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

ObjectiveRestenosis 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.MethodsThis 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.ResultsTwenty 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.ConclusionsAdventitial 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

Measurement of brachial artery endothelial function using a standard blood pressure cuff

The integrity of endothelial function in major arteries (EFMA) is a powerful independent predictor of heart attack and stroke. Existing ultrasound-based non-invasive assessment methods are technically challenging and suitable only for laboratory settings. EFMA, like blood pressure (BP), is both acutely and chronically affected by factors such as lifestyle and medication. Consequently, laboratory-based measurements cannot fully gauge the effects of medical interventions on EFMA. EFMA and BP have, arguably, comparable (but complementary) value in the assessment of cardiovascular health. Widespread deployment of EFMA assessment is thus a desirable clinical goal. To this end, we propose a device based on modifying the measurement protocol of a standard electronic sphygmomanometer. The protocol involves inflating the cuff to sub-diastolic levels to enable recording of the pulse waveform before and after vasodilatory stimulus. The mechanical unloading of the arterial wall provided by the cuff amplifies the distension that occurs with each pulse, which is measured as a pressure variation in the cuff. We show that the height of the rising edge of each pulse is proportional to the change in lumen area between diastole and systole. This allows the effect of vasodilatory stimuli on the artery to be measured with high sensitivity. We compare the proposed cuff flow-mediated dilation (cFMD) method to ultrasound flow-mediated dilation (uFMD). We find significant correlation (r = 0.55, p = 0.003, N = 27) between cFMD- and uFMD-based metrics obtained when the release of a 5 min cuff occlusion is employed to induce endothelial stimulus via reactive hyperemia. cFMD is approximately proportional to the square of uFMD, representing a typical increase in sensitivity to vasodilation of 300-600%. This study illustrates the potential for an individual to conveniently measure his/her EFMA by using a low-cost reprogrammed home sphygmomanometer

Relationship between kidney disease and endothelial function in peripheral artery disease

ObjectiveWe 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.MethodsThis 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.ResultsNinety-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).ConclusionsIn 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

Relationship between kidney disease and endothelial function in peripheral artery disease

ObjectiveWe 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.MethodsThis 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.ResultsNinety-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).ConclusionsIn 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

Clinical correlates of red blood cell omega-3 fatty acid content in male veterans with peripheral arterial disease

ObjectiveDespite available medical therapies, patients with peripheral arterial disease (PAD) remain at high risk for cardiovascular events. The n-3 polyunsaturated fatty acids (PUFA), derived from marine sources, have been shown to improve cardiovascular mortality. The Omega-3 Index (O3I), a proportion of the n-3 PUFA eicosapentaenoic acid and docosahexaenoic acid in the red blood cell membrane, correlates with cardiovascular risk. Previous investigations have found that n-3 PUFA supplementation, fish consumption, older age, and smoking history affect the O3I in different patient populations, although similar correlations have never been explored in PAD. We hypothesized that in our PAD cohort, blood content of omega-3 fatty acids would directly and positively correlate with a history of fish oil supplementation and older age and inversely correlate with a smoking history and obesity.MethodsThis cross-sectional study included 111 patients who had an ankle-brachial index of <0.9 associated with claudication symptoms. We used linear regression to determine the association between clinical factors and the O3I.ResultsThe mean age of the cohort was 69 ± 8 years; 37% had diabetes mellitus (hemoglobin A1c, 7% ± 1%), and 94% reported current smoking or a history of smoking. The mean O3I was 5% ± 2%. In multivariate linear regression analysis, the O3I was associated with older age, increasing body mass index, and a history of smoking and fish oil intake.ConclusionsThis is the first report of the relation between blood content of omega-3 fatty acids and clinical factors in a PAD population. In patients with PAD, older age, elevated body mass index, and prior fish oil supplementation predicted a higher O3I. A history of smoking correlated with a lower O3I. These results demonstrate that the O3I is a reliable measure of dietary n-3 PUFA intake and that clinical factors related to the O3I in PAD are similar to those observed in other populations

