Impact of COVID-19 pandemic on the management of nonculprit lesions in patients presenting with ST-elevation myocardial infarction: Outcomes from the pan-London heart attack centers.

BACKGROUND: The impact of COVID-19 on the diagnosis and management of nonculprit lesions remains unclear. OBJECTIVES: This study sought to evaluate the management and outcomes of patients with nonculprit lesions during the COVID-19 pandemic. METHODS: We conducted a retrospective observational analysis of consecutive primary percutaneous coronary intervention (PPCI) pathway activations across the heart attack center network in London, UK. Data from the study period in 2020 were compared with prepandemic data in 2019. The primary outcome was the rate of nonculprit lesion percutaneous coronary intervention (PCI) and secondary outcomes included major adverse cardiovascular events. RESULTS: A total of 788 patients undergoing PPCI were identified, 209 (60%) in 2020 cohort and 263 (60%) in 2019 cohort had nonculprit lesions (p = .89). There was less functional assessment of the significance of nonculprit lesions in the 2020 cohort compared to 2019 cohort; in 8% 2020 cohort versus 15% 2019 cohort (p = .01). There was no difference in rates of PCI for nonculprit disease in the 2019 and 2020 cohorts (31% vs 30%, p = .11). Patients in 2020 cohort underwent nonculprit lesion PCI sooner than the 2019 cohort (p < .001). At 6 months there was higher rates of unplanned revascularization (4% vs. 2%, p = .05) and repeat myocardial infarction (4% vs. 1%, p = .02) in the 2019 cohort compared to 2020 cohort. CONCLUSION: Changes to clinical practice during the COVID-19 pandemic were associated with reduced rates of unplanned revascularization and myocardial infarction at 6-months follow-up, and despite the pandemic, there was no difference in mortality, suggesting that it is not only safe but maybe more efficacious.

Antithrombotic Effects of Combined PAR (Protease-Activated Receptor)-4 Antagonism and Factor Xa Inhibition.

OBJECTIVE: PAR (protease-activated receptor)-4 antagonism has antiplatelet effects under conditions of high shear stress. We aimed to establish whether PAR4 antagonism had additive antithrombotic activity in the presence of factor Xa inhibition in an ex vivo model of acute arterial injury. Approach and Results: Fifteen healthy volunteers (29±6 years, 7 women) completed a phase zero double-blind randomized controlled crossover trial. Ex vivo platelet activation, platelet aggregation, and thrombus formation were measured following blood perfusion of low shear and high shear stress chambers. Upstream of the chambers, extracorporeal blood was admixed with (1) vehicle, (2) low-dose apixaban (20 ng/mL), (3) high-dose apixaban (80 ng/mL), (4) BMS-986141 (400 ng/mL), (5) BMS-968141 and low-dose apixaban, or (6) BMS-968141 and high-dose apixaban in 6 sequential studies performed in random order. Compared with vehicle, BMS-986141 demonstrated selective inhibition of PAR4-AP (agonist peptide)-stimulated platelet aggregation, platelet-monocyte aggregates, and P-selectin expression (P≤0.01 for all). Total thrombus area was reduced under both low shear and high shear stress conditions for all drug infusions (P<0.0001 for all versus vehicle). BMS-968141 reduced total (≤44.4%) and platelet-rich (≤39.3%) thrombus area, whereas apixaban reduced total (≤42.9%) and fibrin-rich (≤31.6%) thrombus area. Combination of BMS-986141 with apixaban caused a further modest reduction in total thrombus area (9.6%-12.4%), especially under conditions of high shear stress (P≤0.027). CONCLUSIONS: In the presence of factor Xa inhibition, PAR4 antagonism with BMS-986141 further reduces thrombus formation, especially under conditions of high shear stress. This suggests the potential for additive efficacy of combination PAR4 antagonism and factor Xa inhibition in the prevention of atherothrombotic events.

PAR4 (Protease-Activated Receptor 4) Antagonism With BMS-986120 Inhibits Human Ex Vivo Thrombus Formation.

