Occupational exposure to crystalline silica in a sample of the French general population.

OBJECTIVE: To describe the proportions of subjects exposed to crystalline silica and the sectors of activity concerned between 1965 and 2010 in a sample of the general French population. METHODS: We included 2942 participants aged 40 to 65 years, recruited at random from electoral rolls, from the French general population in the cross-sectional ELISABET study between 2011 and 2013. The proportions of subjects exposed to crystalline silica and their sectors of activity were determined on the basis of their career history and the use of the Matgéné job-exposure matrix. RESULTS: In the total sample, occupational exposure to crystalline silica was found for 291 subjects (9.9%) between 1965 and 2010, with a predominance of men (20.2% of exposed subjects among men (282 out of 1394) versus 0.6% among women (9 out of 1548)). The highest proportion of participants exposed to crystalline silica was reached in 1980 with 6.1% and then decreases to 4.4% in 2010. Among men, the most frequently exposed sectors of activity were manufacture of basic metals (41.5% of exposed men (117 out of 282)), specialised construction activities (23.1% of exposed men (65 out of 282)) and construction of buildings (14.2% of exposed men (40 out of 282)). CONCLUSIONS: Although the proportion of workers exposed to crystalline silica has been decreasing since the 1980s, it is still significant at least until 2010, particularly in the construction sector, and further research is needed to improve the monitoring of workers who are or have been exposed to crystalline silica.

Assessment of lung hyperinflation in occupational chronic obstructive pulmonary disease: a multicentric cross-sectional study.

Occupational exposure is associated with elevated morbidity and lower quality of life in patients with chronic obstructive pulmonary disease (COPD). Static hyperinflation is an independent risk factor for all-cause mortality in COPD and for COPD exacerbation. In a multicentre, cross-sectional study (BPROFETIO), we sought to analyse the relationship between static hyperinflation and occupational exposure in patients with COPD with or without occupational exposure. MATERIAL AND METHODS: An overall 'whole working life' cumulative exposure index was calculated for occupational patients with COPD. Spirometry indices and lung volumes were measured according to the 2005 American Thoracic Society/European Respiratory Society guidelines. RESULTS: After adjustment for age, sex, height, body mass index, smoking and coexposure, the analysis for each occupational hazard showed a higher risk for hyperinflation and FEV1 decline or progression of COPD or GOLD stage for patients with COPD exposed to non-metallic inorganic dusts. CONCLUSION: Occupational exposures should be more investigated in clinical practice and studies as they contribute to the COPD heterogeneity and are associated for some with the development of a static hyperinflation; a condition that is known to have a negative impact on quality of life and survival.

Hematopoietic Somatic Mosaicism Is Associated With an Increased Risk of Postoperative Atrial Fibrillation.

BACKGROUND: On-pump cardiac surgery triggers sterile inflammation and postoperative complications such as postoperative atrial fibrillation (POAF). Hematopoietic somatic mosaicism (HSM) is a recently identified risk factor for cardiovascular diseases and results in a shift toward a chronic proinflammatory monocyte transcriptome and phenotype. OBJECTIVES: The aim of this study was to assess the prevalence, characteristics, and impact of HSM on preoperative blood and myocardial myeloid cells as well as on outcomes after cardiac surgery. METHODS: Blood DNA from 104 patients referred for surgical aortic valve replacement (AVR) was genotyped using the HemePACT panel (576 genes). Four screening methods were applied to assess HSM, and postoperative outcomes were explored. In-depth blood and myocardial leukocyte phenotyping was performed in selected patients using mass cytometry and preoperative and postoperative RNA sequencing analysis of classical monocytes. RESULTS: The prevalence of HSM in the patient cohort ranged from 29%, when considering the conventional HSM panel (97 genes) with variant allelic frequencies ≥2%, to 60% when considering the full HemePACT panel and variant allelic frequencies ≥1%. Three of 4 explored HSM definitions were significantly associated with higher risk for POAF. On the basis of the most inclusive definition, HSM carriers exhibited a 3.5-fold higher risk for POAF (age-adjusted OR: 3.5; 95% CI: 1.52-8.03; P = 0.003) and an exaggerated inflammatory response following AVR. HSM carriers presented higher levels of activated CD64+CD14+CD16- circulating monocytes and inflammatory monocyte-derived macrophages in presurgery myocardium. CONCLUSIONS: HSM is frequent in candidates for AVR, is associated with an enrichment of proinflammatory cardiac monocyte-derived macrophages, and predisposes to a higher incidence of POAF. HSM assessment may be useful in the personalized management of patients in the perioperative period. (Post-Operative Myocardial Incident & Atrial Fibrillation [POMI-AF]; NCT03376165).