Annotated record of the detailed examination of Mn deposits from the R/V Rig Seismic Cruise 11 (BMR 66) in 1986 over the Great Australian Bight Basin area

Late Cretaceous and younger sediments dredged from the upper continental slope and canyon walls in the Great Australian Bight Basin between 126° and 136°E broadly confirm the stratigraphy which had been established previously from scattered exploration wells. Late Cretaceous to Early Eocene marine and marginal marine terrigenous sediments are overlain by Middle Eocene and younger pelagic carbonate (fine limestone and calcareous ooze). The samples provide the first evidence of truly marine Maastrichtian sedimentation, with abundant calcareous nannoplankton, on the southern margin of the continent. Other samples of interest include Precambrian sheared granodiorite on the upper slope south of Eyre Terrace, Paleocene phosphatic sediment in 'Eucla' Canyon at 128° 30'E, and terrigenous Early Miocene mudstone at 133° 20' and 134° 50'E. The mudstone is of note as an exception to the uniform pelagic carbonate wackestone and ooze which characterise Middle Eocene and younger sedimentation at all other sites. Fragments of alkali basalt lava of unknown age were recovered in 'Eucla' Canyon. Cores are mostly pelagic calcareous ooze, but those from submarine canyons include terrigenous turbidites

Measurement of brachial artery endothelial function using a standard blood pressure cuff

The integrity of endothelial function in major arteries (EFMA) is a powerful independent predictor of heart attack and stroke. Existing ultrasound-based non-invasive assessment methods are technically challenging and suitable only for laboratory settings. EFMA, like blood pressure (BP), is both acutely and chronically affected by factors such as lifestyle and medication. Consequently, lab-based measurements cannot fully gauge the effects of medical interventions on EFMA. EFMA and BP have, arguably, comparable (but complementary) value in the assessment of cardiovascular health. Widespread deployment of EFMA assessment is thus a desirable clinical goal. To this end, we propose a device based on modifying the measurement protocol of a standard electronic sphygmomanometer. METHODS: The protocol involves inflating the cuff to sub-diastolic levels to enable recording of the pulse waveform before and after vasodilatory stimulus. The mechanical unloading of the arterial wall provided by the cuff amplifies the distension that occurs with each pulse, which is measured as a pressure variation in the cuff. We show that the height of the rising edge of each pulse is proportional to the change in lumen area between diastole and systole. This allows the effect of vasodilatory stimuli on the artery to be measured with high sensitivity. We compare the proposed cuff flow-mediated dilation (cFMD) method to ultrasound FMD (uFMD). RESULTS: We find significant correlation (r=0.55, p = 0.003, N=27) between cFMD- and uFMD-based metrics obtained when the release of a 5-minute cuff occlusion is employed to induce endothelial stimulus via reactive hyperemia. cFMD is approximately proportional to the square of uFMD, representing a typical increase in sensitivity to vasodilation of 300–600%. CONCLUSION: This study illustrates the potential for an individual to conveniently measure his/her EFMA by using a low-cost reprogrammed home sphygmomanometer

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

Switch-off of a major enhanced ice flow unit in East Antarctica

The East Antarctic Ice Sheet (EAIS) is the largest reservoir of ice on the planet by an order of magnitude. Compared with the West Antarctic Ice Sheet (WAIS), it is traditionally considered to be relatively stable, with only minor adjustments to its configuration over glacial-interglacial cycles. Here, we present the results of a radio-echo sounding survey from Coats Land, East Antarctica, which suggests that parts of the EAIS outlet drainage system may have changed significantly since the Last Glacial Maximum. We have identified an enhanced flow unit from buckled internal layering and smooth bed morphology that is no longer active. We believe this feature to have shut down at some point since the Last Glacial Maximum, ∼20 ka BP

A Two-Step Valence Tautomeric Transition in a Dinuclear Cobalt Complex

A dinuclear cobalt complex with cobalt centers bridged by a bis­(dioxolene) ligand exhibits a rare two-step valence tautomeric transition