OBJECTIVE: BMS-986120 is a novel first-in-class oral PAR4 (protease-activated receptor 4) antagonist with potent and selective antiplatelet effects. We sought to determine for the first time, the effect of BMS-986120 on human ex vivo thrombus formation. APPROACH AND RESULTS: Forty healthy volunteers completed a phase 1 parallel-group PROBE trial (Prospective Randomized Open-Label Blinded End Point). Ex vivo platelet activation, platelet aggregation, and thrombus formation were measured at 0, 2, and 24 hours after (1) oral BMS-986120 (60 mg) or (2) oral aspirin (600 mg) followed at 18 hours with oral aspirin (600 mg) and oral clopidogrel (600 mg). BMS-986120 demonstrated highly selective and reversible inhibition of PAR4 agonist peptide (100 µM)-stimulated P-selectin expression, platelet-monocyte aggregates, and platelet aggregation (P<0.001 for all). Compared with pretreatment, total thrombus area (µm2/mm) at high shear was reduced by 29.2% (95% confidence interval, 18.3%-38.7%; P<0.001) at 2 hours and by 21.4% (9.3%-32.0%; P=0.002) at 24 hours. Reductions in thrombus formation were driven by a decrease in platelet-rich thrombus deposition: 34.8% (19.3%-47.3%; P<0.001) at 2 hours and 23.3% (5.1%-38.0%; P=0.016) at 24 hours. In contrast to aspirin alone, or in combination with clopidogrel, BMS-986120 had no effect on thrombus formation at low shear (P=nonsignificant). BMS-986120 administration was not associated with an increase in coagulation times or serious adverse events. CONCLUSIONS: BMS-986120 is a highly selective and reversible oral PAR4 antagonist that substantially reduces platelet-rich thrombus formation under conditions of high shear stress. Our results suggest PAR4 antagonism has major potential as a therapeutic antiplatelet strategy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02439190.

Cardiovascular Outcomes Following Rotational Atherectomy: A UK Multicentre Experience.

OBJECTIVES: To identify factors associated with outcomes following rotational atherectomy (RA). BACKGROUND: RA is an effective way to mechanically modify heavily calcified lesions before stenting; however its outcomes are not well defined. METHODS AND RESULTS: Retrospective evaluation of all patients who underwent RA in three large UK centers (Leeds General Infirmary (LGI), Royal Infirmary of Edinburgh (RIE) and University Hospital of North Staffordshire (UHNS)) from March 2005 to January 2013. Five hundred and eighteen patients had RA with median follow-up period of 22 months. About 68.3% were male, 28.7% had DM and 34.6% were treated because of ACS. Stents were deployed in 97.3% of the patients while 30.7% of the procedures were performed transradially. Maximum burr was ≤1.75 mm in 85.5% and the mean SYNTAX score was 19.5 ± 11.6. Peri-procedural complications occurred in 6.4% and vascular access complications in 1.9%. Outcomes in the follow-up period were: MACE 17.8%, cardiac death 7.1%, MI 11.7%, TVR 7.5%, all-cause death 13.7%, definite stent thrombosis (ST) 1.4% and stroke 2.9%. Patients with intermediate and high SYNTAX scores were more likely to suffer MACE, cardiac death, MI, all-cause death and ST. Patients with a SYNTAX score >32 were also more likely to have a peri-procedural complication. Multiple logistic regression analysis showed that the presence of PVD (P = 0.026, OR = 2.0), DM (P = 0.008, OR = 2.1), ACS presentation (P = 0.011, OR = 2.1) and SYNTAX score ≥23 (P = 0.02, OR = 1.9) had a significant association with MACE. CONCLUSIONS: RA is safe and effective, with high rate of procedural success and relatively low incidence of MACE. PVD, DM, ACS presentation and SYNTAX score were significant predictors for MACE. © 2016 Wiley Periodicals, Inc.

Arctic atmospheric mercury: Sources and changes.

