European Multicentric Experience With Fenestrated-branched ENDOvascular Stent Grafting After Previous FAILed Infrarenal Aortic Repair: The EU-FBENDO-FAIL Registry.

OBJECTIVE: To report the mid-term outcomes of fenestrated-branched endovascular aneurysm repair (F-BEVAR) following a failed previous endovascular aneurysm repair (pEVAR) or previous open aneurysm repair (pOAR). METHODS: Data from consecutive patients who underwent F-BEVAR for pEVAR or pOAR from 2006 to 2021 from 17 European vascular centers were analyzed. Endpoints included technical success, major adverse events, 30-day mortality, and 5-year estimates of survival, target vessel primary patency, freedom from reinterventions, type I/III endoleaks, and sac growth >5 mm. BACKGROUND: Treatment of a failed previous abdominal aortic aneurysm repair is a complex undertaking. F-BEVAR is becoming an increasingly attractive option, although comparative data are limited regarding associated risk factors, indications for treatment, and various outcomes. RESULTS: There were 526 patients included, 268 pOAR and 258 pEVAR. The median time from previous repair to F-BEVAR was 7 (interquartile range, 4-12) years, 5 (3-8) for pEVAR, and 10 (6-14) for pOAR, P <0.001. Predominant indication for treatment was type Ia endoleak for pEVAR and progression of the disease for pOAR. Technical success was 92.8%, pOAR (92.2%), and pEVAR (93.4%), P =0.58. The 30-day mortality was 6.5% overall, 6.7% for pOAR, and 6.2% for pEVAR, P =0.81. There were 1853 treated target vessels with 5-year estimates of primary patency of 94.4%, pEVAR (95.2%), and pOAR (94.4%), P =0.03. Five-year estimates for freedom from type I/III endoleaks were similar between groups; freedom from reintervention was lower for pEVAR (38.3%) than for pOAR (56.0%), P =0.004. The most common indication for reinterventions was for type I/III endoleaks (37.5%). CONCLUSIONS: Repair of a failed pEVAR or pOARis safe and feasible with comparable technical success and survival rates. While successful treatment can be achieved, significant rates of reintervention should be anticipated, particularly for issues related to instability of target vessels/bridging stents.

Comparison of Early and Mid-Term Outcomes After Fenestrated-Branched Endovascular Aortic Repair in Patients With or Without Prior Infrarenal Repair.

OBJECTIVE: The purpose of this study was to compare short- and mid-term outcomes of fenestrated-branched endovascular repair (F-BEVAR) of pararenal (PRAA)/thoracoabdominal (TAAA) aortic aneurysms in patients with or without prior endovascular/open (EVAR/OAR) infrarenal aortic repair. METHODS: Data from consecutive F-BEVAR (2010-2019) at two high-volume aortic centers were retrospectively reviewed. Primary endpoints were technical success, 30-day mortality, and overall survival. Secondary endpoints included 30-day major adverse events (MAE), freedom from type I/III endoleaks, reinterventions, sac expansion, and target vessel (TV) primary patency. RESULTS: A total of 222 consecutive patients were included for analysis; of these 58 (26.1%) had prior infrarenal repair (EVAR=33, OAR=25) and 164 (73.9%) had native PRAA/TAAA. At baseline, patients with prior infrarenal repair were older (mean age=75.1 vs 71.6 years, p=.005) and the proportion of females was lower (8.6% vs 29.3%, p=.002). Technical success was 97.8% (n=217) in the entire cohort, without any significant differences between study groups (94.8% vs 98.8%, p=.08). At 30 days, there were no significant differences between patients with prior infrarenal repair as compared with those without in rate of MAE (44.8% vs 54.9%, p=.59). The 5-year estimate of survival for those who underwent native aortic repair was 61.6%, versus 61.3% for those who had a previous repair (p=.67). The 5-year freedom from endoleaks I/III estimates were significantly lower in patients who had prior infrarenal repair as compared with patients undergoing treatment of native aneurysms (57.1% vs 66.1%, p=.03), mainly owing to TV-related endoleaks (ie, type IC and/or IIIC endoleaks). No significant differences were found between study groups in rates of reinterventions and TV primary patency. Five-year estimates of freedom from sac increase >5mm were significantly lower in patients who received F-BEVAR after previous infrarenal repair as compared with those who underwent treatment of native aneurysms (48.6% vs 77.5%, p=.002). CONCLUSIONS: F-BEVAR is equally safe and feasible for treatment of patients with prior infrarenal repair as compared with those undergoing treatment for native aneurysms. Increased rates of TV-related endoleaks were observed which could lead to lower freedom from aneurysm sac shrinkage during follow-up. Nevertheless, the 5-year rates of reinterventions and TV patency were similar, thereby indicating that overall effectiveness of treatment remained satisfactory at mid-term.

