Hugh F. Alley

USPIO-enhanced MR Angiography of Arteriovenous Fistulas in Patients with Renal Failure

PURPOSE To determine the feasibility of using ferumoxytol-enhanced magnetic resonance (MR) angiography to depict the vasculature of hemodialysis fistulas and improve image quality compared with nonenhanced time-of-flight (TOF) MR angiography. MATERIALS AND METHODS The study was institutional review board approved and was in compliance with HIPAA regulations. All participants provided written informed consent. TOF and first-pass ferumoxytol-enhanced MR angiography were performed in 10 patients with upper extremity autogenous fistulas. Ferumoxytol was administered as a bolus solution containing 430 μmol of elemental iron. A qualitative comparison was performed on maximum intensity projection images. Lumen depiction was evaluated by using a five-point scale. The uniformity of intraluminal signal intensity was measured as the ratio between the mean signal intensity of the entirety of the imaged fistula and its standard deviation. The contrast-to-noise ratio (CNR) between intraluminal signal and adjacent tissue was evaluated as a function of image acquisition time. Lumen depiction scores, luminal signal heterogeneity, and CNR efficiency were compared between TOF and ferumoxytol-enhanced MR angiography by using a Wilcoxon-Mann-Whitney test. RESULTS Flow artifacts were greatly reduced by the use of ferumoxytol-enhanced MR angiography. Ferumoxytol-enhanced MR angiography had significantly better performance than TOF MR angiography as measured with the following: lumen depiction scores in all segments (mean, 4.7±0.1 [standard error of the mean]; vs 3.0±0.3 for arterial inflow, 4.1±0.3 vs 1.9±0.3 for arterial outflow, 3.7±0.3 vs 1.8±0.2 for anastomosis, and 4.5±0.2 vs 2.1±0.2 for venous outflow; P<.001), intraluminal signal homogeneity (0.3±0.02 vs 0.4±0.06, P=.005), and CNR efficiency in the venous outflow (5.1±0.6 vs 2.5±0.4, P=.01). CONCLUSION This study demonstrates the feasibility of using ferumoxytol-enhanced MR angiography in imaging hemodialysis fistulas with consistently superior image quality compared with nonenhanced TOF MR angiography.

Walking Disability in Patients with Peripheral Artery Disease is Associated with Arterial Endothelial Function

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 patients 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.

Association between n-3 polyunsaturated fatty acid content of red blood cells and inflammatory biomarkers in patients with peripheral artery disease.

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.

Safety and feasibility of adjunctive dexamethasone infusion into the adventitia of the femoropopliteal artery following endovascular revascularization

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.

Posttraumatic Stress Disorder Is Associated With Worse Endothelial Function Among Veterans

Background Current research in behavioral cardiology reveals a significant association between posttraumatic stress disorder (PTSD) and increased risk for cardiovascular disease and mortality; however, the underlying mechanisms remain poorly understood. We hypothesized that patients with PTSD would exhibit endothelial dysfunction, a potential mechanism involved in the development and progression of cardiovascular disease. Methods and Results A total of 214 outpatients treated at the San Francisco Veterans Affairs Medical Center underwent tests of endothelial function and evaluation for PTSD. Flow‐mediated vasodilation of the brachial artery was performed to assess endothelial function, and current PTSD status was defined by the PTSD Checklist, based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition), with a score ≥40. Multivariable linear regression models were used to estimate the association between PTSD status and endothelial function. Patients with PTSD (n=67) were more likely to be male (99% versus 91%, P=0.04) and to have depression (58% versus 8%, P<0.0001) and were less likely to be on an angiotensin‐converting enzyme inhibitor (17% versus 36%, P=0.007) or β‐blocker treatment (25% versus 41%, P=0.03). Univariate analysis demonstrated that patients with PTSD had significantly lower flow‐mediated vasodilation (5.8±3.4% versus 7.5±3.7%; P=0.003); furthermore, lower flow‐mediated vasodilation was associated with increasing age (P=0.008), decreasing estimated glomerular filtration rate (P=0.003), hypertension (P=0.002), aspirin (P=0.03), and β‐blocker treatments (P=0.01). In multivariable analysis, PTSD remained independently associated with lower flow‐mediated vasodilation (P=0.0005). Conclusions After adjusting for demographic, comorbidity, and treatment characteristics, PTSD remained associated with worse endothelial function in an outpatient population. Whether poor endothelial function contributes to the higher risk of cardiovascular disease in patients with PTSD deserves further study.

