Cyclosporine before PCI in Patients with Acute Myocardial Infarction.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).

Rationale and design of the Cyclosporine to ImpRove Clinical oUtcome in ST-elevation myocardial infarction patients (the CIRCUS trial).

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.

Nearly five-year continuous atmospheric measurements of black carbon over a suburban area in central France.

Atmospheric black carbon (BC) concentration over a nearly 5 year period (mid-2017-2021) was continuously monitored over a suburban area of Orléans city (France). Annual mean atmospheric BC concentration were 0.75 ± 0.65, 0.58 ± 0.44, 0.54 ± 0.64, 0.48 ± 0.46 and 0.50 ± 0.72 µg m-3, respectively, for the year of 2017, 2018, 2019, 2020 and 2021. Seasonal pattern was also observed with maximum concentration (0.70 ± 0.18 µg m-3) in winter and minimum concentration (0.38 ± 0.04 µg m-3) in summer. We found a different diurnal pattern between cold (winter and fall) and warm (spring and summer) seasons. Further, fossil fuel burning contributed >90 % of atmospheric BC in the summer and biomass burning had a contribution equivalent to that of the fossil fuel in the winter. Significant week days effect on BC concentrations was observed, indicating the important role of local emissions such as car exhaust in BC level at this site. The behavior of atmospheric BC level with COVID-19 lockdown was also analyzed. We found that during the lockdown in warm season (first lockdown: 27 March-10 May 2020 and third lockdown 17 March-3 May 2021) BC concentration were lower than in cold season (second lockdown: 29 October-15 December 2020), which could be mainly related to the BC emission from biomass burning for heating. This study provides a long-term BC measurement database input for air quality and climate models. The analysis of especially weekend and lockdown effect showed implications on future policymaking toward improving local and regional air quality as well.

Diurnal variation and potential sources of indoor formaldehyde at elementary school, high school and university in the Centre Val de Loire region of France.

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.

Fine particles at a background site in Central France: Chemical compositions, seasonal variations and pollution events.

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.

Phenotypic adaptation of the late preconditioned heart: myocardial oxygen consumption is reduced.

OBJECTIVES: Although the signalling pathways of late preconditioning have been extensively investigated, its consequence for myocardial metabolism remains unknown. Thus, myocardial oxygen consumption (MVO2) was evaluated before and under late preconditioning. METHODS: In 7 chronically instrumented dogs, we measured MVO2 in vivo at baseline and during inotropic stimulation with dobutamine (10 and 20 microg/kg/min, i.v.) before (Day 0) and 24 h after (Day 1) a 10-min circumflex coronary artery occlusion. RESULTS: At Day 0, dobutamine dose-dependently increased the triple product (heart ratexleft ventricular systolic pressurexleft ventricular maximum dP/dt), MVO2, coronary blood flow, and coronary sinus pO2. At Day 1, the triple product was similar at baseline and at each dose of dobutamine but MVO2 was significantly blunted as compared to Day 0 (-15+/-4%, -22+/-3% and -19+/-4% at baseline, dobutamine 10 and 20 microg/kg/min, respectively). Importantly, the relationship between MVO2 and triple product was significantly rightward shifted with late preconditioning, i.e., MVO2 was reduced for any level of triple product. At Day 1, the relationship between coronary blood flow and MVO2 was not altered as compared to Day 0 but coronary sinus pO2 was significantly increased vs. Day 0 for any level of coronary blood flow, suggesting that late preconditioning exerted no vasomotor effect but rather changed myocardial oxygen handling. These effects were abolished by administration of S-methyl-isothiourea (1.5 mg/kg, i.v.), a iNOS inhibitor. CONCLUSION: This study demonstrates that ischemic late preconditioning is characterized by a major reduction in MVO2, both at baseline and under inotropic stimulation. NO from iNOS contributes to this modification of metabolic phenotype.

Human exposure and risk assessment to airborne pesticides in a rural French community.

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.

Relationship between ozone and temperature during the 2003 heat wave in France: consequences for health data analysis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Prognostic significance of renal insufficiency in patients presenting with acute coronary syndrome (the Prospective Multicenter SYCOMORE study).

This prospective, multicenter, observational study was designed to assess the in-hospital prognostic importance of renal insufficiency among patients presenting with acute coronary syndrome (ACS). One third of patients with ACS presented with renal insufficiency. After adjustment for potential confounders, decreasing renal function was independently associated with in-hospital death, bleeding, and contrast-induced nephropathy.

The value of a completely automatic ECG gated blood pool SPECT processing method for the estimation of global systolic left ventricular function.

