Presence of asymptomatic Peripheral Arterial Disease in combination with common risk factors elevates the cardiovascular risk Substantially.

Background and aims: This study evaluates the risks for adverse cardiovascular (CV) events in Asymptomatic Peripheral Arterial Disease (APAD) combined with different traditional CV risk factors. Methods: A population-based observational study of 8000 subjects, identified 559 subjects as having APAD through ankle-brachial index (ABI) measurements and questionnaires regarding limb symptoms. This cohort and subgroups classified by presence of different traditional CV risk factors at baseline were assessed for 10 years on CV outcome. The recorded endpoints were all-cause mortality, CV mortality and non-fatal CV events. Results: Before subdividing the APAD subjects, the CV mortality incidence was 28.5 deaths per 1000 person-years as compared to 8.7 deaths for references without APAD. For subjects with hypertension at baseline the CV mortality incidence was 35.4 when combined with APAD and 11.7 without. In women with hypertension but without other risk factors, presence of APAD increased the age-adjusted Hazard Ratio (HR) for fatal and non-fatal CV events by 1.86 [CI 1.54,2.24, p < 0.001]. Conclusions: ABI measurements should be considered an important indication for aggressive multifactorial risk factor reduction in populations with any other prevalent CV risk factor. In hypertension, diabetes mellitus and a smoking history, coexisting APAD contributes significantly to the increased age-adjusted CV risk.

Impact of Ankle Brachial Index Calculations on Peripheral Arterial Disease Prevalence and as a Predictor of Cardiovascular Risk.

OBJECTIVE: The aim of this study was to estimate the prevalence and predictive accuracy for cardiovascular (CV) morbidity by using different ankle brachial index (ABI) calculation methods in the general population. METHODS: ABI measurements and questionnaire data were collected from 5 080 randomly selected citizens aged 60 - 90 years. A 10 year follow up with data from Swedish national health registries was carried out. ABI was calculated using as numerator the highest (ABI-HI) or the lowest (ABI-LO) ankle BP obtained in each leg. Subjects were defined as references or having peripheral arterial disease (PAD) based on ABI-LO (Group 1) or ABI-HI (Group 2). Prevalence, mortality, CV events and risk were then analysed for these three groups, and their predictive power by using the area under the curve (AUC). RESULTS: A total of 4 909 inhabitants were included in the cohort (References: 83.8%, Group 1: 6.7% and Group 2: 9.6%). The prevalence of PAD was 16% using ABI-LO, and 9.6% using ABI-HI. The 10 year all cause mortality for references and Groups 1 and 2 was 27.6%, 48.8%, and 67.2%, respectively. The overall age adjusted hazard ratio (95% confidence interval) for the composite outcome of CV mortality and a non-fatal CV event was 1.25 (1.06 - 1.49) for Group 1 and 2.11 (1.85 - 2.39) for Group 2. The prediction accuracy for ABI < 0.9 in predicting CV event measured with AUC was 0.60 for ABI-HI and 0.62 for ABI-LO. CONCLUSION: An ABI < 0.9 should be considered a strong risk marker for future CV morbidity. Applying the traditional ABI calculation method of using the highest measured ankle BP, a group of subjects with high CV risk may be overlooked for intervention, and this why the lowest ankle BP should be the preferred for risk stratification. However, as a single predictive tool an ABI < 0.9 cannot adequately discriminate which individual will have a future CV event regardless of calculation method used.

Restored strange metal phase through suppression of charge density waves in underdoped YBa2Cu3O7-δ.

The normal state of optimally doped cuprates is dominated by the "strange metal" phase that shows a linear temperature (T) dependence of the resistivity persisting down to the lowest T. For underdoped cuprates, this behavior is lost below the pseudogap temperature T*, where charge density waves (CDWs), together with other intertwined local orders, characterize the ground state. We found that the T-linear resistivity of highly strained, ultrathin, underdoped YBa2Cu3O7­Î´ films is restored when the CDW amplitude, detected by resonant inelastic x-ray scattering, is suppressed. This observation suggests an intimate connection between the onset of CDWs and the departure from T-linear resistivity in underdoped cuprates. Our results illustrate the potential of using strain control to manipulate the ground state of quantum materials.