Global anthropogenic and legacy mercury (Hg) emissions are the main sources of Arctic Hg contamination, primarily transported there via the atmosphere. This review summarizes the state of knowledge of the global anthropogenic sources of Hg emissions, and examines recent changes and source attribution of Hg transport and deposition to the Arctic using models. Estimated global anthropogenic Hg emissions to the atmosphere for 2015 were ~2220 Mg, ~20% higher than 2010. Global anthropogenic, legacy and geogenic Hg emissions were, respectively, responsible for 32%, 64% (wildfires: 6-10%) and 4% of the annual Arctic Hg deposition. Relative contributions to Arctic deposition of anthropogenic origin was dominated by sources in East Asia (32%), Commonwealth of Independent States (12%), and Africa (12%). Model results exhibit significant spatiotemporal variations in Arctic anthropogenic Hg deposition fluxes, driven by regional differences in Hg air transport routes, surface and precipitation uptake rates, and inter-seasonal differences in atmospheric circulation and deposition pathways. Model simulations reveal that changes in meteorology are having a profound impact on contemporary atmospheric Hg in the Arctic. Reversal of North Atlantic Oscillation phase from strongly negative in 2010 to positive in 2015, associated with lower temperature and more sea ice in the Canadian Arctic, Greenland and surrounding ocean, resulted in enhanced production of bromine species and Hg(0) oxidation and lower evasion of Hg(0) from ocean waters in 2015. This led to increased Hg(II) (and its deposition) and reduced Hg(0) air concentrations in these regions in line with High Arctic observations. However, combined changes in meteorology and anthropogenic emissions led to overall elevated modeled Arctic air Hg(0) levels in 2015 compared to 2010 contrary to observed declines at most monitoring sites, likely due to uncertainties in anthropogenic emission speciation, wildfire emissions and model representations of air-surface Hg fluxes.

Temporal trends of mercury in Arctic biota: 10 more years of progress in Arctic monitoring.

Temporal trend analysis of (total) mercury (THg) concentrations in Arctic biota were assessed as part of the 2021 Arctic Monitoring and Assessment Programme (AMAP) Mercury Assessment. A mixed model including an evaluation of non-linear trends was applied to 110 time series of THg concentrations from Arctic and Subarctic biota. Temporal trends were calculated for full time series (6-46 years) and evaluated with a particular focus on recent trends over the last 20 years. Three policy-relevant questions were addressed: (1) What time series for THg concentrations in Arctic biota are currently available? (2) Are THg concentrations changing over time in biota from the Arctic? (3) Are there spatial patterns in THg trends in biota from the Arctic? Few geographical patterns of recent trends in THg concentrations were observed; however, those in marine mammals tended to be increasing at more easterly longitudes, and those of seabirds tended to be increasing in the Northeast Atlantic; these should be interpreted with caution as geographic coverage remains variable. Trends of THg in freshwater fish were equally increasing and decreasing or non-significant while those in marine fish and mussels were non-significant or increasing. The statistical power to detect trends was greatly improved compared to the 2011 AMAP Mercury Assessment; 70% of the time series could detect a 5% annual change at the 5% significance level with power ≥ 80%, while in 2011 only 19% met these criteria. Extending existing time series, and availability of new, powerful time series contributed to these improvements, highlighting the need for annual monitoring, particularly given the spatial and temporal information needed to support initiatives such as the Minamata Convention on Mercury. Collecting the same species/tissues across different locations is recommended. Extended time series from Alaska and new data from Russia are also needed to better establish circumarctic patterns of temporal trends.

A risk assessment review of mercury exposure in Arctic marine and terrestrial mammals.

There has been a considerable number of reports on Hg concentrations in Arctic mammals since the last Arctic Monitoring and Assessment Programme (AMAP) effort to review biological effects of the exposure to mercury (Hg) in Arctic biota in 2010 and 2018. Here, we provide an update on the state of the knowledge of health risk associated with Hg concentrations in Arctic marine and terrestrial mammal species. Using available population-specific data post-2000, our ultimate goal is to provide an updated evidence-based estimate of the risk for adverse health effects from Hg exposure in Arctic mammal species at the individual and population level. Tissue residues of Hg in 13 species across the Arctic were classified into five risk categories (from No risk to Severe risk) based on critical tissue concentrations derived from experimental studies on harp seals and mink. Exposure to Hg lead to low or no risk for health effects in most populations of marine and terrestrial mammals, however, subpopulations of polar bears, pilot whales, narwhals, beluga and hooded seals are highly exposed in geographic hotspots raising concern for Hg-induced toxicological effects. About 6% of a total of 3500 individuals, across different marine mammal species, age groups and regions, are at high or severe risk of health effects from Hg exposure. The corresponding figure for the 12 terrestrial species, regions and age groups was as low as 0.3% of a total of 731 individuals analyzed for their Hg loads. Temporal analyses indicated that the proportion of polar bears at low or moderate risk has increased in East/West Greenland and Western Hudson Bay, respectively. However, there remain numerous knowledge gaps to improve risk assessments of Hg exposure in Arctic mammalian species, including the establishment of improved concentration thresholds and upscaling to the assessment of population-level effects.