OBJECTIVES: Electrocardiographically gated blood pool SPECT (GBPS) is an interesting method for measuring left ventricular (LV) ejection fraction (LVEF) and volume. Recently, the availability of completely automatic GBPS processing software has been reported. We aimed to evaluate its reliability in measuring global LV systolic function. In addition, using the same population, we compared its reliability to that of three previously reported methods for processing GBPS. METHODS: We studied the performances of the new GBPS system for the evaluation of LVEFs and volumes in 29 patients. The LVEF provided by the planar equilibrium radionuclide angiography (planarLAO) and LV volumes provided by radiological LV contrast angiography (X-rays) were used as 'gold standards'. RESULTS: The new GBPS system failed in one patient. It shows good reproducibility for the measurement of both LVEF and volume. LVEF provided by this system is moderately correlated to planarLAO (r = 0.62; P < 0.001). The new GBPS constantly overestimates LVEF (P < 0.05). Results for LV volumes are moderately correlated to those obtained by X-ray investigation (r = 0.7; P < 0.001) but are significantly lower (P < 0.0001). There is a linear correlation between the average and the paired absolute difference for LV volumes (r = 0.52, P = 0.0001). CONCLUSIONS: The new, completely automatic, GBPS processing software is an interesting, moderately reliable method for measuring LVEF and volume. The performance of the method is lower than that previously reported for the same population for the other three GBPS processing methods.

[Heart rate and experimental myocardial ischaemia]. / Fréquence cardiaque et ischémie myocardique expérimentale.

Every increase in heart rate represents a poor prognostic factor in cardiology, and multiple arguments have now led to the belief that reducing heart rate is a major therapeutic challenge. A comparison of the pharmacological effects of If current inhibitors such as zatebradine, and more recently ivabradine (Procoralan) and beta-blockers, have demonstrated experimentally that reductions in heart rate and myocardial contractile force contribute equally to the reduction in myocardial oxygen consumption in the normal heart. Conversely, at a similar level of reduction in heart rate, the lack of a concomitant negative inotropic effect with ivabradine affords longer diastolic perfusion times than beta-blockers. In other words, a negative inotropic effect is deleterious when an increase in coronary blood flow is required. Hence, if the anti-ischaemic effects afforded by an If current inhibitor and a beta-blocker are roughly comparable, the former are clearly of higher benefit than beta-blockers in the treatment of myocardial dysfunction accompanying cardiac ischaemia-reperfusion, especially myocardial stunning.

Conversion of post-systolic wall thickening into ejectional thickening by selective heart rate reduction during myocardial stunning.

AIMS: Post-systolic wall thickening (PSWT) occurs after aortic valve closure. This waste of thickening does not participate in ejection. PSWT increases with myocardial ischaemia and stunning but the effects of anti-anginal drugs on PSWT during myocardial dysfunction remain unknown. The effects of two heart rate reducing agents, i.e. the beta-blocker atenolol and the selective I(f) current inhibitor ivabradine, were compared on PSWT. METHODS AND RESULTS: Coronary stenosis was calibrated in six conscious instrumented dogs to suppress increase in coronary blood flow during a 10 min treadmill exercise to induce myocardial stunning. After exercise completion, stenosis was relieved and saline, atenolol or ivabradine (both at 1 mg/kg iv) were administered. For similar heart rate reduction, ivabradine attenuated stunning, whereas atenolol further depressed systolic wall thickening. PSWT to total wall thickening ratio was significantly decreased by ivabradine vs. saline, whereas total wall thickening was similar. Thus, ivabradine devoted a greater part of thickening to systole by converting PSWT into ejectional thickening. In contrast, atenolol failed to reduce PSWT vs. saline. Atrial pacing abolished the effects of ivabradine but not those of atenolol. CONCLUSION: Selective heart rate reduction with ivabradine converts PSWT into ejectional thickening but not with atenolol secondary to its negative inotropism.

Reduction in postsystolic wall thickening during late preconditioning.