Cardiovascular long-term outcome and prophylactic treatment patterns in peripheral arterial disease in a population-based cohort.

AIMS: This study evaluates 10-year follow-up data on associated comorbidity, mortality, and pharmacological treatment patterns for men and women with different stages of peripheral arterial disease (PAD) in a population-based setting. METHODS AND RESULTS: This was a prospective observational population-based cohort study, based on physical examinations and questionnaires at baseline supplemented with national register data between 2005 and 2015. Subjects were placed in subgroups defined by ankle-brachial index levels and reported symptoms; asymptomatic PAD (APAD), intermittent claudication (IC), severe limb ischaemia (SLI), or references (Ref). Cox proportional hazards regression models were used for analysis with adjustments for sex and baseline age and comorbidity. The cohort consisted of 5080 subjects (45% males). At baseline, APAD, IC, and SLI were prevalent in 559 (11%), 320 (6.3%), and 78 (1.5%) subjects, respectively. A significant increased risk for cardiovascular (CV) death, even when adjusted for age and baseline morbidity, were noted in all PAD stages as compared with reference group with a small difference between APAD and IC, an adjusted hazard ratio 1.80 (confidence interval 1.45-2.22) and 1.95 (1.50-2.53), respectively. Only about 60% of PAD subjects received medical prophylactic treatment as recommended in guidelines. CONCLUSION: Peripheral arterial disease subjects had significantly increased CV morbidity and mortality risks, especially males. Asymptomatic PAD subjects confer similar risk for CV events as symptomatic patients. Our findings motivate enhanced preventive efforts of all PAD stages, including in asymptomatic disease.

Ten Year Mortality in Different Peripheral Arterial Disease Stages: A Population Based Observational Study on Outcome.

OBJECTIVE: The aim was to determine long-term mortality rates and the underlying cause of death for subjects with different peripheral arterial disease (PAD) stages in a population based setting. METHODS: A randomly selected population sample of 5080 subjects was enrolled in the study in 2004-2005. Participants completed health state questionnaires and underwent ankle brachial index (ABI) measurements for classification into PAD severity stages and reference subjects. A follow-up was conducted by the end of 2015 using data from Swedish governmental national registers for cause of death, which was then compared with PAD stage determined at baseline in 2005. RESULTS: The 10 year all cause mortality was 27% for reference cases, 56% for asymptomatic PAD (APAD), 63% for intermittent claudication (IC), and 75% for severe limb ischaemia (SLI). Among all PAD subjects, cardiovascular (CV) causes were the most common main cause of death (45%) and a CV event was present as either the main or one of the three most common contributing causes of death in 64% of the cases. The age adjusted hazard ratios for a main cause of death by a CV event were 1.9 (95% CI 1.5-2.3) for APAD, 2.6 (95% CI 2.1-3.4) for IC, and 3.5 (95% CI 2.3-5.2) for SLI. CONCLUSION: PAD subjects, including the APAD subjects, are still at high risk of CV death. The mortality risks are more than doubled in symptomatic PAD patients compared with reference subjects and increase by severity of PAD stage. Awareness and improved risk reduction management of PAD are still warranted.

A critical review of nuisance foam formation and biological methods for foam management or elimination in nutrient removal facilities.

The classifying selector was introduced to the wastewater industry in 2001, after several successful full-scale applications. The classifying selector concept distinguishes itself from the earlier surface foam wasting schemes in that negative selection pressure is maintained so that nuisance foam-causing organisms cannot gain a foothold in sufficient numbers to cause nuisance foams. The propensity of the nuisance-causing organism to attach to bubbles and establish a rising velocity is used to enrich them in a surface mixed liquor layer, where they are wasted. Neither standard texts nor the Water Environment Federation's Manuals of Practice adequately describe this, and as a result, the benefits of foam elimination obtainable through use of the classifying selector concepts have not been broadly obtained in our industry. In certain types of processes that are inherently foam trapping situations, the only solution is surface foam wasting, as foam cannot be eliminated. Potential efficiency gains possible in these situations are addressed.

Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis.

Molecular mechanisms underlying the cold-associated high cardiovascular risk remain unknown. Here, we show that the cold-triggered food-intake-independent lipolysis significantly increased plasma levels of small low-density lipoprotein (LDL) remnants, leading to accelerated development of atherosclerotic lesions in mice. In two genetic mouse knockout models (apolipoprotein E(-/-) [ApoE(-/-)] and LDL receptor(-/-) [Ldlr(-/-)] mice), persistent cold exposure stimulated atherosclerotic plaque growth by increasing lipid deposition. Furthermore, marked increase of inflammatory cells and plaque-associated microvessels were detected in the cold-acclimated ApoE(-/-) and Ldlr(-/-) mice, leading to plaque instability. Deletion of uncoupling protein 1 (UCP1), a key mitochondrial protein involved in thermogenesis in brown adipose tissue (BAT), in the ApoE(-/-) strain completely protected mice from the cold-induced atherosclerotic lesions. Cold acclimation markedly reduced plasma levels of adiponectin, and systemic delivery of adiponectin protected ApoE(-/-) mice from plaque development. These findings provide mechanistic insights on low-temperature-associated cardiovascular risks.

Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues.

Systemic therapy with anti-VEGF drugs such as bevacizumab is widely used for treatment of human patients with various solid tumors. However, systemic impacts of such drugs in host healthy vasculatures remain poorly understood. Here, we show that, in mice, systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody caused global vascular regression. Among all examined tissues, vasculatures in endocrine glands, intestinal villi, and uterus are the most affected in response to VEGF or VEGFR-2 blockades. Thyroid vascular fenestrations were virtually completely blocked by VEGF blockade, leading to marked accumulation of intraendothelial caveolae vesicles. VEGF blockade markedly increased thyroid endothelial cell apoptosis, and withdrawal of anti-VEGF resulted in full recovery of vascular density and architecture after 14 d. Prolonged anti-VEGF treatment resulted in a significant decrease of the circulating level of the predominant thyroid hormone free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid functions. Conversely, VEGFR-1-specific blockade produced virtually no obvious phenotypes. These findings provide structural and functional bases of anti-VEGF-specific drug-induced side effects in relation to vascular changes in healthy tissues. Understanding anti-VEGF drug-induced vascular alterations in healthy tissues is crucial to minimize and even to avoid adverse effects produced by currently used anti-VEGF-specific drugs.

Opposing effects of circadian clock genes bmal1 and period2 in regulation of VEGF-dependent angiogenesis in developing zebrafish.

Molecular mechanisms underlying circadian-regulated physiological processes remain largely unknown. Here, we show that disruption of the circadian clock by both constant exposure to light and genetic manipulation of key genes in zebrafish led to impaired developmental angiogenesis. A bmal1-specific morpholino inhibited developmental angiogenesis in zebrafish embryos without causing obvious nonvascular phenotypes. Conversely, a period2 morpholino accelerated angiogenic vessel growth, suggesting that Bmal1 and Period2 display opposing angiogenic effects. Using a promoter-reporter system consisting of various deleted vegf-promoter mutants, we show that Bmal1 directly binds to and activates the vegf promoter via E-boxes. Additionally, we provide evidence that knockdown of Bmal1 leads to impaired Notch-inhibition-induced vascular sprouting. These results shed mechanistic insight on the role of the circadian clock in regulation of developmental angiogenesis, and our findings may be reasonably extended to other types of physiological or pathological angiogenesis.

Differences in presentation of symptoms between women and men with intermittent claudication.