The impact of occupational exposure to crystalline silica dust on respiratory function (airway obstruction and FEF25-75) in the French general population.

INTRODUCTION: Although several studies have studied the relationship between occupational exposure to crystalline silica dust and respiratory mortality, few have examined the relationship with impairments in respiratory function and the exposure threshold triggering spirometric monitoring in exposed workers. The objective of the present study was to evaluate the impact of exposure to crystalline silica dust on respiratory function. METHODS: We included 1428 male participants (aged 40 to 65) recruited from the French general population, at random from electoral rolls, in the cross-sectional ELISABET study and for whom data on forced expiratory flow-volume curve indices z-scores (calculated using the Global Lung Function Initiative 2012 equations) and exposure (via a questionnaire) were available. A cumulative exposure index (CEI) for crystalline silica dust (CEIsilica, expressed in mg.m-3.year) was calculated using the Matgéné occupational exposure matrix. RESULTS: 293 of the 1428 participants (20.52%) reported exposure to silica dust. We found that the adjusted z-scores for the forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) ratio decreased significantly as CEIsilica increased. After adjustment, the adjusted z-scores for FEV1/FVC (ß: -0.426 (95% confidence interval (CI): -0.792, -0.060) per 1 mg m-3.year increment) and the mean forced expiratory flow between 25 and 75% of the forced vital capacity (FEF25-75) (ß: -0.552 (95% CI: -0.947, -0.157)) were significantly lower in the participants with CEIsilica ≥1 mg m-3.year than in non-exposed participants. The likelihoods of having airway obstruction (odds ratio (OR): 3.056 (95% CI: 1.107, 7.626)) or having an impaired FEF25-75 (OR: 4.305 (95% CI: 1.393, 11.79)) were also significantly higher in participants with CEIsilica ≥1 mg m-3.year. CONCLUSION: Our results emphasize the importance of spirometry-based monitoring in workers exposed to more than 1 mg m-3.year of crystalline silica dust, in order to identify small airway obstruction or airway obstruction as early as possible.

Mild pulmonary hemodynamic alterations in patients with systemic sclerosis: relevance of the new 2022 ESC/ERS definition of pulmonary hypertension and impact on mortality.

BACKGROUND AND OBJECTIVE: The definition of pre-capillary pulmonary hypertension (PH) has been modified, with lowering of the mean pulmonary arterial pressure (mPAP) threshold from 25 to 20 mmHg and addition of a mandatory criterion of pulmonary vascular resistance (PVR) ≥ 2 Wood units (WU). Our objectives were: 1/ to estimate the proportion of patients reclassified as having pre-capillary PH when using the new 2022 ESC/ERS hemodynamic criteria (i.e. mPAP 21-24 mmHg and PVR ≥ 2 WU), and to describe their clinical characteristics and outcome; and 2/ to study the relationship between PVR and survival in patients with mPAP > 20 mmHg. METHODS: We retrospectively analyzed consecutive SSc patients included in our National Reference Center for a first right-heart catheterization between 2003 and 2018. The association between survival and PVR was studied using smoothing splines. RESULTS: We included 126 SSc patients with mPAP > 20 mmHg. Among them, 16 (13%) had a baseline mPAP value between 21 and 24 mmHg and PVR ≥ 2 mmHg and were reclassified as pre-capillary PH; 10 of which (62%) raised their mPAP ≥ 25 mmHg during follow-up. In patients with mPAP > 20 mmHg, we observed a linear relation between PVR and mortality for values < 6 WU. CONCLUSION: A significant proportion of SSc patients is reclassified as having pre-capillary PH with the new 2022 ESC/ERS hemodynamic definition. Lowering the PVR threshold from 3 to 2 WU captures patients at risk of raising their mPAP > 25 mmHg, with a possibly less severe disease.

