Fontaine Stage Research Articles

Abstract 340: Microvascular Pathology in Peripheral Artery Disease

Background: Peripheral Artery Disease (PAD) is caused by atherosclerotic narrowing of arteries supplying the legs. PAD-induced myopathy is characterized by myofiber degeneration and progressive fibrosis. Qualitative histological review suggests pathological changes in the microvasculature of PAD muscle, in association with advancing fibrosis. We tested the hypothesis that microvessel architecture, pericyte coverage, and collagen profiles systematically change with advancing disease and are consistent with advancing microvascular pathology. Methods: Biopsies of PAD patients at Fontaine Stage II (n=15) and IV (n=16), and controls (n=15) were labeled with antibodies specific for Col I, Col IV, αSMA, or CD31 and analyzed by quantitative wide-field, fluorescence microscopy. Thickness of the basement membrane (BM), peri-microvascular Col I density, and BM lumen diameter were measured. Pericytes were identified by abluminal location within the microvascular BM and αSMA + labeling. Group differences were tested by ANOVA and a post hoc pairwise T Test with Bonferroni correction. Correlations were determined by linear regression analysis. Results: Thickness of the BM was greater in Stage II patients (1.58 μm) compared to controls (1.42 μm) (p<0.043) and in Stage IV (1.75 μm) compared to Stage II patients (p<0.021). Microvascular BM lumen diameter was increased (p<0.001) in Stage IV patients (3.97 μm) compared to control (3.25 μm) and Stage II patients (3.29 μm). Thickened PAD microvessels had greater pericyte coverage than control microvessels. BM thickness correlated positively with microvascular BM lumen diameter (R 2 = 0.513, p<0.001). Peri-microvascular Col I deposition correlated positively with microvascular lumen diameter (R 2 = 0.162, p=0.006), and was greater in Stage IV compared to Stage II patients (p=0.040). Conclusions: Increased perivascular Col I deposition, BM thickening, and BM lumen diameter represent advancing microvascular disease in PAD patients. Pericytes, which deposit BM collagen, are more abundant in thickened microvessels. Pericyte replication and secretion of Col IV may be determining factors in the microvascular pathology of PAD muscle.

Angiopoietin-2 and Survival in Peripheral Artery Disease Patients

Survival of peripheral arterial disease (PAD) patients increased over the last decade due to increased use of secondary preventive medication and rapid revascularization of PAD patients. Angiogenetic markers such as vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2) and its receptor Tie-2 might be useful markers to assess the residual risk for mortality in PAD patients. The aim of this study was to evaluate angiogenetic markers for the prediction of mortality in a PAD cohort. For this purpose, 366 patients (mean age: 69 ± 10 years) with PAD Fontaine stage I or II were included and followed up over a 5-year study period. Serum Ang-2, Tie-2 and VEGF levels were measured by bead-based multiplex assay. All-cause mortality and major cardiovascular events (MACE) including all-cause death, non-fatal stroke and non-fatal myocardial infarction were analysed by Kaplan-Meier and Cox regression analyses after 5 years. Ang-2 was associated with Tie-2 (R = 0.151, p = 0.006) and VEGF levels (R = 0.160, p = 0.002). However, only Ang-2 was linked to all all-cause mortality in PAD patients (hazard ratio [HR]: 1.55 [1.23-2.15], p = 0.008) even after adjustment for age and gender, haemoglobin A1c, low-density lipoprotein cholesterol, systolic blood pressure and glomerular filtration rate (HR: 1.44 [1.03-2.00], p = 0.032). Furthermore, an association of Ang-2 and MACE in PAD patients (HR: 1.36 (1.03-1.78), p = 0.028) was found. This result implies that Ang-2 might be used as an additional marker to stratify PAD patients to predict poor mid-term life expectancy.

Safety and Efficacy of Angio-Seal Closure in Antegrade Superficial Femoral Artery Access