Inhibition of angiotensin-induced aortic aneurysm by metformin in apolipoprotein E-deficient mice.

OBJECTIVE: Metformin is associated with a reduced incidence and growth of abdominal aortic aneurysms (AAAs). The aim of the present study was to investigate the inhibitory effects of metformin on AAA development and possible underlying mechanisms in experimentally induced AAAs in mice, along with the possible synergistic effects of metformin and imatinib. METHODS: Angiotensin II was used to induce AAAs in apolipoprotein E knockout (ApoE -/- ) mice for 28 days. The mice were treated with metformin (n = 11), metformin combined with imatinib (n = 7), or vehicle (n = 12), starting 3 days before angiotensin II infusion. Ultrasound examination was used to analyze aneurysm formation. Cholesterol and blood pressure levels were measured at the start and end of the study. Gene array and quantitative polymerase chain reaction were used to analyze the changes in gene expression in the aorta. Wire myography was used to study vascular function. RESULTS: Metformin (n = 11) suppressed the formation and progression of AAAs by 50% compared with the vehicle controls (n = 12), with no further effects from imatinib (n = 7). Metformin reduced total cholesterol and mRNA expression of SPP1 (encoding osteopontin), MMP12, and the glycoprotein genes Gpnmb and Clec7a. Furthermore, metformin inhibited blood pressure increases and reduced vascular contractions, as determined by wire myography, and restored the anticontractile function of perivascular adipose tissue. CONCLUSION: Metformin inhibited aneurysm formation and progression and normalized vascular function in ApoE -/- mice with no additional effect of imatinib. This might be mediated by the protective effects on vascular endothelial function and perivascular adipose tissue via reduced expression of genes promoting inflammation, including SPP1, MMP12, Gpnmb, and Clec7a. CLINICAL RELEVANCE: Retrospective studies of the effects of metformin in patients with aneurysm have so far only been performed of those with type 2 diabetes. The present study shows that metformin has effects on nondiabetic mice and revealed the mechanistic effects mediated by the drug that could also be important to study as outcomes in humans. Future clinical trials using metformin are warranted in patients without diabetes with abdominal aortic aneurysms.

Editor's Choice - Association Between Metformin Prescription and Abdominal Aortic Aneurysm Growth and Clinical Events: a Systematic Review and Meta-Analysis.

