Background Both acute myocardial ischemia and reperfusion contribute to cardiomyocyte death in ST-elevation myocardial infarction (STEMI). The final infarct size is the principal determinant of ...subsequent clinical outcome in STEMI patients. In a proof-of-concept phase II trial, the administration of cyclosporine prior to primary percutaneous coronary intervention (PPCI) has been associated with a reduction of infarct size in STEMI patients. Methods CIRCUS is an international, prospective, multicenter, randomized, double-blinded, placebo-controlled trial. The study is designed to compare the efficacy and safety of cyclosporine versus placebo, in addition to revascularization by PPCI, in patients presenting with acute anterior myocardial infarction within 12 hours of symptoms onset and initial TIMI flow ≤1 in the culprit left anterior descending coronary artery. Patients are randomized in a 1:1 fashion to 2.5 mg/kg intravenous infusion of cyclosporine or matching placebo performed in the minutes preceding PCI. The primary efficacy end point of CIRCUS is a composite of 1-year all-cause mortality, rehospitalization for heart failure or heart failure worsening during initial hospitalization, and left ventricular adverse remodeling as determined by sequential transthoracic echochardiography. Secondary outcomes will be tested using a hierarchical sequence of left ventricular (LV) ejection fraction and absolute measurements of LV volumes. The composite of death and rehospitalization for heart failure or heart failure worsening during initial hospitalization will be further assessed at three years after the initial infarction. Results Recruitment lasted from April 2011 to February 2014. The CIRCUS trial has recruited 975 patients with acute anterior myocardial infarction. The 12-months results are expected to be available in 2015. Conclusions The CIRCUS trial is testing the hypothesis that cyclosporine in addition to early revascularization with PPCI compared to placebo in patients with acute anterior myocardial infarction reduces the incidence of death, heart failure and adverse LV remodeling at one-year follow-up.
Lowering heart rate reduces myocardial oxygen consumption (MVO2) and produces potent anti-ischemic effects. The development of selective heart rate-reducing agents represents an alternative approach ...to the use of beta-blockers. Therefore, our goal was to establish the dose-response curve of the effects of ivabradine (If channel inhibitor) on MVO2 and diastolic time. Seven conscious and chronically instrumented dogs were investigated during exercise at spontaneous and paced heart rate (250 beats/min) after administration of increasing doses of ivabradine (0.25, 0.5, and 1 mg/kg i.v.). During exercise, ivabradine dose dependently and significantly reduced the exercise-induced tachycardia (-17, -21, and -32% at 0.25, 0.5, and 1 mg/kg, respectively, versus saline) without altering myocardial contractility nor mean ejection wall stress. A linear relationship between heart rate (HR) and MVO2 was demonstrated (MVO2 = 0.044 x HR - 1.4; r = 0.987). These effects of ivabradine on MVO2 were abolished by atrial pacing. Similarly, ivabradine dose dependently increased diastolic time without altering the inverse and non linear relationship between diastolic time and heart rate observed with saline. In conclusion, selective heart rate reduction with ivabradine dose dependently increases diastolic time and reduces MVO2 with a linear relationship between heart rate and MVO2. The lack of "on-off" pharmacological profile will predict the possibility of using a wide range of dose regimen.
The respective contributions of heart rate (HR) reduction and left ventricular (LV) negative inotropy to the effects of antianginal drugs are debated. Accordingly, eight instrumented dogs were ...investigated during exercise at spontaneous and paced HR (250 beats/min) after administration of either saline, atenolol, or ivabradine (selective pacemaker current channel blocker). During exercise, atenolol and ivabradine (both 1 mg/kg iv) similarly reduced HR (-30% from 222 +/- 5 beats/min), and LV mean ejection wall stress was not altered. LV dP/dt(max) was reduced by atenolol but not ivabradine. Diastolic time (DT) was increased by atenolol versus saline (195 +/- 6 vs. 123 +/- 4 ms, respectively) and to a greater extent by ivabradine (233 +/- 11 ms). Myocardial oxygen consumption (MVo(2)) was lower under ivabradine and atenolol versus saline (6.7 +/- 0.6 and 4.7 +/- 0.4 vs. 8.1 +/- 0.6 ml/min, respectively, P < 0.05). Under pacing, DT and MVo(2) were similar between ivabradine and saline but significantly reduced with atenolol. Thus HR reduction and negative inotropy equally contribute to the reduction in MVo(2) during exercise in the normal heart. The negative inotropy limits the increase in DT afforded by HR reduction.