Objective: Arterial access for endovascular revascularization in patients with debilitating peripheral arterial disease is commonly achieved through retrograde common femoral artery (CFA) approach. However, retrograde access presents multiple technical challenges, including long distance from the access site to the target lesion, and mechanical disadvantage of working over the aortic bifurcation and often tortuous iliac vessels. Antegrade CFA access avoids these challenges but has been fraught with its own difficulties, particularly in obese patients. Antegrade superficial femoral artery (SFA) access provides the same mechanical advantages while avoiding the difficulties of antegrade CFA access, but a vascular closure device is required due to distance from the femoral head. This single-center study evaluates the safety and efficacy of the Angio-Seal device (St. Jude Medical, St. Paul, MN) in SFA punctures. Materials and Methods: From May 2011 to January 2015, 140 antegrade SFA punctures were performed on 110 limbs in 88 patients for endovascular revascularization, all with ultrasound guidance. Complications and patient data including age, sex, body mass index, Fontaine stage, sheath size, and intraoperative heparin doses were analyzed. Results: In 140 antegrade SFA punctures, there were 11 access-related complications (7.9%). The majority were hematomas or pseudoaneurysms requiring nominal or no therapy. There were 3 major complications: Two delayed access stenoses ultimately resulted in toe amputations and one hemorrhage required extended hospitalization and transfusion. Patient data analysis showed a statistically significantly increased complication rate in females (20.7%) versus males (4.5%) (p = 0.0105). Conclusions: Antegrade SFA access with Angio-Seal closure is safe and effective. An increased complication rate in females warrants cautious post-procedural follow-up.

Medical Resource Consumption and Quality of Life in Peripheral Arterial Disease in Korea: PAD Outcomes (PADO) Research.

Background and ObjectivesWe aimed to investigate the history of medical resource consumption and quality of life (QoL) in peripheral arterial disease (PAD) patients in Korea.MethodsThis was a prospective, multi-center (23 tertiary-hospitals, division of cardiology), non-interventional study. Adult patients (age ≥20 years) suffering from PAD for the last 12-month were enrolled in the study if they met with any of following; 1) ankle-brachial index (ABI) ≤0.9, 2) lower-extremity artery stenosis on computed tomography angiography ≥50%, or 3) peak-systolic-velocity-ratio (PSVR) on ultrasound ≥2.0. Medical chart review was used to assess patient characteristics/treatment patterns while the history of medical resource consumption and QoL data were collected using a patient survey. QoL was measured using EuroQoL-5-dimensions-3-level (EQ-5D-3L) score system, and the factors associated with QoL were analyzed using multiple linear regression analysis.ResultsThis study included 1,260 patients (age: 69.8 years, male: 77.0%). The most prevalent comorbidities were hypertension (74.8%), hyperlipidemia (51.0%) and diabetes-mellitus (50.2%). The 94.1% of the patients took pharmacotherapy including aspirin (76.2%), clopidogrel (53.3%), and cilostazol (33.6%). The 12.6% of the patients were receiving smoking cessation education/pharmacotherapy. A considerable number of patients (500 patients, 40.0%) had visit history to another hospital before diagnosis/treatment at the current hospital, with visits to orthopedic units (50.4%) being the most common. At the time, 29% (or higher) of the patients were already experiencing symptoms of critical limb ischemia. Baseline EQ-5D index and EQ VAS were 0.64±0.24 and 67.49±18.29. Factors significantly associated with QoL were pharmacotherapy (B=0.05053; p=0.044) compared to no pharmacotherapy, and Fontaine stage improvement/maintain stage I (B=0.04448; p<0.001) compared to deterioration/maintain stage II–IV.ConclusionsIncrease in disease awareness for earlier diagnosis and provision of adequate pharmacotherapy is essential to reduce disease burden and improve QoL of Korean PAD patients.

Auricular vagal nerve stimulation in peripheral arterial disease patients.

Auricular nerve stimulation has been proven effective in different diseases. We investigated if a conservative therapeutic alternative for claudication in peripheral arterial occlusive disease (PAD) via electroacupuncture of the outer ear can be established. In this prospective, double-blinded trial an ear acupuncture using an electroacupuncture device was carried out in 40 PAD patients in Fontaine stage IIb. Twenty patients were randomized to the verum group using a fully functional electroacupuncture device, the other 20 patients received a sham device (control group). Per patient, eight cycles (1 cycle = 1 week) of electroacupuncture were performed. The primary endpoint was defined as a significantly more frequent doubling of the absolute walking distance after eight cycles in the verum group compared to controls in a standardized treadmill testing. Secondary endpoints were a significant improvement of the total score of the Walking Impairment Questionnaire (WIQ) as well as improvements in health related quality of life using the Short Form 36 Health Survey (SF-36). There were no differences in baseline characteristics between the two groups. The initial walking distance significantly increased in both groups (verum group [means]: 182 [95 % CI 128-236] meters to 345 [95 % CI 227-463] meters [+ 90 %], p < 0.01; control group [means]: 159 [95 % CI 109-210] meters to 268 [95 % CI 182-366] meters [+ 69 %], p = 0.01). Twelve patients (60 %) in the verum group and five patients (25 %) in controls reached the primary endpoint of doubling walking distance (p = 0.05). The total score of WIQ significantly improved in the verum group (+ 22 %, p = 0.01) but not in controls (+ 8 %, p = 0.56). SF-36 showed significantly improvements in six out of eight categories in the verum group and only in one of eight in controls. Electroacupuncture of the outer ear seems to be an easy-to-use therapeutic option in an age of increasingly invasive and mechanically complex treatments for PAD patients.

