04). There was also evidence for independent associations between the omega-3 index and IL-6 (P = .001). There were no significant associations between the omega-3 index and vascular function tests.

Conclusions

In a cohort of patients with PAD, the omega-3 index was inversely associated with biomarkers of inflammation even after adjustment for covariates including the ankle-brachial index. Because patients with PAD have a high inflammatory burden, further studies should be conducted to determine if manipulation of omega-3 index via dietary changes or fish oil supplementation could improve inflammation and symptoms in these patients.

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.

Objective

Restenosis following endovascular treatment of the femoropopliteal segment is associated with the inflammatory response produced in the artery wall at the time of the procedure. Although local drug delivery to the superficial femoral and popliteal arteries promises improved patency, data are currently limited. We hypothesized that improved percutaneous delivery of an anti-inflammatory compound into the adventitia of the femoropopliteal at the time of endovascular treatment would be safe, feasible, and decrease the inflammatory response.

Methods

This was a prospective, investigator-initiated, phase I, first-in-man study testing the safety and feasibility of percutaneous adventitial delivery of dexamethasone. Following successful intervention, an adventitial microinfusion catheter was advanced over a 0.014-inch wire to the treated segment. Its microneedle (0.9 mm long × 140-μm diameter) was deployed into the adventitia to deliver dexamethasone (4 mg/mL) mixed with contrast agent (80:20 ratio), providing fluoroscopic visualization. The primary safety outcome measure was freedom from vessel dissection, thrombosis, or extravasation while the primary efficacy outcome was duplex-determined binary restenosis defined as a peak systolic velocity ratio >2.5.

Results

Twenty patients with Rutherford clinical category 2-5 enrolled in this study. The mean age was 66, and 55% had diabetes mellitus. Treated lesion length was 8.9 ± 5.3 cm, and 50% were chronic total occlusions. Eighty percent of treated lesions were in the distal superficial femoral or popliteal arteries. All lesions were treated by balloon angioplasty with provisional stenting (n = 6) for suboptimal result. Three patients were treated with atherectomy as well. A mean of 1.6 ± 1.1 mg (0.5 ± 0.3 mL) of dexamethasone sodium phosphate was injected per centimeter of lesion length. In total, a mean of 12.1 ± 6.1 mg of dexamethasone was injected per patient. The mean number of injections required per lesion was 3.0 ± 1.3 cm, minimum one and maximum six injections. There was 100% technical success of drug delivery and no procedural or drug-related adverse events. The mean Rutherford score decreased from 3.1 ± .7 (median, 3.0) preoperatively to .5 ± .7 at 6 months (median, 0.0; P < .00001). Over this same time interval, the index leg ankle-brachial index increased from .68 ± .15 to .89 ± .19 (P = .0003). The preoperative C-reactive protein in this study was 6.9 ± 8.5 indicating severe baseline inflammation, which increased to 14.0 ± 23.1 mg/L (103% increase) at 24 hours following the procedure. However, this increase did not reach statistical significance of P = .14. Two patients met the primary efficacy end point of loss of primary patency by reoccluding their treated segment of the index lesion during the follow-up period.

Conclusions

Adventitial drug delivery via a microinfusion catheter is a safe and feasible alternative to intimal-based methods for adjunctive treatment in the femoropopliteal segment. The 6-month preliminary results suggest perivascular dexamethasone treatment may improve outcomes following angioplasty to the femoral and popliteal arteries, and support further clinical investigation of this approach.

Objective

We have previously shown that peripheral artery disease (PAD) is associated with marked impairment of endothelial function (EF). Given that poor EF is associated with functional status of PAD patients as well as with increased morbidity and mortality in patients undergoing vascular procedures, determination of factors associated with poor EF in a PAD cohort is important. We hypothesized that decreased kidney function is associated with impaired EF in patients with PAD.

Methods

This was a cross-sectional study of PAD patients presenting to a vascular surgery outpatient clinic at the San Francisco Veterans Affairs Medical Center including patients enrolled in the OMEGA-PAD I trial (NCT01310270) and the OMEGA-PAD Cohort. Brachial artery flow-mediated vasodilation was performed to assess EF. Kidney function was characterized by estimated glomerular filtration rate with the abbreviated Modification of Diet in Renal Disease formula. Linear regression was performed to assess the relationship between EF and kidney function in claudicants.

Results

Ninety-seven patients with intermittent claudication participated in this study. Mean age was 69 ± 8 years, 97% were male, and 79% were white. Comorbidities included hypertension (91%), dyslipidemia (87%), coronary artery disease (42%), and diabetes mellitus (38%). Mean ankle-brachial index was 0.73 ± 0.14 and mean flow-mediated vasodilation was 7.0% ± 3.8%, indicating impaired EF. Linear regression showed an association between kidney function and EF (by 10 mL/min/1.73 m(2); β, 0.12; confidence interval, 0.05-0.20; P = .001). After multivariable regression adjusting for age, race, log tumor necrosis factor α, hypertension, dyslipidemia, and diabetes, estimated glomerular filtration rate remained significantly associated with EF (P = .033).

Conclusions

In patients with PAD, decreased kidney function is associated with endothelial dysfunction. Further longitudinal studies are needed to better understand the impact of kidney function on PAD progression and the role of endothelial dysfunction in this process.