OBJECTIVE: A meta-analysis of the association between metformin prescription and abdominal aortic aneurysm (AAA) growth and events (rupture or surgical repair) was performed. METHODS: Open source databases were searched for observational studies reporting the association between metformin prescription and AAA growth or events. Meta-analyses were performed using random effects models. The risk of bias of included studies was assessed using a quality assessment tool developed in a previous systematic review. Sensitivity analyses restricted to people with diabetes, leave one out analyses, and an individual patient risk factor adjusted sub-analysis were performed. Funnel plots assessed reporting bias. RESULTS: Eight studies comprising 153 553 patients were included, of whom 35 240 were and 118 313 were not prescribed metformin. Pooled weighted mean (± standard deviation) AAA growth was significantly reduced in patients prescribed metformin (0.9 ± 0.4 mm/year) compared with those not receiving the medication (1.8 ± 0.4 mm/year; weighted mean difference [WMD] 0.8 mm/year, 95% confidence interval [CI] 0.5 - 1.1; p < .001; I2 = 89%). Leave one out analysis suggested that the significance of findings did not change after removal of individual studies. A sub-analysis within people with diabetes suggested that metformin reduced AAA growth (WMD 0.7 mm/year, 95% CI 0.3 - 1.0). Metformin prescription was associated with a reduced risk of AAA events (risk ratio 0.6, 95% CI 0.4 - 0.9, p = .028). Three, four, and one studies had low, moderate, and high risk of bias, respectively. Individual patient data analysis suggested that metformin prescription slowed annual AAA growth by 0.5 mm/year (95% CI 0.2 - 0.7). The GRADE summary suggested that the certainty of evidence that metformin limited AAA growth and prevented AAA events was very low. CONCLUSION: Observational studies suggest that metformin prescription is associated with a clinically important significant reduction in both growth and clinically relevant events in people with AAA. These findings support the need for randomised trials to examine the benefit of metformin.

Acute cardiovascular effects of controlled exposure to dilute Petrodiesel and biodiesel exhaust in healthy volunteers: a crossover study.

BACKGROUND: Air pollution derived from combustion is associated with considerable cardiorespiratory morbidity and mortality in addition to environmental effects. Replacing petrodiesel with biodiesel may have ecological benefits, but impacts on human health remain unquantified. The objective was to compare acute cardiovascular effects of blended and pure biodiesel exhaust exposure against known adverse effects of petrodiesel exhaust (PDE) exposure in human subjects. In two randomized controlled double-blind crossover studies, healthy volunteers were exposed to PDE or biodiesel exhaust for one hour. In study one, 16 subjects were exposed, on separate occasions, to PDE and 30% rapeseed methyl ester biodiesel blend (RME30) exhaust, aiming at PM10 300 µg/m3. In study two, 19 male subjects were separately exposed to PDE and exhaust from a 100% RME fuel (RME100) using similar engine load and exhaust dilution. Generated exhaust was analyzed for physicochemical composition and oxidative potential. Following exposure, vascular endothelial function was assessed using forearm venous occlusion plethysmography and ex vivo thrombus formation was assessed using a Badimon chamber model of acute arterial injury. Biomarkers of inflammation, platelet activation and fibrinolysis were measured in the blood. RESULTS: In study 1, PDE and RME30 exposures were at comparable PM levels (314 ± 27 µg/m3; (PM10 ± SD) and 309 ± 30 µg/m3 respectively), whereas in study 2, the PDE exposure concentrations remained similar (310 ± 34 µg/m3), but RME100 levels were lower in PM (165 ± 16 µg/m3) and PAHs, but higher in particle number concentration. Compared to PDE, PM from RME had less oxidative potential. Forearm infusion of the vasodilators acetylcholine, bradykinin, sodium nitroprusside and verapamil resulted in dose-dependent increases in blood flow after all exposures. Vasodilatation and ex vivo thrombus formation were similar following exposure to exhaust from petrodiesel and the two biodiesel formulations (RME30 and RME100). There were no significant differences in blood biomarkers or exhaled nitric oxide levels between exposures. CONCLUSIONS: Despite differences in PM composition and particle reactivity, controlled exposure to biodiesel exhaust was associated with similar cardiovascular effects to PDE. We suggest that the potential adverse health effects of biodiesel fuel emissions should be taken into account when evaluating future fuel policies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01337882 /NCT01883466. Date of first enrollment March 11, 2011, registered April 19, 2011, i.e. retrospectively registered.

Metformin Prescription Associated with Reduced Abdominal Aortic Aneurysm Growth Rate and Reduced Chemokine Expression in a Swedish Cohort.