Sleep apnoea is common in severe peripheral arterial disease.

BackgroundAtherosclerotic conditions have been demonstrated to be associated with sleep- disordered breathing (SDB). Peripheral arterial disease (PAD) represents severe atherosclerosis with a high mortality. In early stages of PAD a substantial prevalence of sleep apnoea has already been shown. Here, we sought to determine the frequency of undiagnosed sleep apnoea in a homogeneous group of advanced PAD patients undergoing percutaneous revascularization.Methods59 consecutive patients (mean age: 71.1 ± 9.8 years, 67.8% males) with PAD in Fontaine stages IIb-IV that underwent percutaneous transluminal angioplasty at our department were enrolled for pre-procedural polygraphy.ResultsPatients appertained to Fontaine clinical stage IIb, III and IV in 54.2%, 23.8% and 22.% of cases, respectively, and were principally intervened for femoropopliteal occlusive disease (71.2% of total study population). Polygraphy revealed sleep apnoea in 48 out of 59 patients (81.4%), of whom 60.4% offered a primarily obstructive-driven genesis. Among those patients with polygraphically confirmed sleep apnoea, mean apnoea hypopnoea index (AHI) and mean oxygen desaturation index (ODI) averaged 28.2 ± 19.5/h and 26.7 ± 18.8/h, respectively. 18 patients even offered an AHI ≥30/h that is indicative of severe sleep apnoea. For obstructive-driven apnoeic events, AHI correlated significantly with PAD severity stages (p = 0.042).ConclusionsIn our PAD collective, sleep apnoea was frequent and obstructive sleep apnoea´s severity correlated with PAD severity stages. Long-term results regarding the vasoprotective impact of CPAP treatment on PAD course remains to be determined.

Abstract 115: Microvascular Response to Ramipril in Peripheral Artery Disease

Background: The myopathy of Peripheral Artery Disease (PAD), a consequence of ischemia caused by atherosclerotic plaques in arteries supplying the legs, is characterized by myofiber degeneration and fibrosis of the vascular walls and extramyofiber matrix. In association with fibrosis we have found a robust expression of the profibrotic cytokine TGFβ1 in vascular smooth muscle cells. Additionally, we have observed microvascular endothelial “swelling” in PAD muscle. Published data indicate that inhibitors of the angiotensin system reduce fibrosis in multiple organ systems and improve walking performance, in diverse patient populations. We hypothesize that “swelling” of microvasculature endothelial cells represents abnormal accumulation of basement membrane Collagen Type IV (Col-IV) and that treatment with Ramipril will improve the microvasculature. Methods and Results: Gastrocnemius biopsies of PAD patients at Fontaine Stage II (N=5) before and after six months of Ramipril intervention and control patients (N=4) were labeled with an antibody specific for Col-IV. Images were acquired with an automated wide-field microscope and then processed with Image Pro Plus® and AutoQuant® deconvolution software. We used Col IV label to measure wall thickness and lumen diameter of 230 to 360 microvessels per patient, with a custom MatLab program based on the Expectation Maximization algorithm coupled with a Gaussian Mixture Model. Microvessel wall thickness was significantly greater (p &lt; 0.04) in PAD patients before (1.54 ± 0.04 μ) and after (1.61 ± 0.06 μ) Ramipril treatment compared to control (1.42 ± 0.02). Lumen diameter was significantly greater (p &lt; 0.02) in Post-Ramipril (3.49 ± 0.04 μ) compared to Pre-Ramipril (3.18 ± 0.08 μ) and control (3.00 ± 0.11 μ) patients. Conclusions: The increase of microvessel lumen diameter with Ramipril treatment is expected to increase microvascular perfusion and thereby improve walking distance. Our study will be expanded to increase cohort size and evaluate the association of microvascular measurements with microperfusion determined by Contrast Enhanced Ultrasonography and with walking performance.

Circulating mircoRNA-21 as a predictor for vascular restenosis after interventional therapy in patients with lower extremity arterial occlusive disease.

