Central sleep apnea after acute coronary syndrome and association with ticagrelor use.

STUDY OBJECTIVES: By modifying the apneic threshold, the antiplatelet agent ticagrelor could promote central sleep apnea hypopnea syndrome (CSAHS). We aimed to assess the association between CSAHS and ticagrelor administration. METHODS: Patients were prospectively included within 1 year after acute coronary syndrome (ACS), if they had no heart failure (and left ventricular ejection fraction ≥ 45%) and no history of sleep apnea. After an overnight sleep study, patients were classified as "normal" with apnea hypopnea index (AHI) < 15, "CSAHS patients" with AHI ≥ 15 mostly with central sleep apneas, and "obstructive sleep apnea hypopnea syndrome (OSAHS) patients" with AHI ≥ 15 mostly with obstructive sleep apneas. RESULTS: We included 121 consecutive patients (mean age 56.8 ± 10.8, 88% men, mean body mass index 28.3 ± 4.4 kg/m2, left ventricular ejection fraction 56 ± 5%, at a mean of 67 ± 60 days (median 40 days, interquartile range: 30-80 days) after ACS. In total, 49 (45.3%) patients had AHI ≥ 15 (27 [22.3%] CSAHS %, 22 [18.2%] OSAHS). For 80 patients receiving ticagrelor, 24 (30%) had CSAHS with AHI ≥ 15, and for 41 patients not taking ticagrelor, only 3 (7.3%) had CSAHS with AHI ≥ 15 (chi-square = 8, p = 0.004). On multivariable analysis only age and ticagrelor administration were associated with the occurrence of CSAHS, (p = 0.0007 and p = 0.0006). CONCLUSION: CSA prevalence after ACS is high and seems promoted by ticagrelor administration. Results from monocentric study suggest a preliminary signal of safety. CLINICAL TRIALS. GOV ID: NCT03540459.

Excited-state electronic structure of molecules using many-body Green's functions: Quasiparticles and electron-hole excitations with VOTCA-XTP.

We present the open-source VOTCA-XTP software for the calculation of the excited-state electronic structure of molecules using many-body Green's function theory in the GW approximation with the Bethe-Salpeter equation (BSE). This work provides a summary of the underlying theory and discusses the details of its implementation based on Gaussian orbitals, including resolution-of-identity techniques and different approaches to the frequency integration of the self-energy or acceleration by offloading compute-intensive matrix operations using graphics processing units in a hybrid OpenMP/Cuda scheme. A distinctive feature of VOTCA-XTP is the capability to couple the calculation of electronic excitations to a classical polarizable environment on an atomistic level in a coupled quantum- and molecular-mechanics (QM/MM) scheme, where a complex morphology can be imported from Molecular Dynamics simulations. The capabilities and limitations of the GW-BSE implementation are illustrated with two examples. First, we study the dependence of optically active electron-hole excitations in a series of diketopyrrolopyrrole-based oligomers on molecular-architecture modifications and the number of repeat units. Second, we use the GW-BSE/MM setup to investigate the effect of polarization on localized and intermolecular charge-transfer excited states in morphologies of low-donor content rubrene-fullerene mixtures. These showcases demonstrate that our implementation currently allows us to treat systems with up to 2500 basis functions on regular shared-memory workstations, providing accurate descriptions of quasiparticle and coupled electron-hole excited states of various characters on an equal footing.

A stochastic surrogate Hamiltonian approach of coherent and incoherent exciton transport in the Fenna-Matthews-Olson complex.

The capture and transduction of energy in biological systems is clearly necessary for life, and nature has evolved remarkable macromolecular entities to serve these purposes. The Fenna-Matthews-Olson (FMO) complex serves as an intermediate to transfer the energy from the chlorosome to the special pairs of different photo systems. Recent observations have both suggested the importance of coherent exciton transport within the FMO and motivated an elegant and appropriate theoretical construct for interpreting these observations. Here we employ a different approach to exciton transport in a relaxing environment, one based on the stochastic surrogate Hamiltonian method. With it, we calculate the quantum trajectories through the FMO complex both for the model involving seven bacteriochlorophylls that has been used before, and for one involving an eighth bacteriochlorophyll, which has been observed in some new and very important structural work. We find that in both systems, efficient energy transfer to the ultimate receptor occurs, but that because of the placement of, and energy relaxation among, the different bacteriochlorophyll subunits in the FMO complex, the importance of coherent oscillation that was discussed extensively for the seven site system is far less striking for the eight site system, effectively because of the weak mixing between the initial site and the remainder of the system. We suggest that the relevant spectral densities can be determinative for the energy transport route and may provide a new way to enhance energy transfer in artificial devices.