Assessing the applicability of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide in a large population set.

BACKGROUND: The single-breath diffusing capacity of the lung for carbon monoxide (DLCO) interpretation needs the comparison of measured values to reference values. In 2017, the Global Lung Function Initiative published new reference values (GLI-2017) for DLCO, alveolar volume (VA) and transfer coefficient of the lung for carbon monoxide (KCO). We aimed to assess the applicability of GLI-2017 reference values for DLCO on a large population by comparing them to the European Community of Steel and Coal equations of 1993 (ECSC-93) widely used. METHODS: In this retrospective study, spirometric indices, total lung capacity, DLCO, VA and KCO were measured in adults classified in 5 groups (controls, asthma, chronic bronchitis, cystic fibrosis, and interstitial lung diseases (ILD)). Statistical analysis comparing the 2 equations sets were stratified by sex. RESULTS: 4180 tests were included. GLI-2017 z-scores of the 3 DLCO indices of the controls (n = 150) are nearer to 0 (expected value in a normal population) than ECSC-93 z-scores. All groups combined, in both genders, DLCO GLI-2017 z-scores and %predicted are significantly higher than ECSC z-scores and %predicted. In the ILD group, differences between the 2 equation sets depend on the DLCO impairment severity: GLI-2017 z-scores are higher than ECSC z-scores in patients with no or "mild" decrease in DLCO, but are lower in "moderate" or "severe" decrease. CONCLUSION: GLI-2017 reference values for DLCO are more suitable to our population and influence the diagnostic criteria and severity definition of several lung diseases.

Reproducibility of reading echocardiographic parameters to assess severity of mitral regurgitation. Insights from a French multicentre study.

BACKGROUND: Poor reproducibility in assessment of mitral regurgitation (MR) has been reported. AIM: To investigate the robustness of echocardiographic MR assessment in 2019, based on improvements in technology and the skill of echocardiographists regarding MR quantification. METHODS: Reproducibility in parameters of MR severity and global rating were tested using transthoracic echocardiography in 25 consecutive patients independently analysed by 16 junior and senior cardiologists specialized in echocardiography (400 analyses per parameter). RESULTS: Overall interobserver agreement for mechanism definition, effective regurgitant orifice area (EROA) and regurgitant volume (RVol) was moderate, and was lower in secondary MR. Interobserver agreement was substantial for EROA [0.61, 95% confidence interval (CI) 0.45-0.75] and moderate for RVol with the PISA method (0.50, 95% CI 0.33-0.56) in senior physicians and was fair in junior physicians (0.33, 95% CI 0.19-0.51 and 0.36, 95% CI 0.36-0.43, respectively). Using a multiparametric approach, overall interobserver agreement for grading MR severity was fair (0.30), was slightly better in senior than in junior physicians (0.31 vs. 0.28, respectively) with substantial or almost perfect agreement more frequently observed in senior versus junior physicians (52% vs. 36%, respectively). CONCLUSION: Reproducible transthoracic echocardiography MR quantification remains challenging in 2019, despite the expected high skills of echocardiographers regarding MR at the time of dedicated percutaneous intervention. The multiparametric approach does not entirely alleviate the substantial dispersion in measurement of MR severity parameters, whereas reader experience seems to partially address the issue. Our study emphasizes the continuing need for multimodality imaging and education in the evaluation of MR among cardiologists.

Residential exposure to outdoor air pollution and adult lung function, with focus on small airway obstruction.