The present study was designed to investigate the role of circulating miRNA-21 (miR-21) in vascular restenosis of lower extremity arterial occlusive disease (LEAOD) patients after interventional therapy. A total of 412 LEAOD patients were enrolled randomly in the present study. According to computed tomography angiography (CTA) and ankle-brachial index (ABI), patients were assigned into the restenosis group and the non-restenosis group. miR-21 expression was detected with quantitative real-time PCR (qRT-PCR) before and after patients underwent interventional therapy. A follow-up period of 6 months was achieved. A receiver operating characteristic (ROC) curve was drawn and the area under the curve (AUC) was calculated to assess the predictive value of miR-21 in vascular restenosis. Patients were older in the restenosis group than in the non-restenosis group. The percentages of patients with diabetes and hypertension were higher in the restenosis group than in the non-restenosis group, and the Fontaine stage exhibited a significant difference between the two groups. miR-21 expression was higher in the restenosis group than in the non-restenosis group. miR-21 expression level was related to age, diabetes and hypertension in the restenosis group. Using miR-21 to predict vascular restenosis yielded an AUC of 0.938 (95% confidence interval (CI): 0.898–0.977), with Youden index of 0.817, sensitivity of 83.5% and specificity of 98.2%. Logistic regression analysis revealed that diabetes and miR-21 expression were the major risk factors for vascular restenosis of LEAOD. miR-21 can be used as a predictive indicator for vascular restenosis of LEAOD after interventional therapy.

Efficacy and Safety of Alprostadil in Patients with Peripheral Arterial Occlusive Disease Fontaine Stage IV: Results of a Placebo Controlled Randomised Multicentre Trial (ESPECIAL)

Efficacy and Safety of Alprostadil in Patients with Peripheral Arterial Occlusive Disease Fontaine Stage IV: Results of a Placebo Controlled Randomised Multicentre Trial (ESPECIAL)

Influence of Transcutaneous Electrical Nerve Stimulation on Clinical Measures and Functional Capacity in Patients with Peripheral Artery Disease

Peripheral Arterial Disease (PAD), which is characterized by occlusive plaques in the arteries perfusing the legs, often manifests in intermittent claudication. Home‐based exercise is commonly suggested for individuals with PAD, but adherence to such programs is often poor, resulting in limited clinical benefits. Therefore, this patient population would benefit from low‐risk, inexpensive, and simple to use therapeutic interventions that can improve exercise tolerance and capacity. One such potentially beneficial intervention is transcutaneous electrical nerve stimulation (TENS), which may induce transient increases in leg blood flow sufficient to improve the matching of oxygen supply and demand distal to the site of stenosis in patients with peripheral artery disease (PAD). Thus, the purpose of this study was to test the hypothesis that a single bout of TENS applied to the lower leg (for 15 or 45 minutes) will increase resting popliteal artery blood flow and 6‐minute walk distance (6MWD) in patients with PAD. Five subjects with PAD (67–81 yrs.; Intermittent Claudication, Fontaine stage II) participated in the protocol. Four subjects attended the laboratory for three randomized visits during which bilateral lower leg TENS (burst mode; 3Hz burst rate; 100Hz freq.; 250 μs pulse duration) sufficient to evoke skeletal muscle contraction was carried out for either 15 or 45 minutes or subjects participated in a control visit. One subject completed only the control and 15 minute TENS trials. Clinical and cardiovascular measures including resting single leg popliteal artery blood flow (Doppler ultrasound), ankle‐brachial index (ABI), and toe oxygen saturation (pulse oximetry) were carried out prior to and beginning 10 minutes following TENS. Popliteal vascular conductance (PVC) was calculated as flow/mean arterial pressure. 6MWD and time/distance to claudication onset were measured on the control day and each experimental day 35 minutes post‐TENS. The 15‐minute TENS trial increased popliteal artery blood flow from 63.5 ± 10.9 to 89.8 ± 21.8 mL min−1 (42.2%; P &lt; 0.05; n=5), PVC from 0.70 ± 0.12 to 0.92 ± 0.21 mL min−1 mmHg−1 (31.5%; P &lt; 0.05; n=5), and 6MWD from 1018.0 ± 133.8 to 1141.6 ± 149.2 feet (12.1%; P &lt; 0.05; n=5). The 45‐minute TENS trial increased popliteal artery blood flow from 56.4 ± 9.3 to 74.4 ± 15.9 mL min−1 (32.1%; P = 0.056; n=4), PVC from 0.66 ± 0.15 to 0.81 ± 0.20 mL min−1 mmHg−1 (23.2%; P &lt; 0.05; n=4), and 6MWD from 943.8 ± 128.5 to 1096.3 ± 146.9 feet (14.9%; P &lt; 0.05; n=4). Furthermore, the subjects reported onset of claudication at 573.8 ± 84.4 feet of the control visit 6MW, which was compared to 810.0 ± 199.2 feet after the 15 minute TENS trial and 690.0 ± 60.1 feet after the 45 minute TENS trial (both P &gt; 0.05). Neither of the TENS trials evoked changes in ABI or toe oxygen saturation. These preliminary findings suggest that acute lower leg TENS in patients with PAD may increase leg perfusion and exercise tolerance which, if undertaken routinely, could increase either patient adherence to or efficacy of exercise prescription in this population.Support or Funding InformationSupported by the Salisbury University Faculty Mini‐Grant