Quantum design rules for single molecule logic gates.

Recent publications have demonstrated how to implement a NOR logic gate with a single molecule using its interaction with two surface atoms as logical inputs [W. Soe et al., ACS Nano, 2011, 5, 1436]. We demonstrate here how this NOR logic gate belongs to the general family of quantum logic gates where the Boolean truth table results from a full control of the quantum trajectory of the electron transfer process through the molecule by very local and classical inputs practiced on the molecule. A new molecule OR gate is proposed for the logical inputs to be also single metal atoms, one per logical input.

A time-dependent approach to electronic transmission in model molecular junctions.

We present a simple method to compute the transmission coefficient of a quantum system embedded between two conducting electrodes. Starting from the solution of the time-dependent Schrodinger equation, we demonstrate the relationship between the temporal evolution of the state vector, |ψ(t)>, initially localized on one electrode and the electronic transmission coefficient, T(E). We particularly emphasize the role of the oscillation frequency and the decay rate of |ψ(t)> in the line shape of T(E). This method is applied to the well-known problems of the single impurity, two-site systems and the benzene ring, where it agrees with well-accepted time-independent methods and gives new physical insight to the resonance and interference patterns widely observed in molecular junctions.

Accuracy of a portable international normalized ratio monitor for patients receiving a low molecular weight heparin as a bridge pending full oral anticoagulant efficacy.

BACKGROUND: Point of care (POC) devices measuring the international normalized ratio (INR) are accurate for patients with stable disease, but their efficiency has not been prospectively assessed during the "bridging period" when patients are receiving a low molecular weight heparin (LMWH) on top of a vitamin K antagonist (VKA) until the target INR is reached. METHODS: 188 dual INR measurement using the POC (INR(POC)) and the laboratory (INR(lab)) at the same time were consecutively determined : 69 in patients receiving LMWH+VKA (bridging group) and 119 in patients receiving only a VKA (control group). INRpoc was compared to INR(lab). RESULTS: Test strip failure rate was higher in the bridging group than in the control group (29% vs 4%; p<0,001). In successful tests, POC accuracy was not modified by LMWH administration: the correlation coefficients between POC and lab INR values for the bridging group and the control group were 0,81 and 0,87 respectively, and the relative measure of divergence (RMD=INR(lab) - INR(poc)/INR(lab)) was lower in the bridging group than in the control group (4+/-7% vs 10+/-14%; p=0,02). Finally, clinically relevant agreement between POC and laboratory was of 90% in the bridging group and 92.1% in the control group (p=0.6). CONCLUSION: With the POC used (INRatio), in patients receiving LMWH when the POC gives a result, it is as accurate as in patients not receiving a LMWH.

[BNP and echocardiography can predict the occurrence of acute cardiac decompensation during titration of bisoprolol in chronic systolic heart failure]. / Le BNP et l'échocardiographie prédisent la survenue de décompensation cardiaque aigue au cours de la titration du bisoprolol dans l'insuffisance cardiaque chronique systolique.