BACKGROUND: Recent reports suggest that the negative association between diabetes mellitus and abdominal aortic aneurysm (AAA) may be driven by metformin, the world's most common antidiabetic drug rather than diabetes per se. We sought to investigate the association among AAA growth rate, chemokine profile, and metformin prescription in a contemporary Swedish cohort. METHODS: Patients under surveillance for small AAA were identified at 4 Swedish vascular centers with active AAA screening programs. Annual AAA growth rate, medical history, and prescribed medications were recorded for linear regression analysis. In a subset of patients with AAA and control subjects without AAA or diabetes, plasma samples were available and analyzed for 40 inflammatory chemokines. RESULTS: A total of 526 patients were included for AAA growth analysis: 428 without type 2 diabetes mellitus (T2DM), 65 with T2DM and metformin prescription, and 33 with T2DM but without metformin prescription. Patients were included from 2005 to 2017 with mean follow-up of 3.2 (1.7) years and median annual AAA growth rate 1.6 mm, range -4.8 to 15.4 mm. Mean (standard deviation) annual AAA growth rates were 2.3 (2.2) mm in non-T2DM patients versus 1.1 (1.1) mm in patients with T2DM with metformin prescription and 1.6 (1.4) mm among those with T2DM without metformin prescription. With non-T2DM patients as reference in an unadjusted and 2 adjusted models, metformin prescription was significantly associated with reduced AAA growth rate (P < 0.001, P = 0.005, and P = 0.024, respectively), but not T2DM without metformin prescription (P = 0.137, P = 0.331, and P = 0.479, respectively). Among 240 patients with AAA (152 without T2DM, 51 with T2DM and metformin, and 37 with T2DM without metformin) and 59 without AAA or T2DM, metformin prescription was associated with reduced expression of chemokines representing all classes of leukocytes. CONCLUSIONS: Metformin prescription is associated with reduced AAA growth rate, possibly mediated by broad anti-inflammatory effects. A randomized controlled trial is needed to determine what role metformin may play in AAA disease, particularly in the absence of T2DM.

Quality of life and gastric acid-suppression medication 20 years after laparoscopic fundoplication.

BACKGROUND: Laparoscopic fundoplication is an effective treatment for gastro-oesophageal reflux disease (GERD). We aimed to assess quality of life (QoL), long-term residual symptoms, patient satisfaction and use of acid-suppression medication at 5, 10 and 20 years after surgery. METHODS: We identified a cohort of 100 patients who underwent laparoscopic fundoplication between 1993 and 1998. The validated QoL questionnaires Short Form health survey (SF-36), and Quality-of-Life in Reflux and Dyspepsia (QOLRAD), as well as a specific questionnaire regarding post-fundoplication symptoms, were sent to the patients at 5, 10 and 20 years after surgery. Furthermore, patients who reported using the acid-suppression medication after 20 years were interviewed by telephone regarding their reason for taking it. RESULTS: Eighty-eight percent of the patients responded at 5 and 10 years post-surgery. Twenty years following fundoplication, 68 (84% of those still alive) patients completed the questionnaires. The patients had equivalent health-related QoL scores in both the QOLRAD and SF-36 questionnaires after 10 and 20 years, and those scores were in line with a Swedish age-matched population. After 20 years, 87% were satisfied with the results, and 84% of the patients would recommend reflux surgery to a relative or a friend. At the telephone interview, 32% (22/68) confirmed using acid-suppression medication, but only half (11/68) used it because of reflux symptoms. CONCLUSION: The long-term, satisfying outcomes in GERD symptoms and QoL 5 and 10 years after surgery were maintained at a 20-year follow-up. Half of the patients used acid-suppression medication for reasons other than GERD symptoms.

Mass spectrometry profiling reveals altered plasma levels of monohydroxy fatty acids and related lipids in healthy humans after controlled exposure to biodiesel exhaust.