BACKGROUND: More women than men have PAD with exception for the stage intermittent claudication (IC). The purpose of this study was to evaluate differences in disease characteristics between men and women when using current diagnostic criteria for making the diagnosis IC, defined as ABI < 0.9 and walking problems. STUDY DESIGN: Cohort study METHODS: 5040 elderly (median age 71) subjects participated in a point-prevalence study 2004. They had their ABI measured and filled out questionnaires covering medical history, current medication, PAD symptoms and walking ability. The prevalence of IC was 6.5% for women and 7.2% for men (P = 0.09). A subset of subjects with IC (N = 56) was followed up four years later with the same procedures. They also performed additional tests aiming to determine all factors influencing walking ability. RESULTS: Men with IC had more concomitant cardiovascular disease and a more profound smoking history than women. Women, on the other hand, reported a lower walking speed (P < 0.01) and more joint problems (P = 0.018). In the follow up cohort ABI, walking ability and amount of atherosclerosis were similar among the sexes, but women more often reported atypical IC symptoms. CONCLUSION: Sex differences in the description of IC symptoms may influence diagnosis even if objective features of PAD are similar. This may influence accuracy of prevalence estimates and selection to treatment.

Zebrafish models to study hypoxia-induced pathological angiogenesis in malignant and nonmalignant diseases.

Most in vivo preclinical disease models are based on mouse and other mammalian systems. However, these rodent-based model systems have considerable limitations to recapitulate clinical situations in human patients. Zebrafish have been widely used to study embryonic development, behavior, tissue regeneration, and genetic defects. Additionally, zebrafish also provides an opportunity to screen chemical compounds that target a specific cell population for drug development. Owing to the availability of various genetically manipulated strains of zebrafish, immune privilege during early embryonic development, transparency of the embryos, and easy and precise setup of hypoxia equipment, we have developed several disease models in both embryonic and adult zebrafish, focusing on studying the role of angiogenesis in pathological settings. These zebrafish disease models are complementary to the existing mouse models, allowing us to study clinically relevant processes in cancer and nonmalignant diseases, which otherwise would be difficult to study in mice. For example, dissemination and invasion of single human or mouse tumor cells from the primary site in association with tumor angiogenesis can be studied under normoxia or hypoxia in zebrafish embryos. Hypoxia-induced retinopathy in the adult zebrafish recapitulates the clinical situation of retinopathy development in diabetic patients or age-related macular degeneration. These zebrafish disease models offer exciting opportunities to understand the mechanisms of disease development, progression, and development of more effective drugs for therapeutic intervention.

Hypoxia-induced metastasis model in embryonic zebrafish.

Hypoxia facilitates tumor invasion and metastasis by promoting neovascularization and co-option of tumor cells in the peritumoral vasculature, leading to dissemination of tumor cells into the circulation. However, until recently, animal models and imaging technology did not enable monitoring of the early events of tumor cell invasion and dissemination in living animals. We recently developed a zebrafish metastasis model to dissect the detailed events of hypoxia-induced tumor cell invasion and metastasis in association with angiogenesis at the single-cell level. In this model, fluorescent DiI-labeled human or mouse tumor cells are implanted into the perivitelline cavity of 48-h-old zebrafish embryos, which are subsequently placed in hypoxic water for 3 d. Tumor cell invasion, metastasis and pathological angiogenesis are detected under fluorescent microscopy in the living fish. The average experimental time for this model is 7 d. Our protocol offers a remarkable opportunity to study molecular mechanisms of hypoxia-induced cancer metastasis.

Endovascular treatment in postthrombotic syndrome.