Vascular effects of serelaxin in patients with stable coronary artery disease: a randomized placebo-controlled trial.

AIMS: The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD). METHODS AND RESULTS: In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of -9.6 mmHg (P = 0.01) and -13.5 mmHg (P = 0.0003) for systolic blood pressure and -5.2 mmHg (P = 0.02) and -8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (-0.24 vs. -0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up. CONCLUSION: In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

Benign paroxysmal positional vertigo after decompression sickness: a first case report and review of the literature.

Benign paroxysmal positional vertigo is a common cause of vertigo. We describe a previously unreported case of this clinical entity in a young, fit recreational water diver, having experienced decompression illness. Full recovery occurred after hyperbaric recompression therapy, and he remained symptom free on 6-week follow-up. We review the literature and discuss the pathogenesis of benign paroxysmal positional vertigo, proposing that semicircular canal nitrogen bubble formation could have been the primary etiological event leading to this condition.

Incidence of "shocktopics" and asynchronous cardiac pacing in patients undergoing coronary intravascular lithotripsy.

AIMS: Coronary intravascular lithotripsy (IVL) is a novel approach to vascular calcium modification that restores vessel compliance allowing effective lesion expansion. In this study we report the capacity for coronary IVL to precipitate ventricular ectopics ("shocktopics") and asynchronous cardiac pacing. METHODS AND RESULTS: This was a retrospective review of all cases of coronary IVL (n=54) undertaken in the Royal Victoria Hospital, Belfast, between September 2018 and March 2019. The indication for PCI was chronic stable angina in 46.1% (n=26), non-ST-elevation acute coronary syndrome (NSTEACS) in 33.3% (n=18) and ST-elevation myocardial infarction (STEMI) in 18.5% (n=10) of patients. The incidence of coronary IVL-provoked ventricular capture was 77.8% (n=42). Multivariable logistic regression analysis identified heart rate as the only independent predictor of an increased risk of IVL-induced ventricular capture. Patients with a heart rate <65 bpm prior to IVL were sixteen-fold more likely (OR 16.3 [2.4-110.8], p=0.004) to experience events compared to patients with a heart rate ≥65 bpm. "Shocktopic" beat morphology was largely uniform in each patient and appeared dependent on the target lesion location, in keeping with mechano-electric coupling through activation of local stretch-activated cardiomyocyte channels. No adverse clinical events occurred as a result of coronary IVL-induced capture. CONCLUSIONS: Coronary IVL with the Shockwave Medical system is associated with a high incidence of "shocktopics" and asynchronous cardiac pacing that is largely dependent on the resting heart rate. There have been no clinical events associated with this phenomenon, but further systematic evaluation is warranted.

Intravascular Healing Is Not Affected by Approaches in Contemporary CTO PCI: The CONSISTENT CTO Study.