Experimental human exposure studies are an effective tool to study adverse health effects from acute inhalation of particulate matter and other constituents of air pollution. In this randomized and double-blinded crossover study, we investigated the systemic effect on bioactive lipid metabolite levels after controlled biodiesel exhaust exposure of healthy humans and compared it to filtered air at a separate exposure occasion. Eicosanoids and other oxylipins, as well as endocannabinoids and related lipids, were quantified in plasma from 14 healthy volunteers at baseline and at three subsequent time points (2, 6, and 24 h) after 1 h exposure sessions. Protocols based on liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS) methods were developed to detect temporal changes in circulating levels after biodiesel exhaust exposure. The exhaust was generated by a diesel engine fed with an undiluted rapeseed methyl ester fuel. Among the 51 analyzed lipid metabolites, PGF2α, 9,10-DiHOME, 9-HODE, 5-HETE, 11-HETE, 12-HETE, and DEA displayed significant responsiveness to the biodiesel exhaust exposure as opposed to filtered air. Of these, 9-HODE and 5-HETE at 24 h survived the 10% false discovery rate cutoff (p < 0.003). Hence, the majority of the responsive lipid metabolites were monohydroxy fatty acids. We conclude that it is possible to detect alterations in circulating bioactive lipid metabolites in response to biodiesel exhaust exposure using LC-MS/MS, with emphasis on metabolites with inflammation related properties and implications on cardiovascular health and disease. These observations aid future investigations on air pollution effects, especially with regard to cardiovascular outcomes.

Mass spectrometry profiling of oxylipins, endocannabinoids, and N-acylethanolamines in human lung lavage fluids reveals responsiveness of prostaglandin E2 and associated lipid metabolites to biodiesel exhaust exposure.

The adverse effects of petrodiesel exhaust exposure on the cardiovascular and respiratory systems are well recognized. While biofuels such as rapeseed methyl ester (RME) biodiesel may have ecological advantages, the exhaust generated may cause adverse health effects. In the current study, we investigated the responses of bioactive lipid mediators in human airways after biodiesel exhaust exposure using lipidomic profiling methods. Lipid mediator levels in lung lavage were assessed following 1-h biodiesel exhaust (average particulate matter concentration, 159 µg/m3) or filtered air exposure in 15 healthy individuals in a double-blinded, randomized, controlled, crossover study design. Bronchoscopy was performed 6 h post exposure and lung lavage fluids, i.e., bronchial wash (BW) and bronchoalveolar lavage (BAL), were sequentially collected. Mass spectrometry methods were used to detect a wide array of oxylipins (including eicosanoids), endocannabinoids, N-acylethanolamines, and related lipid metabolites in the collected BW and BAL samples. Six lipids in the human lung lavage samples were altered following biodiesel exhaust exposure, three from BAL samples and three from BW samples. Of these, elevated levels of PGE2, 12,13-DiHOME, and 13-HODE, all of which were found in BAL samples, reached Bonferroni-corrected significance. This is the first study in humans reporting responses of bioactive lipids following biodiesel exhaust exposure and the most pronounced responses were seen in the more peripheral and alveolar lung compartments, reflected by BAL collection. Since the responsiveness and diagnostic value of a subset of the studied lipid metabolites were established in lavage fluids, we conclude that our mass spectrometry profiling method is useful to assess effects of human exposure to vehicle exhaust.

Multi-platform metabolomics assays for human lung lavage fluids in an air pollution exposure study.