OBJECTIVES: Based on the fact that NYHA class, plasma BNP level, and echocardiographic indices of left ventricular filling pressures are prognostic factors in chronic systolic heart failure, we evaluated their predictive value for acute decompensation following initiation and titration of bisoprolol in this illness. METHODS AND RESULTS: Bisoprolol was initiated and/or increased according to the ESC/ACC/AHA recommendations in 50 patients with stable chronic systolic heart failure (age: 60+/-2 years, males: 88%) in NYHA class? 2 with a left ventricular ejection fraction (LVEF)<40% and a plasma creatinine<250 micromol/l. The clinical parameters, plasma BNP levels and echocardiographic indices were measured blind on the same day, on admission and then once a week for three weeks. On admission, the NYHA was 2.9+/-0.1, mean plasma creatinine 99+/-3 micromol/l, plasma BNP 503+/-57 pg/ml, LVEF 29+/-1%, E/A ratio 1.9+/-0.2, E/Ea ratio 8.8+/-0.3, E wave deceleration time 155+/-9 ms, systolic pulmonary artery pressure 40+/-2 mmHg and the diameter of the inferior vena cava was 16+/-1 mm. Over the course of follow up, an episode of acute decompensation occurred in 16% of the patients (8/50). Using univariate analysis, age and initial (admission) values for NYHA class, blood pressure, plasma BNP level, E/A ratio, E wave deceleration time, E/Ea ratio and the systolic pulmonary arterial pressure allowed prediction of the occurrence of acute decompensation following initiation and titration of bisoprolol. The use of the initial value of NYHA class alone allowed prediction of the occurrence of acute decompensation in just 56% of the patients, and the absence of an occurrence of acute decompensation in 93% of them. Normal results for the echocardiographic indices (systolic pulmonary arterial pressure<40 mmHg or E/A ratio<1.4 or E wave deceleration time>145 ms) as recorded on admission were associated with the absence of an occurrence of acute decompensation is 100% of cases. The combined use of NYHA class>3 and either a BNP>398 pg/ml or echocardiographic indices in favour of an elevation in left ventricular filling pressures (systolic pulmonary arterial pressure>40 mmHg, E/A ratio>1.4 or E wave deceleration time<145 ms) allowed prediction of the occurrence of acute heart failure in 100% of cases CONCLUSION: The combined use of NYHA class, BNP level and echocardiographic indices for measuring left ventricular filling pressures is more pertinent than the isolated use of clinical parameters for predicting tolerance to bisoprolol in chronic heart failure with a LVEF<40%.

[Exercise training in cardiac patients: usefulness of the cardiopulmonary exercise test]. / Réadaptation des patients porteurs d'une cardiopathie: intérêt de la mesure des echanges gazeux a l'effort (VO2).

Exercise training is currently including in the treatment of coronary arterial disease patients, in patients with left ventricular dysfunction as well as in patients who underwent cardiac transplantation or cardiac surgery. However methods of prescribing exercise-training programs are difficult to determine and must be adapted for each patient Exercise test with gas analysis through the determination of anaerobic threshold may help to understand the physiopathological mechanism related to exercise limitation in these patients. Exercise test may help to precise exercise intensity during cardiac rehabilitation and may assess the benefits on exercise tolerance.

[Treatment of left intraventricular thrombosis with low molecular weight heparin]. / Traitement des thrombus intraventriculaires gauches par héparine de bas poids moléculaire.

UNLABELLED: Following the discovery of a left intra ventricular thrombus (LIVT), the classical approach consists of treatment with non-fractionated heparin (NFH) followed by oral anticoagulants. The use of NFH for this indication has only been evaluated in one open, non randomised study of 23 patients with no control group. Low molecular weight heparins (LMWH) have not been the object of any study although they are routinely used by certain teams. The objective of this study was to evaluate the feasibility of the use of LMWH in the treatment of left intra ventricular thrombus. This was an open, non randomised prospective study. All patients having a newly diagnosed LIVT between September 2000 and September 2002 were treated with enoxaparine (100 IU/kg twice daily) for an average duration of 13 days; replacement with fluindione was started on the fifth day. The progression of the LIVT was followed using twice weekly transthoracic echocardiography for 3 weeks. RESULTS: 19 LIVT were discovered in 2 years (13 complicating an anterior infarct and 6 with a dilated cardiomyopathy). The average area was between 2.64 +/- 0.41 cm2 and 0.43 +/- 0.21 cm2 (p < 0.0001). Thirteen out of 19 thrombi disappeared with treatment (68.5%). There was no thrombocytopenia or haemorrhage. One transient ischaemic attack was noted. CONCLUSION: This preliminary work shows that LMWH are well tolerated and effective to make a thrombus disappear or to reduce its size.

A non isotopic method for the measurement of cell membrane integrity.

In vitro cytotoxic assays often use various technical approaches for the measurement of cell mortality. Assays such as trypan blue exclusion or chromium release measure cell membrane integrity but they are either time consuming, not sensitive enough or they generate radioactive wastes. We have developed a dehydrogenase release assay which takes advantage of a new fluorescent amplification system. Mouse L929 fibroblasts and tumor necrosis factor (TNF-alpha) were used as a model system. This approach is sensitive, rapid, reproducible and may be used advantageously for mixed lymphocyte reaction (MLR). This new economical assay may be easily automated for large scale cytotoxicity testing using cell membrane integrity.