OBJECTIVES: The aim of this study was to assess angiographic, imaging, and clinical outcomes following chronic total occlusion (CTO) percutaneous coronary intervention (PCI) with dissection and re-entry techniques (DART) and subintimal (SI) stenting compared with intimal techniques. BACKGROUND: Reliable procedural success and safety in CTO PCI require the use of DART to treat the most complex patients. Potential concerns regarding the durability of DART with SI stenting still need to be addressed. METHODS: This was a prospective, multicenter, single-arm trial of patients with appropriate indications for CTO PCI. RESULTS: Successful CTO PCI was performed in 210 of 231 patients (91% success). At 1 year, the primary endpoint of target vessel failure (cardiac death, myocardial infarction related to the target vessel, or any ischemia-driven revascularization) occurred in 5.7% of patients, meeting the pre-set performance goal. Major adverse cardiovascular events (all-cause mortality, myocardial infarction, or target vessel revascularization) occurred in 10% at 1 year and 17% by 2 years and was not influenced by DART. Quality-of-life measures significantly improved from baseline to 12 months. There was no difference in intravascular healing assessed using optical coherence tomography at 12 months for patients treated with DART and SI stenting compared with intimal strategies. CONCLUSIONS: Contemporary CTO PCI is associated with medium-term clinical outcomes comparable with those achieved in other complex PCI cohorts and significant improvements in quality of life. The use of DART with SI stenting does not adversely affect intravascular healing at 12 months or medium-term major adverse cardiovascular events. (Consistent CTO Trial; NCT02227771).

COVID-19 pandemic and STEMI: pathway activation and outcomes from the pan-London heart attack group.

OBJECTIVES: To understand the impact of COVID-19 on delivery and outcomes of primary percutaneous coronary intervention (PPCI). Furthermore, to compare clinical presentation and outcomes of patients with ST-segment elevation myocardial infarction (STEMI) with active COVID-19 against those without COVID-19. METHODS: We systematically analysed 348 STEMI cases presenting to the PPCI programme in London during the peak of the pandemic (1 March to 30 April 2020) and compared with 440 cases from the same period in 2019. Outcomes of interest included ambulance response times, timeliness of revascularisation, angiographic and procedural characteristics, and in-hospital clinical outcomes RESULTS: There was a 21% reduction in STEMI admissions and longer ambulance response times (87 (62-118) min in 2020 vs 75 (57-95) min in 2019, p<0.001), but that this was not associated with a delays in achieving revascularisation once in hospital (48 (34-65) min in 2020 vs 48 (35-70) min in 2019, p=0.35) or increased mortality (10.9% (38) in 2020 vs 8.6% (38) in 2019, p=0.28). 46 patients with active COVID-19 were more thrombotic and more likely to have intensive care unit admissions (32.6% (15) vs 9.3% (28), OR 5.74 (95%CI 2.24 to 9.89), p<0.001). They also had increased length of stay (4 (3-9) days vs 3 (2-4) days, p<0.001) and a higher mortality (21.7% (10) vs 9.3% (28), OR 2.72 (95% CI 1.25 to 5.82), p=0.012) compared with patients having PPCI without COVID-19. CONCLUSION: These findings suggest that PPCI pathways can be maintained during unprecedented healthcare emergencies but confirms the high mortality of STEMI in the context of concomitant COVID-19 infection characterised by a heightened state of thrombogenicity.

Exosite 1 thrombin inhibition with JNJ-64179375 inhibits thrombus formation in a human translational model of thrombosis.

AIMS: JNJ-64179375 (hereafter JNJ-9375) is a first-in-class, highly specific, large molecule, exosite 1 thrombin inhibitor. In preclinical studies, JNJ-9375 demonstrated robust antithrombotic protection with a wider therapeutic index when compared to apixaban. The purpose of the present study was to examine for the first time the antiplatelet, anticoagulant and antithrombotic effects of JNJ-9375 in a translational model of ex vivo human thrombosis. METHODS AND RESULTS: Fifteen healthy volunteers participated in a double-blind randomized crossover study of JNJ-9375 (2.5, 25, and 250 µg/mL), bivalirudin (6 µg/mL; positive control), and matched placebo. Coagulation, platelet activation, and thrombus formation were determined using coagulation assays, flow cytometry, and an ex vivo perfusion chamber, respectively.JNJ-9375 caused concentration-dependent prolongation of all measures of blood coagulation (prothrombin time, activated partial thromboplastin time, and thrombin time; P < 0.001 for all) and agonist selective inhibition of thrombin (0.1 U/mL) stimulated platelet p-selectin expression (P < 0.001) and platelet-monocyte aggregates (P = 0.002). Compared to placebo, JNJ-9375 (250 µg/mL) reduced mean total thrombus area by 41.1% (95% confidence intervals 22.3 to 55.3%; P < 0.001) at low shear and 32.3% (4.9 to 51.8%; P = 0.025) at high shear. Under both shear conditions, there was a dose-dependent decrease in fibrin-rich thrombus (P < 0.001 for both) but not platelet-rich thrombus (P = ns for both). CONCLUSION: Exosite 1 inhibition with JNJ-9375 caused prolongation of blood coagulation, selective inhibition of thrombin-mediated platelet activation, and reductions in ex vivo thrombosis driven by a decrease in fibrin-rich thrombus formation. JNJ-9375 represents a novel class of anticoagulant with potential therapeutic applications.