Metabolomics protocols are used to comprehensively characterize the metabolite content of biological samples by exploiting cutting-edge analytical platforms, such as gas chromatography (GC) or liquid chromatography (LC) coupled to mass spectrometry (MS) assays, as well as nuclear magnetic resonance (NMR) assays. We have developed novel sample preparation procedures combined with GC-MS, LC-MS, and NMR metabolomics profiling for analyzing bronchial wash (BW) and bronchoalveolar lavage (BAL) fluid from 15 healthy volunteers following exposure to biodiesel exhaust and filtered air. Our aim was to investigate the responsiveness of metabolite profiles in the human lung to air pollution exposure derived from combustion of biofuels, such as rapeseed methyl ester biodiesel, which are increasingly being promoted as alternatives to conventional fossil fuels. Our multi-platform approach enabled us to detect the greatest number of unique metabolites yet reported in BW and BAL fluid (82 in total). All of the metabolomics assays indicated that the metabolite profiles of the BW and BAL fluids differed appreciably, with 46 metabolites showing significantly different levels in the corresponding lung compartments. Furthermore, the GC-MS assay revealed an effect of biodiesel exhaust exposure on the levels of 1-monostearylglycerol, sucrose, inosine, nonanoic acid, and ethanolamine (in BAL) and pentadecanoic acid (in BW), whereas the LC-MS assay indicated a shift in the levels of niacinamide (in BAL). The NMR assay only identified lactic acid (in BW) as being responsive to biodiesel exhaust exposure. Our findings demonstrate that the proposed multi-platform approach is useful for wide metabolomics screening of BW and BAL fluids and can facilitate elucidation of metabolites responsive to biodiesel exhaust exposure. Graphical Abstract Graphical abstract illustrating the study workflow. NMR Nuclear Magnetic Resonance, LC-TOFMS Liquid chromatography-Time Of Flight Mass Spectrometry, GC Gas Chromatography-Mass spectrometry.

Acute exposure to wood smoke from incomplete combustion--indications of cytotoxicity.

BACKGROUND: Smoke from combustion of biomass fuels is a major risk factor for respiratory disease, but the underlying mechanisms are poorly understood. The aim of this study was to determine whether exposure to wood smoke from incomplete combustion would elicit airway inflammation in humans. METHODS: Fourteen healthy subjects underwent controlled exposures on two separate occasions to filtered air and wood smoke from incomplete combustion with PM1 concentration at 314 µg/m(3) for 3 h in a chamber. Bronchoscopy with bronchial wash (BW), bronchoalveolar lavage (BAL) and endobronchial mucosal biopsies was performed after 24 h. Differential cell counts and soluble components were analyzed, with biopsies stained for inflammatory markers using immunohistochemistry. In parallel experiments, the toxicity of the particulate matter (PM) generated during the chamber exposures was investigated in vitro using the RAW264.7 macrophage cell line. RESULTS: Significant reductions in macrophage, neutrophil and lymphocyte numbers were observed in BW (p < 0.01, <0.05, <0.05, respectively) following the wood smoke exposure, with a reduction in lymphocytes numbers in BAL fluid (<0.01. This unexpected cellular response was accompanied by decreased levels of sICAM-1, MPO and MMP-9 (p < 0.05, <0.05 and <0.01). In contrast, significant increases in submucosal and epithelial CD3+ cells, epithelial CD8+ cells and submucosal mast cells (p < 0.01, <0.05, <0.05 and <0.05, respectively), were observed after wood smoke exposure. The in vitro data demonstrated that wood smoke particles generated under these incomplete combustion conditions induced cell death and DNA damage, with only minor inflammatory responses. CONCLUSIONS: Short-term exposure to sooty PAH rich wood smoke did not induce an acute neutrophilic inflammation, a classic hallmark of air pollution exposure in humans. While minor proinflammatory lymphocytic and mast cells effects were observed in the bronchial biopsies, significant reductions in BW and BAL cells and soluble components were noted. This unexpected observation, combined with the in vitro data, suggests that wood smoke particles from incomplete combustion could be potentially cytotoxic. Additional research is required to establish the mechanism of this dramatic reduction in airway leukocytes and to clarify how this acute response contributes to the adverse health effects attributed to wood smoke exposure. TRIAL REGISTRATION: NCT01488500.

Relative and absolute reliability of measures of linoleic acid-derived oxylipins in human plasma.