Efficacy and Safety of Alprostadil in Patients with Peripheral Arterial Occlusive Disease Fontaine Stage IV: Results of a Placebo Controlled Randomised Multicentre Trial (ESPECIAL)

The aim was to assess the efficacy and safety of alprostadil in patients with peripheral arterial occlusive disease (PAOD) Fontaine Stage IV. This was a multinational, prospective, randomised, double blind, placebo controlled, parallel group trial. Patients with Stage IV PAOD were equally randomised to either 4 weeks of alprostadil treatment twice daily or to placebo treatment twice daily. The primary efficacy variables were the rate of complete healing of all necrosis and ulceration 12 weeks after the end of treatment and the frequency of major amputations 24 weeks after the end of treatment. A total of 840 patients were randomised between 2004 and 2013. At baseline, no major differences between treatment groups were found. The rate of "complete healing" was 18.4% in patients on alprostadil and 17.2% in patients on placebo. The rates of "major amputations" were 12.6% in patients on alprostadil and 14.6% in patients on placebo. The adjusted difference between alprostadil and placebo including their 95% confidence intervals was 1.1 (-4.0 to 6.3) for "complete healing" and-2.1 (-6.7 to 2.5) for "major amputations." In the subgroup of diabetic patients the rates of major amputations were numerically lower in the alprostadil than placebo group (10.6% vs. 17.4%). Within the total cohort a non-significant difference in "decrease in ulcer area ≥50%" was reached in 30.2% of patients on alprostadil and in 24.3% of patients on placebo at end of treatment. In this study, superiority of alprostadil over placebo could not be shown. Nevertheless, a slight numerical but not clinically relevant advantage for alprostadil emerged from the "area decrease of ulcers by≥50%," indicating that a healing effect may have started. The results have to be considered in the light of several limitations in study design and conduct.

Investigation of Asymmetric and Symmetric Dimethylarginine Levels after Iloprost Treatment in Patients with Buerger's Disease

The aim of this study was to compare the levels of acetyl-dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the l-arginine/ADMA ratio before and after iloprost treatment in patients with Buerger's disease. Between January 2011 and December 2015, data from 44 patients (36 males, 8 females, mean age 48.7±18.1 years) with the diagnosis of Fontaine Stage III-IV Buerger's disease were included. Iloprost infusion was administered intravenously through the forearm veins for 7 days at a dose of 0.5-1.5ng/kg/min over 16h. Blood samples were collected before and after treatment for measurement of ADMA, SDMA, and l-arginine. ADMA, SDMA, l-arginine levels were measured using high performance liquid chromatography (HPLC). After iloprost treatment, ADMA and SDMA levels significantly decreased (p=.001). The increase in the l-arginine levels was not significant (p=.16). However, the l-arginine/ADMA ratio increased significantly (p=.001). Iloprost treatment decreases ADMA and SDMA, which are associated with endothelial dysfunctions in patients with Buerger's disease. Of note, the still higher than normal range of SDMA levels after iloprost treatment suggests that treatment should continue until SDMA levels are within the normal range in this patient population.

Results of an International Postmarketing Surveillance Study of pl-VEGF165 Safety and Efficacy in 210 Patients with Peripheral Arterial Disease.