Brief coronary artery occlusion (CAO) and reperfusion induce myocardial stunning and late preconditioning. Postsystolic wall thickening (PSWT) also develops with CAO and reperfusion. However, the time course of PSWT during stunning and the regional function pattern of the preconditioned myocardium remain unknown. The goal of this study was to investigate the evolution of PSWT during myocardial stunning and its modifications during late preconditioning. Dogs were chronically instrumented to measure (sonomicrometry) systolic wall thickening (SWT), PSWT, total wall thickening (TWT = SWT + PSWT), and maximal rate of thickening (dWT/dt(max)). Two 10-min CAO (circumflex artery) were performed 24 h apart (day 0 and day 1, n = 7). At day 0, CAO decreased SWT and increased PSWT. During the first hours of the subsequent stunning, evolution of PSWT was symmetrical to that of SWT. At day 1, baseline SWT was similar to day 0, but PSWT was reduced (-66%), while dWT/dt(max) and SWT/TWT ratio increased (+48 and +14%, respectively). After CAO at day 1, stunning was reduced, indicating late preconditioning. Simultaneously vs. day 0, PSWT was significantly reduced, and dWT/dt(max) as well as SWT/TWT ratio were increased, i.e., a greater part of TWT was devoted to ejection. Similar decrease in PSWT was observed with a nonischemic preconditioning stimulus (rapid ventricular pacing, n = 4). In conclusion, a major contractile adaptation occurs during late preconditioning, i.e., the rate of wall thickening is enhanced and PWST is almost abolished. These phenotype adaptations represent potential approaches for characterizing stunning and late preconditioning with repetitive ischemia in humans.

Heart rate reduction during exercise-induced myocardial ischaemia and stunning.

AIMS: The respective contributions of reduction in heart rate and inotropism in the beneficial effects of beta-blockade in ischaemic heart disease remains debated. The effects of selective heart rate reduction by ivabradine (If inhibitor) were compared to those of atenolol on exercise-induced ischaemia and stunning. METHODS AND RESULTS: In seven instrumented dogs, coronary stenosis was calibrated to suppress increase in coronary blood flow during a 10-min treadmill exercise. When administered before exercise, atenolol and ivabradine similarly reduced heart rate versus saline at rest and during exercise (154+/-2 and 155+/-9 vs 217+/-13 beats/min, respectively). During exercise, left ventricular wall thickening (LVWth) was reduced to 2+/-1% from 23+/-4% under saline but ivabradine limited this effect (10+/-3%) and reduced the subsequent myocardial stunning vs saline. Atenolol also limited LVWth decrease during exercise (17+/-4%) but had no effect during recovery. When administered after exercise, ivabradine attenuated stunning and this effect disappeared when heart rate reduction was corrected by atrial pacing. Atenolol administered after exercise severely depressed LVWth vs saline. CONCLUSION: Selective heart rate reduction not only provides an anti-ischaemic effect but also per se improves contractility of the stunned myocardium. Additional negative inotropism is protective against ischaemia but deleterious during stunning.

Effect of graded heart rate reduction with ivabradine on myocardial oxygen consumption and diastolic time in exercising dogs.

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.

Estimation of left ventricular performance through temporal pressure variations measured by MR velocity and acceleration mappings.

PURPOSE: To describe a method for assessing pressure variation vs. time (dp/dt) using blood flow acceleration measured by MRI, and to demonstrate its applicability in estimating left ventricular (LV) function. MATERIALS AND METHODS: The method was tested in vitro using a pulsatile phantom, and a strong correlation was found between transducer and MRI determinations of dp/dt (r = 0.98). Selected aortic flow parameters were then measured in 10 patients and the results were compared with transducer measurements of the LV dp/dt. RESULTS: The correlation coefficients for the reference estimations of global myocardial function and MRI were 0.59 for aortic velocity, 0.74 for aortic acceleration, and 0.86 for aortic dp/dt. CONCLUSION: MR measurements of velocity and acceleration within the ascending aorta offer a noninvasive method for determining indices, such as the aortic dp/dt, that are closely correlated with the global myocardial contractility function.

Contributions of heart rate and contractility to myocardial oxygen balance during exercise.

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.

Differential effects of heart rate reduction and beta-blockade on left ventricular relaxation during exercise.

Left ventricular (LV) relaxation is crucial for LV function, especially during exercise. We compared the effects of increasing doses of ivabradine, a selective inward hyperpolarization-activated current inhibitor, and atenolol on the rate and extent of LV relaxation (best fit method: time constant tau(BF), pressure asymptote P(BF)) at rest and during exercise. Eight dogs were chronically instrumented to measure LV pressure and LV wall stresses. During exercise under saline, heart rate increased from 108 +/- 5 to 220 +/- 6 beats/min and tau(BF) was significantly reduced from 22 +/- 1 to 14 +/- 2 ms. At rest, atenolol but not ivabradine increased tau(BF). For similar heart rate reductions during exercise, atenolol impeded the shortening of tau(BF) (23 +/- 2 ms) whereas ivabradine had no effect (15 +/- 2 ms). The extent of the relaxation process (P(BF)) at peak exercise was increased by ivabradine, and to a greater extent by atenolol, compared with saline. Thus, for a similar reduction in heart rate at rest and during exercise, ivabradine, in contrast with atenolol, does not exert any negative lusitropic effect.