On the basis of the windkessel model, the stroke volume-to-aortic pulse pressure ratio (SV/PP) has been proposed as an estimate of total arterial compliance, but recent studies have questioned this ...approximation. Aortic pressure was obtained at rest in 31 adults undergoing cardiac catheterization (47 +/- 14 yr): controls (n = 7), patients with dilated cardiomyopathy (n = 10), and patients with other cardiac diseases (n = 14). We calculated PP, mean aortic pressure (MAoP), heart period (T), SV (thermodilution cardiac output/heart rate), total peripheral resistance (R), total arterial compliance estimated by area method (Carea), and the time constant of aortic pressure decay in diastole (RCarea). In the overall population (n = 31), there was no significant difference between SV/PP and Carea. SV/PP was linearly related to Carea (SV/PP = 0.99Carea + 0.05; r = 0.98; P < 0.001); the slope and intercept did not differ from unity and zero, respectively. Similar results were obtained in the three subgroups. These results implied that PP/MAoP and T/RCarea were proportionally related (T/RCarea = 1.18PP/MAoP - 0.07; r = 0.96; P < 0.001). We conclude that for humans at rest 1) SV/PP gave a reliable estimate of Carea, and 2) T normalized by the time constant of aortic pressure decay in diastole was proportionally related to PP/MAoP. This last relationship could be considered an aspect of the coupling between the left ventricle and its load.
Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical ...outcomes and prevent adverse left ventricular remodeling.
In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. Adverse left ventricular remodeling was defined as an increase of 15% or more in the left ventricular end-diastolic volume.
A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval CI, 0.78 to 1.39; P=0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups.
In patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year. (Funded by the French Ministry of Health and NeuroVive Pharmaceutical; CIRCUS ClinicalTrials.gov number, NCT01502774; EudraCT number, 2009-013713-99.).
Outdoor air samples collected during the pesticide agricultural application period (spring and summer) from a rural community in the Centre Region (France) were analyzed to investigate temporal ...variation of atmospheric pesticide levels (2006–2013) and human inhalation exposure in adults, children and infants.
The most frequently detected pesticides were herbicides (trifluralin, pendimethalin), fungicides (chlorothalonil) and insecticides (lindane and α-endosulfan). The three currently-used pesticides most frequently detected presented concentrations ranging from 0.18 to 1128.38ngm−3; 0.13 to 117.32ngm−3 and 0.16 to 25.80ngm−3 for chlorothalonil, pendimethalin and trifluralin, respectively.
The estimated chronic inhalation risk, expressed as Hazard Quotient (HQ), for adults, children and infants, was <1 for all measured pesticides. Likewise, the cumulative exposure for detected organophosphorus and chloroacetamide pesticides, was estimated using the Relative Potency Factor (RPF) and Hazard Index (HI) as metrics, which was indicated that no risk was observed. The cancer risk classified as likely or possibly carcinogen was estimated to be <8.93 E−05 in infants, for the detected pesticides.
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•Human inhalation risk assessment of outdoor airborne pesticides was performed.•The levels of 41 detected pesticides ranged from 0.12ngm−3 to 1128ngm−3.•All measured reported Hazard Quotients <1•The cumulative risk for the two pesticide types assessed is acceptable.•For infants the estimated cancer risk was lower than 8.93×10−05.
We investigated the effects of the selective bradycardic agent ivabradine, an I(f) channel inhibitor, on exercise-induced ischemia and resulting myocardial stunning. Seven dogs were chronically ...instrumented to measure left ventricular (LV) wall thickening (Wth), aortic pressure and coronary blood flow (CBFv) (Doppler). Circumflex coronary artery stenosis was set up to suppress the increase in CBFv during a 10 min treadmill exercise. During exercise under saline, LVWth in the ischemic zone was depressed (-70 +/- 4%) and a prolonged myocardial stunning was subsequently observed. Infusion of ivabradine started before exercise significantly reduced heart rate (HR) at rest (-22 +/- 7%), during exercise (-33 +/- 4%) and throughout the recovery period (-21 +/- 2%). By reducing HR during exercise, ivabradine simultaneously improved LVWth compared with saline (14 +/- 1% versus 7 +/- 1%, respectively) and subendocardial perfusion (microspheres). This anti-ischemic effect was subsequently responsible for a strong decrease in the intensity and severity of myocardial stunning. All these beneficial effects were abolished when HR reduction during exercise was suppressed by atrial pacing. Interestingly, when ivabradine infusion was started after exercise, LVWth was still significantly enhanced and myocardial stunning strongly attenuated. This direct effect of ivabradine on the stunned myocardium disappeared when HR reduction was suppressed by atrial pacing at rest. In conclusion, this study demonstrates that ivabradine exerts an anti-ischemic effect that is responsible for subsequent protection against myocardial stunning. Furthermore, administration of ivabradine after the ischemic insult still improves LVWth of the stunned myocardium.