IntroductionThe effective treatment of chronic lower limb ischemia is one of the most challenging issues confronting vascular surgeons. Current pharmacological therapies play an auxiliary role and cannot prevent disease progression, and new treatment methods are needed. pl-VEGF165, a gene therapy drug, was approved in Russia for the treatment of atherosclerotic peripheral arterial disease (PAD) after clinical studies in 2011. The study drug is an original gene construction in which pl-VEGF165 1.2 mg is the active substance.ObjectiveThis postmarketing surveillance study was undertaken to evaluate the safety (identification of uncommon side effects) and efficacy of gene therapy in patients in routine clinical practice.MethodsIn total, 210 patients with stage II–III chronic limb ischemia (according to the Fontaine classification modified by AV Pokrovsky) in 33 healthcare facilities in Russia and the Ukraine were enrolled in the study. The control group (n = 60) received conservative therapy without prostaglandins and prostacyclins, and the treatment group (n = 150) received treatment with pl-VEGF165 as two intramuscular injections for a total dose of 2.4 mg. Pain-free walking distance (PWD) (the primary efficacy criterion for Fontaine stages II–III), blood flow linear velocity (BFLV), and ankle-brachial index (ABI) were monitored for 6 months. The safety of pl-VEGF165 gene transfer in terms of the trial protocol was initially evaluated 6 months after the start of the study; adverse events (AEs) and serious adverse events (SAEs) were recorded during both routine visits and unscheduled requests for medical care.ResultsOverall, PWD increased by 177%, from 100.3 ± 6.9 to 277.1 ± 16.2 m (p = 0.0001), in the treatment group, whereas the mean value was unchanged in the control group (p = 0.218). Both BFLV and ABI values increased by 24% (p = 0.0001) in the treatment group but decreased in the control group. The greatest therapeutic effect was observed for stage III disease: PWD increased by 683% (p = 0.0001). No angiogenic therapy-related AEs or side effects were recorded, and target limb salvage was 96 and 97% in the treatment and control groups, respectively. The results obtained in this study are not significantly different from those observed in the phase IIb/III registration clinical study completed in 2011.Conclusionpl-VEGF165 intramuscular gene transfer is an effective treatment for moderate to severe claudication due to chronic lower limb ischemia in routine clinical practice.ClinicalTrials.gov identifier: NCT02369809.

Carotid arterial wall inflammation in peripheral artery disease is augmented by type 2 diabetes: a cross-sectional study.

BackgroundPatients with peripheral artery disease (PAD) are at increased risk of secondary events, which is exaggerated in the presence of type 2 diabetes mellitus. Diabetes is associated with a systemic pro-inflammatory state. We therefore investigated the cumulative impact of PAD and type 2 diabetes on carotid arterial wall inflammation. As recent data suggest a detrimental role of exogenous insulin on cardiovascular disease, we also included a group of insulin users.Results 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) imaging showed increased carotid arterial wall inflammation, assessed as target-to-background ratio (TBR), in PAD patients without diabetes (PAD-only: n = 11, 1.97 ± 0.57) compared with matched controls (n = 12, 1.49 ± 0.57; p = 0.009), with a significant further TBR increase in PAD patients with type 2 diabetes (PAD-DM, n = 23, 2.90 ± 1, p = 0.033 vs PAD-only). TBR of insulin users (n = 12, 3.31 ± 1.14) was higher compared with patients on oral medication only (n = 11, 2.44 ± 0.76, p = 0.035), despite comparable PAD severity (Fontaine stages), BMI and CRP. Multivariate regression analysis showed that Hba1c and plasma insulin levels, but not dose of exogenous insulin, correlated with TBR.ConclusionsConcurrent diabetes significantly augments carotid arterial wall inflammation in PAD patients. A further increase in those requiring insulin was observed, which was associated with diabetes severity, rather than with the use of exogenous insulin itself.Electronic supplementary materialThe online version of this article (doi:10.1186/s12872-016-0397-x) contains supplementary material, which is available to authorized users.

Abstract 13221: Efficacy and Safety of Therapeutic Angiogenesis by Basic Fibroblast Growth Factor With Atelocollagen Solution in Patients With Critical Limb Ischemia

Objectives: To evaluate efficacy and safety of a treatment comprising basic fibroblast growth factor (bFGF) with atelocollagen solution in patients with critical limb ischemia (CLI) due to peripheral artery disease (PAD) or Burger’s disease (TAO). Methods: Human recombinant bFGF (200μg) with 4.8 mL of 3% atelocollagen solution was prepared and injected into forty administration sites in the gastrocnemius muscle of the ischemic leg. The primary endpoint was the safety of the treatment, as evaluated by adverse events. The secondary endpoint was the efficacy of the treatment, as defined by improvements in Fontaine stage, the Rutherford category, rest pain, 6-minute walking distance, ankle brachial pressure index (ABPI), ulcerous/necrotic lesions, and cyanosis 2, 4, 8, 12, 24, and 48 weeks after the treatment from baseline values. Results: 10 CLI subjects received the treatment between November 2009 and November 2011. No serious procedure-related adverse events were observed during the follow-up. Within 48 weeks, the Fontaine stage improved in 4 subjects and was stable in 6 other subjects. The rest pain scale improved in 9 subjects while pain disappeared in 7 subjects. The maximum 6-minute walking distance increased in 7 subjects while 2 regained the ability to walk. Conclusions: The results of the present study demonstrated that angiogenic therapy using bFGF with atelocollagen solution was safe and feasible in patients with CLI.