Saphenous Vein Graft Sacrifice Following Native Vessel PCI is Safe and Associated with Favourable Longer-Term Outcomes.

BACKGROUND: Competitive flow from saphenous vein grafts (SVG) that remain patent following percutaneous coronary intervention (PCI) of the native vessel may compromise durability of the reconstructed vessel. SVG sacrifice has been advocated, but the safety and longer-term outcomes of this are unknown. METHODS: We retrospectively reviewed all post-bypass patients who following successful PCI of the native vessel underwent attempted saphenous vein graft (SVG) closure between January 2014 and July 2018 in two institutions. The co-primary end-points of interest were safety and target lesion failure (TLF), defined as a composite of cardiac death, target vessel recurrent myocardial infarction or clinically driven target lesion revascularisation (TLR). RESULTS: Of the 33 consecutive patients included, the reconstructed native vessel was a chronic total occlusion (CTO) in 93.9% of patients (n = 31) with a mean J-CTO score of 3.2 (±1.1) SVG closure was successful in 97.0% of patients (n = 32). Amplatzer Vascular Plugs (AVP; Abbott Vascular) were used in all patients with most grafts closed by a single plug (72.7%). The average procedure time was 20.1 min with evidence of a short learning curve. Over a mean follow up of 602 (±393) days from the date of SVG closure, the incidence of TLF was 9.1% (n = 3). There was an additional case of targe vessel failure (TVF) due to progression of native vessel disease not treated at the index procedure. SVG closure resulted in only 1 episode of "slow flow" that was transient and self-resolving. There were no other associated peri-procedural or in-hospital complications. CONCLUSION: Following native vessel PCI, SVG sacrifice may be considered to terminate the potentially deleterious effects of residual competitive flow. In selected cases, this approach achieves high success rate and favourable longer-term outcomes.

Effects of Diesel Exhaust on Cardiovascular Function and Oxidative Stress.

SIGNIFICANCE: Air pollution is a major global health concern with particulate matter (PM) being especially associated with increases in cardiovascular morbidity and mortality. Diesel exhaust emissions are a particularly rich source of the smallest sizes of PM ("fine" and "ultrafine") in urban environments, and it is these particles that are believed to be the most detrimental to cardiovascular health. Recent Advances: Controlled exposure studies to diesel exhaust in animals and man demonstrate alterations in blood pressure, heart rate, vascular tone, endothelial function, myocardial perfusion, thrombosis, atherogenesis, and plaque stability. Oxidative stress has emerged as a highly plausible pathobiological mechanism by which inhalation of diesel exhaust PM leads to multiple facets of cardiovascular dysfunction. CRITICAL ISSUES: Diesel exhaust inhalation promotes oxidative stress in several biological compartments that can be directly associated with adverse cardiovascular effects. FUTURE DIRECTIONS: Further studies with more sensitive and specific in vivo human markers of oxidative stress are required to determine if targeting oxidative stress pathways involved in the actions of diesel exhaust PM could be of therapeutic value. Antioxid. Redox Signal. 28, 819-836.

Patent haemostasis prevents radial artery occlusion in patients with an acute coronary syndrome.