Modern analytical techniques allow for the measurement of oxylipins derived from linoleic acid in biological samples. Most validatory work has concerned extraction techniques, repeated analysis of aliquots from the same biological sample, and the influence of external factors such as diet and heparin treatment upon their levels, whereas less is known about the relative and absolute reliability of measurements undertaken on different days. A cohort of nineteen healthy males were used, where samples were taken at the same time of day on two occasions, at least 7 days apart. Relative reliability was assessed using Lin's concordance correlation coefficients (CCC) and intraclass correlation coefficients (ICC). Absolute reliability was assessed by Bland-Altman analyses. Nine linoleic acid oxylipins were investigated. ICC and CCC values ranged from acceptable (0.56 [13-HODE]) to poor (near zero [9(10)- and 12(13)-EpOME]). Bland-Altman limits of agreement were in general quite wide, ranging from ±0.5 (12,13-DiHOME) to ±2 (9(10)-EpOME; log10 scale). It is concluded that relative reliability of linoleic acid-derived oxylipins varies between lipids with compounds such as the HODEs showing better relative reliability than compounds such as the EpOMEs. These differences should be kept in mind when designing and interpreting experiments correlating plasma levels of these lipids with factors such as age, body mass index, rating scales etc.

Effect of wood smoke exposure on vascular function and thrombus formation in healthy fire fighters.

BACKGROUND: Myocardial infarction is the leading cause of death in fire fighters and has been linked with exposure to air pollution and fire suppression duties. We therefore investigated the effects of wood smoke exposure on vascular vasomotor and fibrinolytic function, and thrombus formation in healthy fire fighters. METHODS: In a double-blind randomized cross-over study, 16 healthy male fire fighters were exposed to wood smoke (~1 mg/m³ particulate matter concentration) or filtered air for one hour during intermittent exercise. Arterial pressure and stiffness were measured before and immediately after exposure, and forearm blood flow was measured during intra-brachial infusion of endothelium-dependent and -independent vasodilators 4-6 hours after exposure. Thrombus formation was assessed using the ex vivo Badimon chamber at 2 hours, and platelet activation was measured using flow cytometry for up to 24 hours after the exposure. RESULTS: Compared to filtered air, exposure to wood smoke increased blood carboxyhaemoglobin concentrations (1.3% versus 0.8%; P < 0.001), but had no effect on arterial pressure, augmentation index or pulse wave velocity (P > 0.05 for all). Whilst there was a dose-dependent increase in forearm blood flow with each vasodilator (P < 0.01 for all), there were no differences in blood flow responses to acetylcholine, sodium nitroprusside or verapamil between exposures (P > 0.05 for all). Following exposure to wood smoke, vasodilatation to bradykinin increased (P = 0.003), but there was no effect on bradykinin-induced tissue-plasminogen activator release, thrombus area or markers of platelet activation (P > 0.05 for all). CONCLUSIONS: Wood smoke exposure does not impair vascular vasomotor or fibrinolytic function, or increase thrombus formation in fire fighters. Acute cardiovascular events following fire suppression may be precipitated by exposure to other air pollutants or through other mechanisms, such as strenuous physical exertion and dehydration.

Controlled exposures to air pollutants and risk of cardiac arrhythmia.

BACKGROUND: Epidemiological studies have reported associations between air pollution exposure and increases in cardiovascular morbidity and mortality. Exposure to air pollutants can influence cardiac autonomic tone and reduce heart rate variability, and may increase the risk of cardiac arrhythmias, particularly in susceptible patient groups. OBJECTIVES: We investigated the incidence of cardiac arrhythmias during and after controlled exposure to air pollutants in healthy volunteers and patients with coronary heart disease. METHODS: We analyzed data from 13 double-blind randomized crossover studies including 282 participants (140 healthy volunteers and 142 patients with stable coronary heart disease) from whom continuous electrocardiograms were available. The incidence of cardiac arrhythmias was recorded for each exposure and study population. RESULTS: There were no increases in any cardiac arrhythmia during or after exposure to dilute diesel exhaust, wood smoke, ozone, concentrated ambient particles, engineered carbon nanoparticles, or high ambient levels of air pollution in either healthy volunteers or patients with coronary heart disease. CONCLUSIONS: Acute controlled exposure to air pollutants did not increase the short-term risk of arrhythmia in participants. Research employing these techniques remains crucial in identifying the important pathophysiological pathways involved in the adverse effects of air pollution, and is vital to inform environmental and public health policy decisions.