BACKGROUND: The postthrombotic syndrome is a chronic complication of deep venous thrombosis that leads to considerable pain and suffering to patients. We evaluated our experience of endovascular treatment for patients with chronic postthrombotic femoroiliocaval venous disease. MATERIALS AND METHODS: From January 2003 through December 2007, 50 patients (51 limbs; 60% women; mean age 45 years; range: 24-74 years) with chronic postthrombotic venous disease were referred to our institution for interventional assessment. All patients underwent duplex ultrasonography as well as ascending and descending venography. The CEAP (clinical, etiologic, anatomic, and pathophysiologic classification) clinical scores were class 0 (no signs) in 2% of limbs, class 3 (edema) in 63%, class 4a (pigmentation or eczema) in 18%, class 5 (healed venous ulcer) in 14%, and class 6 (active venous ulcer) in 4%. The etiology was secondary (postthrombotic) in all patients. The anatomical distribution of reflux and obstruction were deep veins in 63% and a combination of deep and superficial veins in 37%. The underlying pathophysiology due to obstruction of the deep venous outflow with no reflux was found in 25% of limbs, only reflux was found in 14%, and a combination of obstruction and reflux was found in 61%. RESULTS: There were 21 limbs in 20 (38%) patients that underwent endovascular and/or surgical treatment. One limb underwent femoral endovenectomy and 1 limb superficial femoral vein to deep femoral vein transposition. In all, 19 limbs were scheduled for endovascular treatment. The technical success rate was 84%, 3 limbs with iliac vein occlusions could not be recanalized. A total of 11 patients (11 limbs) underwent solely endovascular intervention and 4 patients (5 limbs) underwent endovascular intervention combined with femoral endovenectomy. The endovascular and surgical procedures were performed with no perioperative or postoperative mortality as well as no major bleeding or cardiac, pulmonary, or renal 30-day complications. Early thrombosis (<30 days) of the stented iliac veins occurred in 3 limbs which were lysed and restented successfully. The mean follow-up time was 23 months (range: 1-69 months). Primary and assisted-primary/secondary patency rates at 12 months were 61% and 81%, respectively. The Venous Clinical Severity score was 9.1 (range: 5-15) before endovascular treatment and 6.0 (range: 3-13) after the treatment (P < .0001). There were 30 patients (62%) with symptoms attributable to venous dysfunction or with deep venous pathology that did not undergo interventional treatment after workup. These patients continued with appropriate thromboprophylaxis and elastic compression stockings. CONCLUSION: Endovascular treatment of chronic postthrombotic femoroiliocaval venous disease is a safe technique that can be performed with acceptable patency rates in this challenging patient population.

Risk factor profiles and use of cardiovascular drug prevention in women and men with peripheral arterial disease.

OBJECTIVE: To determine cardiovascular comorbidities and use of cardiovascular disease preventive drugs in patients with peripheral arterial disease (PAD), with special attention to sex differences. DESIGN: A cross-sectional point-prevalence study. PATIENTS: A population sample of patients that are 60-90 years old. SETTING: Primary care areas in four Swedish regions. MAIN OUTCOME MEASURES: Prevalence of PAD stages, comorbidities and medication use. RESULTS: The prevalence of any type of PAD was 18.0% (range 16-20), of asymptomatic peripheral arterial disease (APAD) was 11.1% (range 9-13), intermittent claudication was 6.8% (range 6.5-7.1), and of critical limb ischemia (CLI) was 1.2% (range 1.0-1.5). APAD and CLI were more common in women. Statins were used by 17.5% (range 16.9-18.2), 29.4% (range 29.0-30.1), and 30.3% (range 29.9-30.8) of the patients with APAD, intermittent claudication, and CLI, respectively, and antiplatelet therapy was reported by 34.1% (range 33.7-34.3), 47.6% (range 47.3-47.9), and 60.2% (range 59.1-60.7). The odds ratio for having APAD was 1.7 (range 1.2-2.4) for women with a smoking history of 10 years in relation to nonsmokers. This association was observed only in men who had smoked for at least 30 years or more. Preventive drug use was more common in men with PAD. Compared with women they had an odds ratio of 1.3 (range 1.1-1.5) for lipid-lowering therapy, 1.3 (range 1.0-1.7) for [beta]-blockers or angiotensin-converting enzyme inhibitors, and 1.5 (range 1.2-1.9) for antiplatelet therapy. CONCLUSION: The patients' risk factor profiles differed among the PAD stages. Smoking duration already seemed to be a risk factor for women with PAD after 10 years of smoking, as compared with 30 years for men, and fewer women reported use of preventive medication. These observations may partly explain the sex differences in prevalence that were observed.