Although a growing body of evidence suggests that chronic exposure to outdoor air pollution is linked to a decline in lung function, data on flow at low lung volumes that may be more specific of small airway obstruction are still scarce. We aimed to study the associations between residential exposure to air pollution and lung function, with specific focus on small airways obstruction. We assessed 2995 French participants (aged between 40 and 65) in the ELISABET cross-sectional survey. Residential exposures to nitrogen dioxide (NO2), particulate matter with a diameter <10 µm (PM10) and sulphur dioxide (SO2) were assessed. The spirometric parameters were forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and forced expiratory flow between 25% and 75% of FVC (FEF25-75) and at 75% of FVC (FEF75). Coefficients in linear regression models were expressed as the z-score [95% confidence interval] for an increment of 5 µg/m3 in NO2 and 2 µg/m3 in PM10 and SO2. NO2 was associated with significantly lower values of FEV1 (-0.10 [-0.15;-0.05]), FVC (-0.06 [-0.11;-0.02]), FEV1/FVC (-0.07 [-0.11;-0.03]), FEF25-75 (-0.09 [-0.14;-0.05]) and FEF75 (-0.08 [-0.12;-0.04]). PM10 was associated with significantly lower values of FEV1 (-0.10 [-0.15;-0.04]), FVC (-0.06 [-0.11;-0.01]), FEV1/FVC (-0.06 [‒0.11;-0.01]), FEF25-75 (-0.08 [-0.13;-0.03]) and FEF75 (-0.08 [-0.12;-0.04]). SO2 was associated with significantly lower values of FEV1 (-0.09 [-0.16;-0.02]), FEV1/FVC (-0.07 [-0.13;-0.01]), FEF25-75 (-0.09 [-0.15;-0.02]) and FEF75 (-0.08 [-0.14;-0.03]) but not FVC (-0.05 [-0.11; 0.009]). Even though spatial variations in pollutant levels were low, residential exposure to outdoor air pollution was associated with lower lung function, including lower FEF25-75 and FEF75 suggesting small airway obstruction.

Exposure to metal fumes and circulating miRNAs in Algerian welders.

PURPOSE: A cross-sectional study was conducted in a group of Algerian welders to study the relationship between the exposure to metal particles from welding fumes and the concentration of three circulating miRNAs, miR-21, miR-146a and miR-155, as markers of renal function injury. METHODS: Characteristics of the subjects and the curriculum laboris were determined by questionnaires. We measured the concentrations of metals in blood and urine samples using ICP-MS. The three circulating miRNAs studied were measured by quantitative PCR. Associations between miRNAs and internal exposure markers were assessed by simple and multiple regression analyses. RESULTS: miR-21 was significantly lower among welders (p = 0.017), compared with controls, adjusted for age, body mass index, smoking status and seniority. Significant adjusted associations were observed between miR-21 or miR-155 and urinary chromium (p = 0.005 or p = 0.041, respectively), miR-146a and urinary nickel (p = 0.019). The results of the multivariate analysis showed that duration of employment was the main factor responsible for the variation of miRNAs among welders. CONCLUSION: In conclusion, a recent exposure to certain metals, mainly chromium and nickel, appears to be associated to a decrease in plasma expression of miR-21, miR-146a and miR-155. Further larger studies would help to determine the mechanisms of action of metal particles on miRNA expression.

Early Effect Markers and Exposure Determinants of Metalworking Fluids Among Metal Industry Workers: Protocol for a Field Study.

BACKGROUND: Exposure to aerosols from metalworking fluids (MWF) has previously been related to a series of adverse health outcomes (eg, cancer, respiratory diseases). Our present epidemiological study focuses on occupational exposures to MWF and a panel of exposure and effect biomarkers. We hypothesize that these health outcomes are caused by particle exposure that generates oxidative stress, leading to airway inflammation and ultimately to chronic respiratory diseases. We aimed to assess whether MWF exposure, in particular as characterized by its oxidative potential, is associated with biomarkers of oxidative stress and inflammation as well as genotoxic effects. OBJECTIVE: The ultimate goal is to develop exposure reduction strategies based on exposure determinants that best predict MWF-related health outcomes. The following relationships will be explored: (1) exposure determinants and measured exposure; (2) occupational exposure and preclinical and clinical effect markers; (3) exposure biomarkers and biomarkers of effect in both exhaled breath condensate and urine; and (4) biomarkers of effect, genotoxic effects and respiratory symptoms. METHODS: At least 90 workers from France and Switzerland (30 controls, 30 exposed to straight MWF and 30 to aqueous MWF) were followed over three consecutive days after a nonexposed period of at least two days. The exposure assessment is based on MWF, metal, aldehyde, and ultrafine particle number concentrations, as well as the intrinsic oxidative potential of aerosols. Furthermore, exposure biomarkers such as metals, metabolites of polycyclic aromatic hydrocarbons and nitrosamine are measured in exhaled breath condensate and urine. Oxidative stress biomarkers (malondialdehyde, 8-isoprostane, 8-hydroxy-2'-deoxyguanosine, nitrates, and nitrites) and exhaled nitric oxide, an airway inflammation marker, are repeatedly measured in exhaled breath condensate and urine. Genotoxic effects are assessed using the buccal micronucleus cytome assay. The statistical analyses will include modelling exposure as a function of exposure determinants, modelling the evolution of the biomarkers of exposure and effect as a function of the measured exposure, and modelling respiratory symptoms and genotoxic effects as a function of the assessed long-term exposure. RESULTS: Data collection, which occurred from January 2018 until June 2019, included 20 companies. At the date of writing, the study included 100 subjects and 29 nonoccupationally exposed controls. CONCLUSIONS: This study is unique as it comprises human biological samples, questionnaires, and MWF exposure measurement. The biomarkers collected in our study are all noninvasive and are useful in monitoring MWF exposed workers. The aim is to develop preventative strategies based on exposure determinants related to health outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/13744.