Exposure to wood smoke increases arterial stiffness and decreases heart rate variability in humans.

BACKGROUND: Emissions from biomass combustion are a major source of indoor and outdoor air pollution, and are estimated to cause millions of premature deaths worldwide annually. Whilst adverse respiratory health effects of biomass exposure are well established, less is known about its effects on the cardiovascular system. In this study we assessed the effect of exposure to wood smoke on heart rate, blood pressure, central arterial stiffness and heart rate variability in otherwise healthy persons. METHODS: Fourteen healthy non-smoking subjects participated in a randomized, double-blind crossover study. Subjects were exposed to dilute wood smoke (mean particle concentration of 314±38 µg/m3) or filtered air for three hours during intermittent exercise. Heart rate, blood pressure, central arterial stiffness and heart rate variability were measured at baseline and for one hour post-exposure. RESULTS: Central arterial stiffness, measured as augmentation index, augmentation pressure and pulse wave velocity, was higher after wood smoke exposure as compared to filtered air (p < 0.01 for all), and heart rate was increased (p < 0.01) although there was no effect on blood pressure. Heart rate variability (SDNN, RMSSD and pNN50; p = 0.003, p < 0.001 and p < 0.001 respectively) was decreased one hour following exposure to wood smoke compared to filtered air. CONCLUSIONS: Acute exposure to wood smoke as a model of exposure to biomass combustion is associated with an immediate increase in central arterial stiffness and a simultaneous reduction in heart rate variability. As biomass is used for cooking and heating by a large fraction of the global population and is currently advocated as a sustainable alternative energy source, further studies are required to establish its likely impact on cardiovascular disease. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01488500.

Altered nitric oxide bioavailability contributes to diesel exhaust inhalation-induced cardiovascular dysfunction in man.

BACKGROUND: Diesel exhaust inhalation causes cardiovascular dysfunction including impaired vascular reactivity, increased blood pressure, and arterial stiffness. We investigated the role of nitric oxide (NO) bioavailability in mediating these effects. METHODS AND RESULTS: In 2 randomized double-blind crossover studies, healthy nonsmokers were exposed to diesel exhaust or filtered air. Study 1: Bilateral forearm blood flow was measured during intrabrachial infusions of acetylcholine (ACh; 5 to 20 µg/min) and sodium nitroprusside (SNP; 2 to 8 µg/min) in the presence of the NO clamp (NO synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) 8 µg/min coinfused with the NO donor SNP at 90 to 540 ng/min to restore basal blood flow). Study 2: Blood pressure, arterial stiffness, and cardiac output were measured during systemic NO synthase inhibition with intravenous l-NMMA (3 mg/kg). Following diesel exhaust inhalation, plasma nitrite concentrations were increased (68±48 versus 41±32 nmol/L; P=0.006) despite similar l-NMMA-induced reductions in basal blood flow (-20.6±14.7% versus -21.1±14.6%; P=0.559) compared to air. In the presence of the NO clamp, ACh and SNP caused dose-dependent vasodilatation that was not affected by diesel exhaust inhalation (P>0.05 for both). Following exposure to diesel exhaust, l-NMMA caused a greater increase in blood pressure (P=0.048) and central arterial stiffness (P=0.007), but reductions in cardiac output and increases in systemic vascular resistance (P>0.05 for both) were similar to those seen with filtered air. CONCLUSIONS: Diesel exhaust inhalation disturbs normal vascular homeostasis with enhanced NO generation unable to compensate for excess consumption. We suggest the adverse cardiovascular effects of air pollution are, in part, mediated through reduced NO bioavailability. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00845767 and NCT01060930.