Differential roles of PDGFR-alpha and PDGFR-beta in angiogenesis and vessel stability.

Preclinical and clinical evaluations of individual proangiogenic/arteriogenic factors for the treatment of ischemic myocardium and skeletal muscle have produced unfulfilled promises. The establishment of functional and stable arterial vascular networks may require combinations of different angiogenic and arteriogenic factors. Using in vivo angiogenesis and ischemic hind-limb animal models, we have compared the angiogenic and therapeutic activities of fibroblast growth factor 2 (FGF-2) in combinations with PDGF-AA and PDGF-AB, two members of the platelet-derived growth factor (PDGF) family, with distinct receptor binding patterns. We show that both PDGF-AA/FGF-2 and PDGF-AB/FGF-2 in combinations synergistically induce angiogenesis in the mouse cornea. FGF-2 up-regulates PDGFR-alpha and -beta expression levels in the newly formed blood vessels. Interestingly, PDGF-AB/FGF-2, but not PDGF-AA/FGF-2, is able to stabilize the newly formed vasculature by recruiting pericytes, and an anti-PDGFR-beta neutralizing antibody significantly blocks PDGF-AB/FGF-2-induced vessel stability. These findings demonstrate that PDGFR-beta receptor is essential for vascular stability. Similarly, PDGF-AB/FGF-2 significantly induces stable collateral growth in the rat ischemic hind limb. The high number of collaterals induced by PDGF-AB/FGF-2 leads to dramatic improvement of the paw's skin perfusion. Immunohistochemical analysis of the treated skeletal muscles confirms that a combination of PDGF-AB and FGF-2 significantly induces arteriogenesis in the ischemic tissue. A combination of PDGF-AB and FGF-2 would be optimal proangiogenic agents for the treatment of ischemic diseases.

Risk attitudes to treatment among patients with severe intermittent claudication.

OBJECTIVES: To determine claudication patients' risk attitude to invasive treatment and whether this treatment is cost effective. METHODS: Quality of life and health state utility status of 50 consecutive patients with severe intermittent claudication was assessed and compared with ankle-brachial pressure index values (ABPI) and results from treadmill tests before and after endovascular or open revascularization. Health utility scores were then calculated and used in a cost-utility analysis. RESULTS: Before surgery, patients were assigned a utility score of 0.51 (EQ-5D index) for their disease, and the standard gamble (SG) and time trade-off (TTO) median scores were 0.88 and 0.70, respectively. Before treatment, a weak correlation (r = 0.43, P < .001) between having a high risk perception of treatment and patients' walking distance were observed, where patients able to walk short distances accepted a higher risk. After treatment, ABI (P = .003) and walking distance (P = .002) improved significantly as well the physical components of the quality of life instruments (P < .001). The surgical treatment generated an improvement in quality of life expressed in QALYs equivalent to 0.17. With an estimated survival of 5 years, it adds up to a value of 0.85, corresponding to a sum of 51,000 US dollars gained. CONCLUSIONS: Patients with severe intermittent claudication are risk-seeking when it comes to surgical treatment and their risk attitude is correlated to their walking ability and quality of life. The incremental QALYs gained by treatment are achieved at a reasonable cost and revascularization appears to be cost effective.

Analyzing wet weather flow management using state of the art tools.

Optimal secondary clarifier performance is crucial to meet treatment requirements, especially when treating peak wet weather flows (PWWFs), to prevent high effluent suspended solids (ESS) concentrations and elevated sludge blankets. A state-of-the-art computational fluid dynamic (CFD) model was successfully used as a design and diagnostic tool to optimize performance for municipal wastewater treatment plants subject to significant PWWFs. Two case studies are presented. For Case Study 1, the model was used to determine the number of secondary clarifiers that will be necessary to treat future PWWF conditions for a plant under design. For Case Study 2, the model was used to identify modifications that are currently being made to increase the clarifier capacity for handling PWWF.