Short-term exposure to air pollution: Associations with lung function and inflammatory markers in non-smoking, healthy adults.

INTRODUCTION: Air pollution impacts health by increasing mortality and the incidence of acute events in unhealthy individuals. In contrast, the acute effects of pollution in healthy individuals are less obvious. The present study was designed to evaluate the associations between short-term exposure to air pollution on one hand and lung function, and inflammatory markers on the other in middle-aged, non-smoking adults with no respiratory disease, in two urban areas in northern France. METHODS: A sample of 1506 non-smoking adults (aged from 40 to 65) with no respiratory disease was selected from the participants in the 2011-2013 cross-sectional Enquête Littoral Souffle Air Biologie Environnement (ELISABET) survey in two urban areas in the northern France. We evaluated the associations between (i) mean levels of particulate matter with aerodynamic diameter < 10 µm (PM10), nitrogen dioxide (NO2) and ozone (O3) exposure on the day and the day before the study examination for each participant, and (ii) spirometry data and levels of inflammatory markers. Coefficients of multiple linear regression models were expressed (except for the forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio) as the percentage change [95% confidence interval] per 10 µg increment in each pollutant. RESULTS: Levels of PM10, NO2 and O3 exposure were below or only close to the World Health Organization's recommended limits in our two study areas. An increment in NO2 levels was significantly associated with a lower FEV1/FVC ratio (-0.38 [-0.64; -0.12]), a lower forced expiratory flow between 25% and 75% of FVC (FEF25-75%) (-1.70 [-3.15; -0.23]), and a lower forced expiratory flow measured at 75% of FVC (FEF75%) (-3.07 [-4.92; -1.18]). An increment in PM10 levels was associated with lower FEF75% (-1.41 [-2.79; -0.01]) and a non-significant elevation in serum levels of high-sensitivity C-reactive protein (+3.48 [-0.25; 7.36], p = 0.07). Lastly, an increment in O3 levels was associated with a significantly higher blood eosinophil count (+2.41 [0.10; 4.77]) and a non-significant elevation in fractional exhaled nitric oxide (+2.93 [-0.16; 6.13], p = 0.06). CONCLUSION: A short-term exposure to air pollution was associated with a subclinical decrement in distal lung function and increment in inflammatory markers in healthy inhabitants of two urban areas in France. If these exploratory results are confirmed, this could suggest that even moderate levels of air pollution could have an impact on respiratory health on the general population, and not solely on susceptible individuals.

Peri-operative acute kidney injury upon cardiac surgery time-of-day.