Percutaneous endovascular treatment of infrainguinal PAOD: Results of the PSI register study in 74German vascular centers.

BackgroundThe percutaneous infrainguinal stent (PSI) register study aimed to collate all percutaneous endovascular procedures for infrainguinal peripheral arterial occlusive disease (PAOD) conducted in 74 German vascular centers between September and November 2015 (3 months). In order to obtain representative results all consecutive treatment procedures had to be submitted by the participating trial centers.Material and methodsThis was a prospective, nonrandomized multicenter study design. All patients suffering from intermittent claudication (IC, Fontaine stage II) or critical limb ischemia (CLI, Fontaine stages III and IV) were included. Trial centers with less than 5 cases reported within the 3‑month trial period or centers that could not ensure the submission of all treated patients were excluded.ResultsIn the final assessment 2798 treated cases from 74 trial centers were reported of which 65 (87.8 %) centers were under the leadership of a vascular surgeon. Approximately 33 % of the interventions in centers under the leadership of vascular surgeons were conducted by radiologists. Risk factors, especially chronic renal disease, diabetes and cardiac risk factors were significantly different between patients with IC and CLI. Of the patients with Fontaine stage II PAOD 41.3 % had 3 patent crural vessels compared to only 10.8 % of patients with Fontaine stage IV. With respect to peri-interventional complications, percutaneous endovascular treatment of IC was a safe procedure with severe complications in less than 1 % and no fatalities. Only 4.5 % of the procedures were conducted under ambulatory conditions. In the supragenual region self-expanding bare metal stents, standard percutaneous transluminal angioplasty (PTA) and drug-coated balloons were the most frequently used procedures. For interventions below the knee, standard PTA was the most commonly employed treatment.ConclusionThe main aim of the PSI study was to obtain a realistic picture of percutaneous endovascular techniques used to treat suprapopliteal and infrapopliteal PAOD lesions and to describe the treatment procedures used by vascular specialists in Germany. To investigate the change in trends for treatment over time, this study has to be repeated in the future in order to test how quickly the results of randomized studies can be implemented in practice.Electronic supplementary materialA complete list of the PSI study collaborators is available under doi: 10.1007/s00772-016-0202-2.

Lower extremity and carotid artery disease in COPD.

In view of their common chronic inflammatory process, we sought to determine the linkage between peripheral artery disease and chronic obstructive pulmonary disease (COPD).107 COPD patients (mean±sd age 64.6±10.4 years, 52.2% male) and 22 control smokers without previously diagnosed peripheral artery disease underwent standardised angiological examination for lower extremity artery disease (LEAD) and carotid artery disease.LEAD was significantly more prevalent in COPD patients than in controls (80.4% versus 54.5%, p=0.002). Among COPD patients, 57.0%, 12.2%, 10.3% and 0.9% were found to be in Fontaine stages I, IIA, IIB and III, respectively. As with carotid artery disease, its frequency increased from 36.4% in controls to 58.9% in COPD patients (p=0.003). Carotid plaque burden, LEAD Fontaine degrees as well as pulse wave index and ankle–brachial index manifested significant impairment over percentage predicted forced expiratory volume in 1 s (FEV1 % pred) (p=0.02, p<0.001, p=0.01 and p<0.001, respectively). Multivariate analysis revealed that COPD Global Initiative for Chronic Obstructive Lung Disease status was the strongest independent predictor for the presence of plaque in lower extremity arteries (odds ratio 1.63, 95% CI 1.19–2.25, p=0.003) and carotids (odds ratio 1.66, 95% CI 1.14–2.44, p=0.009).As compared with control smokers, peripheral artery disease is diagnosed in a sizeable proportion of COPD patients and exhibits significant distributive differences over FEV1 % pred that exceed the susceptibility conferred by common cardiovascular stressors.

Hyperbaric Oxygen Therapy in the Treatment of Fontaine Stage IV Thromboangiitis Obliterans.