Formaldehyde (HCHO) is one of the abundant indoor pollutants and has been classified as a human carcinogen by the International Agency for Research on Cancer (IARC). Indoor HCHO at schools is ...particularly important due to the high occupancy density and the health effects on children. In this study, high time resolved measurement of formaldehyde concentration was conducted in the classrooms at elementary school, high school and university under normal students' activities in three different locations in the Region Centre Val de Loire-France. Indoor average formaldehyde concentrations at those three educational institutions were observed to be in the range 10.96–17.95 μg/m3, not exceeding the World Health Organization (WHO) guideline value of 100 μg/m3. As expected, ventilation was found playing an important role in the control of indoor formaldehyde concentration. After opening windows for 30 min, formaldehyde level decreased by ~25% and 38% in the classroom at the elementary school and the high school, respectively. In addition to the primary sources, the objective of this study was also to determine potential secondary sources of indoor formaldehyde in these schools by measuring the other volatile organic compounds (VOCs) present in the classrooms by a Proton Transfer Reaction Time-of-Flight Mass Spectrometry (PTR-ToF-MS). The measurements suggest that the release of residue from tobacco smokers is one of the major sources of indoor HCHO at the high school, which increases HCHO by ~55% averagely within 1 h. Moreover, the control experiments conducted in the university suggests that VOCs such as that released from cleaning products like terpenes, can contribute to the increase of indoor formaldehyde levels through chemical reactions with ozone. This study confirms simple recommendations to reduce the indoors HCHO concentration in schools: use ventilation systems, limit the emissions like cigarette smoke or cleaning products. It also points out that the secondary sources of formaldehyde must be also considered in the classroom.
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•Indoor HCHO concentration was observed 10.96–17.95 μg/m3 at schools in France.•Ventilation is important in the control of indoor HCHO concentration at schools.•Release of residue from smokers is a major source of indoor HCHO at the high school.•Cleaning products can contribute to indoor HCHO through chemical reactions.
PAPRICA is a research program designed to estimate the impact on the health of patients with chronic respiratory insufficiency of a prevention strategy based on notification of ozone pollution. The ...first year of this study was conducted during the 2003 heat wave, and high temperatures were therefore considered as a confounding factor in the data analysis. The aim of the present study was to assess the relationship between ozone and temperature in order to propose a methodology to distinguish between the effects of ozone and temperature on the impact of a prevention strategy with regard to ozone pollution.
Multivariate analyses were used to identify associated climate and ozone pollution profiles. This descriptive method is of great value to highlight the complexity of interactions between these parameters.
Ozone concentration and temperature were strongly correlated, but the health impact of ozone pollution alone will be evaluated by focusing on situations characterized by ozone concentrations above 110 mug/m3/8h (air quality guidelines to protect human health defined by the French legislation) and temperatures lower than 26 degrees C, below the discomfort threshold.
The precise relationship between ambient ozone concentration and temperature identified during the PAPRICA 2003 study period will be used in analysing the PAPRICA health data.
To expand our knowledge of regional fine particles in Central France (Centre-Val de Loire region), a field observation study of PM2.5 was carried out at Verneuil site (46.81467N, 2.61012E, ...180m.a.s.l.) from 2011 to 2014. The mass concentrations of water-soluble inorganic ions (WSIIs), organic carbon (OC), elemental carbon (EC) and biomass burning tracer (Levoglucosan) in PM2.5 were measured. Annual average PM2.5 mass concentrations were 11.8, 9.5, 12.6 and 10.2μg·m−3 in 2011, 2012, 2013 and 2014, respectively, three of four higher than the WHO guideline of 10μg·m−3. Secondary inorganic aerosol (SIA) and organic matter (OM) appeared to be the major components in PM2.5 in Verneuil, contributing 30.1–41.8% and 36.9–46.3%, respectively. Main chemical species were observed in the following order: winter≥spring>autumn>summer. Backward atmospheric trajectories were performed using Hysplit model and suggested that the PM2.5 pollutants caused by atmospheric transport were mainly originated from European inland, mainly east to north-east areas. During the observation period, five pollution events were reported and indicated that not only the polluted air masses from central Europe but also the biomass burning from East Europe significantly influenced the air quality in Verneuil site.
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•PM2.5 and its major chemical components were characterized in Central France.•OM and SIA were major components in PM2.5.•The impact of biomass burning on the particle pollution was proved by levoglucosan and K+.•Air masses with high PM2.5 levels had strong relationship with atmospheric transport from central Europe.•Five pollution events were identified.
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