BACKGROUND: A relevant morning-afternoon variation in ischemia-reperfusion (IR) insult after cardiac surgery has been demonstrated. We speculated that the biorhythm might also impact systemic reactions involved in acute kidney injury (AKI) following cardiac surgery. We aimed at investigating incidence, determinants and prognostic impact of AKI in a large cohort of patients referred for surgical aortic valve replacement (SAVR) according to surgery time-of-day. METHODS: Between 2009 and 2015, we explored consecutive patients referred to our Heart Valve Center (CHU Lille) for first SAVR. Patients undergoing morning and afternoon SAVR were matched into pairs by propensity score and followed for major events (ME) i.e. cardiovascular death, cardiac hospitalization for acute heart failure (HF) and post-operative myocardial infarction. AKI was defined using KDIGO classification. RESULTS: In the matched population (n = 596 patients), AKI occurred in 20% of patients. After multivariable adjustment, medical history of hypertension, pre-operative renal function impairment and cardio-pulmonary bypass duration were independent predictors of AKI onset. Post-operative AKI was significantly associated with increased occurrence of ME and specifically of cardiac hospitalization for HF (p = 0.0035 and p = 0.0071, respectively) during the 500 days following SAVR. Finally, AKI occurrence and severity were similar between morning and afternoon groups (p = 0.98 and p = 0.99, respectively). CONCLUSION: We showed that despite current high-quality patient management during and following SAVR, peri-operative AKI remains frequent, developing in 20% of patients, and clearly worsens mid-term post-operative outcomes. AKI more often develops in patients with pre-operative chronic kidney disease and long duration of cardiac surgery but is not influenced by surgery time-of-day.

Exhaled breath NOx levels in a middle-aged adults population-based study: reference values and association with the smoking status.

BACKGROUND: Biomarkers in exhaled breath condensate (EBC) are potentially sensitive indicators of early biochemical changes in airways following exposure to pneumotoxic substances, particularly in susceptible subjects. NOx are the stable end products of the nitrite-nitrate-NO oxidative stress pathway and can be used to monitor airway inflammatory diseases, especially in asthma. Nevertheless, population-based surveys are needed to better interpret EBC NOx levels in clinical studies. The aim of this study was to establish reference values of EBC NOx in a large group of middle-aged, healthy adults of a sample of the general population with particular focus on the smoking status. METHODS: The EBC NOx levels were analysed from 2872 subjects among the ELISABET population-based cross sectional study including a representative sample of men and women aged from 40 to 66 years olds conducted in northern France, which included comprehensive questionnaires by interview and spirometry data. Healthy participants were defined as participants with no self-reported respiratory disease. RESULTS: For the healthy subjects (n = 1251), the median NOx concentration (IQR) was equal to 7.2  µM (3.12) and concentrations of NOx in EBC did not differ significantly according to smoking status. The upper fifth percentile (95%) (ULN) of NOx concentrations among healthy subjects was equal to 13.6  µM, ranging from 12.7  µM (smokers) to 14.4  µM (ex smokers). Among subjects with EBC NOx values higher than the ULN and compared with subjects that had EBC NOx values lower than the ULN, we found a significant higher proportion of subjects with current asthma (10.5% vs 6.5%) or with chronic bronchitis symptoms (7.6% vs 3.3%). CONCLUSION: This population-based study has provided the distribution and the upper limit reference value of a nitrosative stress biomarker (NOx) in EBC of middle aged, healthy adults. EBC NOx levels were not associated with smoking status.

Sources of household air pollution: The association with lung function and respiratory symptoms in middle-aged adult.

INTRODUCTION: The objective of the present study was to investigate the relationship between sources of household air pollution, respiratory symptoms and lung function. METHODS: 3039 adults aged from 40 to 65 participated in the 2011-2013 ELISABET cross-sectional survey in northern France. Lung function was measured using spirometry. During a structured interview, respiratory symptoms, household fuels, exposure to moulds, and use of ventilation were recorded on a questionnaire. RESULTS: The self-reported presence of mould in at least two rooms (not including the bathroom and the kitchen) was associated with a 2.5% lower predicted forced expiratory volume in 1 s (95% confidence interval, -4.7 to -0.29; p-trend <0.05) and a higher risk of wheezing (p-trend < 0.001). Visible condensation was associated with wheezing (p < .05) and chronic cough (p < .05). There were no significant associations with the type of household fuel or inadequate ventilation/aeration. Similar results were found when the analyses were restricted to participants without known respiratory disease. CONCLUSION: Our results suggest that the presence of mould (known to be associated with more severe asthma symptoms) could also have an impact on respiratory symptoms and lung function in the general population and in populations without known respiratory disease.