BACKGROUND: A haemostatic technique that maintains radial artery flow ("patent haemostasis") following transradial catheterization reduces rates of radial artery occlusion (RAO) in patients with stable coronary disease. It is unclear whether this benefit extends to patients with an acute coronary syndrome (ACS). METHODS: Patients undergoing inpatient transradial catheterization for an ACS were prospectively enrolled in a consecutive cohort study (n=300). Radial haemostasis was obtained using standard radial compression (cohort 1; n=150) or patent haemostasis (cohort 2; n=150). An end-of-case activated clotting time (ACT) was recorded and radial artery patency assessed within 24 hours of sheath removal by reverse Barbeau's test. RESULTS: The incidence of RAO was 16.0% following standard radial compression and 5.3% following patent haemostasis (p=0.003). Univariate predictors of RAO were patent haemostasis (OR 0.30; [0.13-0.68], p=0.004), hyperlipidaemia (OR 0.46; [0.21-0.98], p=0.04), history of current smoking (OR 2.86; [1.3-6.0], p=0.015) and longer procedure times (OR 1.03/additional minute; [1.01-1.05], p=0.003). There was no association between the end-of-case ACT and RAO (OR 1.00; [0.9-1.01] p=1.00). After adjusting for covariates, patent haemostasis reduced the risk of RAO by 70% compared to standard compression (OR 0.30; [0.12-0.77], p=0.12). The c-statistic for model discrimination was 0.79 (95% CI [0.71-0.86], p<0.001). Inverse probability treatment weighted analysis also confirmed patent haemostasis as an independent predictor of reduced RAO (OR 0.38 [0.15-0.95], p=0.039). CONCLUSION: Patent haemostasis is highly effective in preventing early RAO in patients with ACS.

Toward an Assessment of the Global Inventory of Present-Day Mercury Releases to Freshwater Environments.

Aquatic ecosystems are an essential component of the biogeochemical cycle of mercury (Hg), as inorganic Hg can be converted to toxic methylmercury (MeHg) in these environments and reemissions of elemental Hg rival anthropogenic Hg releases on a global scale. Quantification of effluent Hg releases to aquatic systems globally has focused on discharges to the global oceans, rather than contributions to freshwater systems that affect local exposures and risks associated with MeHg. Here we produce a first-estimate of sector-specific, spatially resolved global aquatic Hg discharges to freshwater systems. We compare our release estimates to atmospheric sources that have been quantified elsewhere. By analyzing available quantitative and qualitative information, we estimate that present-day global Hg releases to freshwater environments (rivers and lakes) associated with anthropogenic activities have a lower bound of ~1000 Mg· a-1. Artisanal and small-scale gold mining (ASGM) represents the single largest source, followed by disposal of mercury-containing products and domestic waste water, metal production, and releases from industrial installations such as chlor-alkali plants and oil refineries. In addition to these direct anthropogenic inputs, diffuse inputs from land management activities and remobilization of Hg previously accumulated in terrestrial ecosystems are likely comparable in magnitude. Aquatic discharges of Hg are greatly understudied and further constraining associated data gaps is crucial for reducing the uncertainties in the global biogeochemical Hg budget.

The first clinical experience with a novel "locking" microcatheter in chronic coronary total occlusions.

AIMS: A novel "locking" microcatheter has been developed to address residual failure modes in chronic total occlusion (CTO) percutaneous coronary intervention (PCI). The aim of this study was to report the first clinical experience of this device. METHODS AND RESULTS: The microcatheter was assessed prospectively in 92 unselected CTO cases across six European sites. Overall technical success was 85.9% (79/92) and 97.5% for patients with a J-CTO score of <3 (39/40). Within-CTO tortuosity was the only lesion characteristic to predict reduced technical success (OR 0.10 [0.01-0.97], p=0.047). Calcification (OR 0.45 [0.04-5.31], p=0.53), lesion length >20 mm (OR 0.58 [0.05-6.81], p=0.66) and a blunt proximal cap (OR 0.47 [0.08-2.90], p=0.42) were not associated with technical failure in this case series. Locking facilitated guidewire crossing (after initial failure) of the proximal cap in 23 cases, distal cap in 11 cases and CTO body in 10 cases, and delivery of the microcatheter through to the distal vessel in 22 cases. The overall procedural complication rate was 1.1% (1/92) with no major events. CONCLUSIONS: Guidewire locking with this novel microcatheter assists penetration and crossing of fibrocalcific anatomy with a high degree of safety. Using this device in CTO PCI may lead to improved primary wiring and overall procedural success rates.