Ischemic wounds unresponsive to standard treatment in thromboangiitis obliterans are associated with amputation, morbidity, and mortality. In this study, hyperbaric oxygen therapy was added to standard treatment of 36 patients with thromboangiitis obliterans with ischemic ulcerated wounds in the extremities. Full recovery was observed in 52.7% of cases (25% at discharge, 27.7% during follow-up). Resting pain after treatment decreased significantly compared to pretreatment levels based on visual analog scale scores (7.1 ± 1.7 vs 2.2 ± 3.0, P = .0001). Mean wound area also decreased significantly after treatment (22.6 ± 17.5 vs 13.02 ± 16.5, P = .0001). The number of patients requiring no assistance during routine daily activities increased significantly (25% vs 55.5%, P = .001). All patients were at Fontaine stage IV before hyperbaric oxygen therapy. The number of patients at stage IIB increased significantly after treatment, while that of patients at stage IV decreased significantly (0% vs 47.2%, P = .0001, and 100% vs 47.2%, P = .0001, respectively). None of our patients was able to walk without pain before treatment; however, walking distance was significantly extended in 16 patients who were capable of walking (0 vs 190.6 ± 129.4 meters, P = .0001). In addition, 11.1% of patients underwent major amputation during follow-up.

The Impact of Chronic Kidney Disease on Hospitalized Patients With Peripheral Arterial Disease and Critical Limb Ischemia.

Peripheral arterial disease (PAD) and chronic kidney disease (CKD) are major public health problems worldwide. Evaluations of large-scale data on morbidity, outcome, and costs in patients having PAD with CKD are essential. Cross-sectional nationwide population-based analysis of all hospitalizations for PAD during 2009 in Germany focused on the stage-related impact of CKD on morbidity, in-hospital mortality, amputations, length of hospital stay, and health-related expenditure. The total number of hospitalizations was 483 961. Of those, 132 993 (27.5%) had CKD. Chronic kidney disease caused 1.8-fold higher amputation rate ( P < .001) with a stepwise increasing rate with higher CKD stage. Chronic kidney disease doubled in-hospital mortality of patients with PAD (7.8%; n = 10 421) versus 4.0% (n = 14 174, P < .001) with a stepwise increasing risk with higher CKD stage ( P < .001). The highest in-hospital mortality occurred in patients with coprevalence of CKD stage 4 and Fontaine stage IV (16.4%, n = 1176, P < .001). Chronic kidney disease caused 15% higher costs and 21% increased length of stay compared to the whole PAD cohort. This analysis demonstrates the stage-related influence of CKD on morbidity, in-hospital mortality, amputations, length of hospital stay, and reimbursement costs of hospitalized patients with PAD.

Adaptation of external counterpulsation based on individual shear rate therapy improves endothelial function and claudication distance in peripheral artery disease.

External counterpulsation therapy enhances blood flow and was shown to improve endothelial function and quality of life in coronary artery disease patients. However, high pressures of up to 300 mmHg may lead to malperfusion of the ischaemic limb. To improve the clinical outcome of patients with peripheral artery disease (PAD), we adjusted external counterpulsation and developed a novel non-invasive approach termed individual shear rate therapy (ISRT). In the present study, 14 patients with a Fontaine stage IIb and femoral-popliteal PAD underwent 30 hours of ISRT over 5 weeks. For ISRT, individual treatment pressures that do not exceed 160 mmHg were assessed by Doppler flow parameters during counterpulsation (individual shear rate diagnosis) in order to enhance and maximise peripheral perfusion. The study aimed to enhance peripheral perfusion and evaluate the primary clinical endpoint endothelial function, as well as to perform preliminary analysis of the ankle brachial index (ABI) and walking distance. Doppler flow measurements in the lower limb (ankle) validated that maximum blood flow velocity during systole and acceleration doubled during ISRT. Study results demonstrated that long-term ISRT significantly increased flow-mediated dilation (FMD) in the brachial artery (0.13+/- 0.09 mm to 0.38+/- 0.05 mm; p < 0.05), while nitromediated dilation (0.36+/- 0.10 mm to 0.45+/- 0.08 mm) remained and common femoral artery FMD did not reach statistical significance (0.38+/- 0.08 mm to 0.67+/- 0.19 mm; p<0.05). Initial claudication distance considerably improved for all patients after 30 hours of ISRT (92.6 +/- 8.2 metres to 280+/- 101.3 metres, p<0.05), just like the absolute claudication distance, which showed a more than 2.5-fold increase (167.8+/- 18.1 metres to 446.7+/- 133.3 metres; p<0.05). The ABI did not improve (0.58+/- 0.03 to 0.65+/- 0.04). Our data demonstrate that long-term ISRT is a potential novel non-invasive treatment to improve endothelial function and absolute pain-free walking distance for PAD patients.