Low-grade systemic inflammation: a partial mediator of the relationship between diabetes and lung function.

PURPOSE: An association has been consistently found between diabetes mellitus and decreased lung function. We evaluated to what extent low-grade inflammation (as measured by the level of high-sensitivity C-reactive protein [hs-CRP]) could explain this relationship. METHODS: A sample of 1878 middle-aged adults from the cross-sectional Enquête Littoral Souffle Air Biologie Environnement survey without self-reported pulmonary and atherosclerosis disease was included. A mediation analysis was performed to assess and quantify the hs-CRP level as a mediator of the relationship between diabetes and lung function. RESULTS: Diabetes was associated with higher hs-CRP level (+22.9%, 95% confidence interval = [5.1, 43.6]). The hs-CRP (>4 vs. ≤1 mg/L) was associated with lower percentage predicted values for the forced expiratory volume in the first second (FEV1) (-4% [-6.1, -1.9]) and forced vital capacity (FVC) (-4.4% [-6.5, -2.3]). Diabetes was associated with FEV1 (-3.5% [-5.8, -1.3]) and FVC (-3.6% [-5.9, -1.3]). The proportion of the effect that is mediated by hs-CRP was 12% [2.4, 37] and 13% [3.7, 39.4] for FEV1 and FVC, respectively. CONCLUSIONS: Our results suggest that low-grade systemic inflammation could only explain a small part of the relationship between diabetes and lung function.

Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbα antagonism: a single-centre propensity-matched cohort study and a randomised study.

BACKGROUND: On-pump cardiac surgery provokes a predictable perioperative myocardial ischaemia-reperfusion injury which is associated with poor clinical outcomes. We determined the occurrence of time-of-the-day variation in perioperative myocardial injury in patients undergoing aortic valve replacement and its molecular mechanisms. METHODS: We studied the incidence of major adverse cardiac events in a prospective observational single-centre cohort study of patients with severe aortic stenosis and preserved left ventricular ejection fraction (>50%) who were referred to our cardiovascular surgery department at Lille University Hospital (Lille, France) for aortic valve replacement and underwent surgery in the morning or afternoon. Patients were matched into pairs by propensity score. We also did a randomised study, in which we evaluated perioperative myocardial injury and myocardial samples of patients randomly assigned (1:1) via permuted block randomisation (block size of eight) to undergo isolated aortic valve replacement surgery either in the morning or afternoon. We also evaluated human and rodent myocardium in ex-vivo hypoxia-reoxygenation models and did a transcriptomic analysis in myocardial samples from the randomised patients to identify the signalling pathway(s) involved. The primary objective of the study was to assess whether myocardial tolerance of ischaemia-reperfusion differed depending on the timing of aortic valve replacement surgery (morning vs afternoon), as measured by the occurrence of major adverse cardiovascular events (cardiovascular death, myocardial infarction, and admission to hospital for acute heart failure). The randomised study is registered with ClinicalTrials.gov, number NCT02812901. FINDINGS: In the cohort study (n=596 patients in matched pairs who underwent either morning surgery [n=298] or afternoon surgery [n=298]), during the 500 days following aortic valve replacement, the incidence of major adverse cardiac events was lower in the afternoon surgery group than in the morning group: hazard ratio 0·50 (95% CI 0·32-0·77; p=0·0021). In the randomised study, 88 patients were randomly assigned to undergo surgery in the morning (n=44) or afternoon (n=44); perioperative myocardial injury assessed with the geometric mean of perioperative cardiac troponin T release was significantly lower in the afternoon group than in the morning group (estimated ratio of geometric means for afternoon to morning of 0·79 [95% CI 0·68-0·93; p=0·0045]). Ex-vivo analysis of human myocardium revealed an intrinsic morning-afternoon variation in hypoxia-reoxygenation tolerance, concomitant with transcriptional alterations in circadian gene expression with the nuclear receptor Rev-Erbα being highest in the morning. In a mouse Langendorff model of hypoxia-reoxygenation myocardial injury, Rev-Erbα gene deletion or antagonist treatment reduced injury at the time of sleep-to-wake transition, through an increase in the expression of the ischaemia-reperfusion injury modulator CDKN1a/p21. INTERPRETATION: Perioperative myocardial injury is transcriptionally orchestrated by the circadian clock in patients undergoing aortic valve replacement, and Rev-Erbα antagonism seems to be a pharmacological strategy for cardioprotection. Afternoon surgery might provide perioperative myocardial protection and lead to improved patient outcomes compared with morning surgery. FUNDING: Fondation de France, Fédération Française de Cardiologie, EU-FP7-Eurhythdia, Agence Nationale pour la Recherche ANR-10-LABX-46, and CPER-Centre Transdisciplinaire de Recherche sur la Longévité.