N-3 Polyunsaturated fatty acids supplementation in peripheral artery disease: The OMEGA-PAD trial

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. ClinicalTrials.gov Identifier: NCT01310270

Short‐Term, High‐Dose Fish Oil Supplementation Increases the Production of Omega‐3 Fatty Acid–Derived Mediators in Patients With Peripheral Artery Disease (the OMEGA‐PAD I Trial)

Background Patients with peripheral artery disease (PAD) experience significant morbidity and mortality. The OMEGA-PAD I Trial, a randomized, double-blinded, placebo-controlled trial, addressed the hypothesis that short-duration, high-dose n-3 polyunsaturated fatty acids (n-3 PUFA) oral supplementation improves endothelial function and inflammation in PAD. Methods and Results Eighty patients with stable claudication received 4.4 g of fish oil or placebo for 1 month. The primary end point was endothelial function as measured by brachial artery flow-mediated vasodilation. Secondary end points included biomarkers of inflammation, n-3 polyunsaturated fatty acids metabolome changes, lipid profile, and walking impairment questionnaires. Although there was a significant increase in FMD in the fish oil group following treatment (0.7±1.8% increase from baseline, P=0.04), this response was not different then the placebo group (0.6±2.5% increase from baseline, P=0.18; between-group P=0.86) leading to a negative finding for the primary endpoint. There was, however, a significant reduction in triglycerides (fish oil: −34±46 mg/dL, P<0.001; placebo −10±43 mg/dL, P=0.20; between-group differential P-value: 0.02), and an increase in the omega-3 index of 4±1% (P<0.001) in the fish oil group (placebo 0.1±0.9%, P=0.49; between-group P<0.0001). We observed a significant increase in the production of pathway markers of specialized pro-resolving mediators generated from n-3 polyunsaturated fatty acids in the fish oil group. Conclusions High-dose, short-duration fish oil supplementation did not lead to a different response in the primary end point of endothelial function between the treatment and placebo group, but improved serum triglycerides and increased the production of downstream n-3 polyunsaturated fatty acids–derived products and mediators in patients with PAD. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01310270.

Ultrasound Assessment of Endothelial-Dependent Flow-Mediated Vasodilation of the Brachial Artery in Clinical Research

The vascular endothelium is a monolayer of cells that cover the interior of blood vessels and provide both structural and functional roles. The endothelium acts as a barrier, preventing leukocyte adhesion and aggregation, as well as controlling permeability to plasma components. Functionally, the endothelium affects vessel tone. Endothelial dysfunction is an imbalance between the chemical species which regulate vessel tone, thombroresistance, cellular proliferation and mitosis. It is the first step in atherosclerosis and is associated with coronary artery disease, peripheral artery disease, heart failure, hypertension, and hyperlipidemia. The first demonstration of endothelial dysfunction involved direct infusion of acetylcholine and quantitative coronary angiography. Acetylcholine binds to muscarinic receptors on the endothelial cell surface, leading to an increase of intracellular calcium and increased nitric oxide (NO) production. In subjects with an intact endothelium, vasodilation was observed while subjects with endothelial damage experienced paradoxical vasoconstriction. There exists a non-invasive, in vivo method for measuring endothelial function in peripheral arteries using high-resolution B-mode ultrasound. The endothelial function of peripheral arteries is closely related to coronary artery function. This technique measures the percent diameter change in the brachial artery during a period of reactive hyperemia following limb ischemia. This technique, known as endothelium-dependent, flow-mediated vasodilation (FMD) has value in clinical research settings. However, a number of physiological and technical issues can affect the accuracy of the results and appropriate guidelines for the technique have been published. Despite the guidelines, FMD remains heavily operator dependent and presents a steep learning curve. This article presents a standardized method for measuring FMD in the brachial artery on the upper arm and offers suggestions to reduce intra-operator variability.

Relationship between kidney disease and endothelial function in peripheral artery disease.

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.

Differences in nutrition status by body mass index in patients with peripheral artery disease

Peripheral Arterial Disease (PAD) is most prevalent in the elderly and associated with increased cardio vascular disease (CVD) morbidity and mortality. Treatment focuses on improving functional capacity and reducing CVD risk factors. To date, little is understood about dietary habits and weight in this patient population. Nutritional and weight recommendations are based on heart health, and little is known about the unique needs of elderly PAD patients with multiple comorbidities. This prospective study compared 1) the dietary intake of nonobese PAD patients in comparison with those who were obese and; 2) dietary intake of those patients with the Estimated Average Requirement (EAR) based on age, gender and BMI. Nutritional intake was assessed with the Block 98 Food Frequency Questionnaire. Body mass index (BMI) was calculated in accordance with the National Heart, Lung, and Blood Institute (NHLBI) guidelines.The study population was divided into obese (BMI ≥ 30) and nonobese (NO) groups. Comparisons between groups were performed using the Mann-Whitney U test for continuous variables and the Chi-square test for ordinal variables. All tests were two-tailed and P < 0.05 was considered significant. The Estimated Average Requirement (EAR) cut-point method was used to compare nutritional variables with Dietary Reference Intakes (DRI). The study population included 189 NO (BMI < 30) and 111 obese (BMI > 30) individuals. Obese participants reported greater intake of foods containing cholesterol and trans-fatty acids and more frequent intake of B vitamins in comparison with the NO BMI group. Additionally, the nutrient intake of all participants by age, gender and BMI was lower than the EAR for magnesium, folate, and Vitamin E. These results suggest that the nutritional intake of PAD patients differs based on gender and BMI. Additionally, EAR was lower for specific nutrients than recommended. Further investigation is needed to examine the association between nutritional intake and nutrition-related deficits.