Cardiopulmonary exercise testing is a better outcome predictor than exercise echocardiography in asymptomatic aortic stenosis.

BACKGROUND: Objective assessment of maximal aerobic capacity using peak oxygen consumption (peak VO2) can be helpful in the management of patients with asymptomatic aortic stenosis (AS). The relationship between peak VO2 and AS severity criteria derived from rest and supine exercise echocardiography (SEE) has never been explored. OBJECTIVES: We aimed to determine whether low peak VO2 (<85% of predicted value) is associated with severity parameters in SEE, and poor clinical outcome. METHODS: Fifty one asymptomatic patients (mean age of 54±21years) with moderate to severe aortic stenosis (Vmax>3m/s) and left ventricle ejection fraction>50% prospectively underwent resting and SEE and cardiopulmonary exercise testing (CPX). RESULTS: Peak VO2 was lower than expected (21.9±7.4mL/kg/min), i.e. <85% of predicted value in 57% patients, secondary to cardiac limitation in most of them (69%). In multiple regression analysis, age, BMI and female gender were the only independent determinants of peak VO2. Interestingly no parameter derived from SEE was associated with peak VO2. After 21±7month follow-up, no patient died, 20 underwent cardiac surgery. Peak VO2<85% of predicted value was associated with lower event free survival compared to normal peak VO2 (57%±11% vs 93±6%, p=0.036) whereas no exercise echocardiographic parameter could predict such events. Peak VO2≥85% had a negative predictive value of 97%. CONCLUSION: CPX detects a high proportion of false asymptomatic AS patients with poorer outcome that cannot be predicted by SEE markers of AS severity. Assessment of aerobic capacity should be part of current approach within a "watchful waiting" strategy.

Chronotropic incompetence can limit exercise tolerance in COPD patients with lung hyperinflation.

PURPOSE: Metabolic-chronotropic relationship is the only concept that assesses the entire chronotropic function during exercise, as it takes into account individual fitness. To better understand interrelationships between chronotropic incompetence (CI), dynamic hyperinflation (DH) and exercise limitation among Global initiative for chronic Obstructive Lung Disease (GOLD) stages of chronic obstructive pulmonary disease (COPD) disease severity, we evaluated cardiopulmonary responses to symptom-limited cycle exercise in stable patients. PATIENTS AND METHODS: We prospectively studied 47 COPD patients classified by GOLD stage severity. Pulmonary function tests and cardiopulmonary responses to symptom-limited incremental exercise were studied. CI was defined by regression line between percent heart rate (HR) reserve and percent oxygen uptake (V'O2) reserve, ie, chronotropic-metabolic index (CMI). DH was defined from the knot resulting from the nonlinear regressions of inspiratory capacity changes from rest to peak (dynamic inspiratory capacity (ICdyn)) with percentage of maximal HR and CMI. RESULTS: Aerobic capacity (median interquartile ranges) peak V'O2, 24.3 (23.6; 25.2), 18.5 (15.5; 21.8), 17.5 (15.4; 19.1) mL·kg-1·min-1 and CMI worsened according to GOLD severity. The optimal knot of ICdyn was equal to -0.34 L. The multivariate logistic regression showed a strong relationship between CI (outcome) and DH (odds ratio [confidence interval 95]) 25 (3.5; 191.6). CONCLUSION: COPD patients with DH have a poor cardiovascular response to exercise, which may be attributed to CI.