Coronary angioscopic findings in the infarct-related vessel within 1 month of acute myocardial infarction: natural history and the effect of thrombolysis.

BACKGROUND: Limited angioscopic information is available on the natural history of infarct-related plaque after myocardial infarction (MI), in particular the effect of thrombolysis. METHODS AND RESULTS: We studied with angioscopy the morphological characteristics of the infarct-related lesion in 56 patients between 24 hours and 4 weeks after MI. Forty of these patients were initially treated with a thrombolytic agent. Most lesions were complex (complex + ulcerated shape = 54%). The predominant color of the plaque was yellow in 79% of cases; only 6% were uniformly white. Angioscopically visible thrombus was found in 77% of cases. Despite angioscopic evidence of instability, only 7% of the patients had post-MI angina. During the 1-month time window since the occurrence of MI, there was no significant difference in the angioscopic appearance of the plaque except for a slight increase in uniformly white plaques (P=.07). The use of a thrombolytic agent at the onset of MI was associated with a reduction in thrombus size and less protruding thrombi (P=.02) but not with a decreased frequency of plaque containing thrombi. Furthermore, a trend for more frequently ulcerated plaques (45% versus 16%, P=.06) was associated with the use of a thrombolytic agent. CONCLUSIONS: These results suggest that healing of the infarct-related lesion requires more than 1 month and that an "unstable" yellow plaque with adherent thrombus is common during that period. This finding may partly explain the unique behavior of recent infarct-related lesions, which are more prone to occlude than other lesions.

Morphological changes after percutaneous transluminal coronary angioplasty of unstable plaques. Insights from serial angioscopic follow-up.

OBJECTIVE: To describe the morphological changes occurring in the months following percutaneous transluminal coronary angioplasty (PTCA) of unstable plaques. BACKGROUND: Coronary angioscopy is a relatively new technique to assess plaque morphology. Previous angioscopic studies have shown that unstable coronary lesions are characterized by complex morphology, evidence of plaque rupture, and intraluminal thrombi. No serial angioscopic studies have investigated the effects of PTCA on plaque morphology at such lesions. METHODS: We studied 15 patients who underwent successful PTCA for an unstable coronary syndrome (unstable angina: n = 5; recent myocardial infarction: n = 10). Angioscopy was performed immediately before PTCA in 14 patients, immediately after PTCA in 13 patients, and at follow-up (225 +/- 62 days after PTCA) in all patients. RESULTS: Pre-PTCA, plaque morphology was defined as complex in 18%, ulcerated in 27%; the vessel was totally occluded in 18% of cases. Plaque colour was yellow in 75% of patients. A thrombus was identified at the lesion site in 71% of patients. Immediately post-PTCA, small surface disruptions and dissections were observed in 62% of patients. Plaque colour was yellow in 85% of cases. Seventy-seven percent of patients had an angioscopically visible thrombus at the PTCA site. At follow-up, however, plaque shape was almost uniformly classified as smooth concentric (93%); plaque colour was white in 93%; no thrombus was observed. CONCLUSIONS: These results demonstrate the healing of unstable plaques in the months following PTCA. The angioscopic appearance at 6 months is that of a stable plaque (smooth concentric, white, without thrombus). Whether this stable angioscopic appearance predicts long-term clinical stability remains to be determined.

[Doppler echocardiography in the evaluation of left ventricular diastolic function]. / Apport de l'échocardiographie-Doppler à l'évaluation de la fonction diastolique ventriculaire gauche.

It is now well recognized that a disorder of left ventricular filling can be sufficient to account for congestive heart failure. Furthermore, evaluation of heart disease would not be complete if it did not include assessment of left ventricular filling, improvement of which probably ensures better control of the heart disease. An efficient and reliable tool for the study of diastolic function is therefore essential. The authors review the current state of knowledge and the more recent developments in Doppler echocardiography in the evaluation of left ventricular diastolic function. After revising the pathophysiology, the methods of studying ventricular filling are described. The recording technique is described, taking into account recent developments in transthoracic and transoesophageal approaches. This investigation provides parameters allowing semiquantitative estimation of filling pressures (mean left atrial pressure, end-diastolic pressure) and reliable evaluation of overall diastolic performance.

In vivo and in vitro effects of arginine-vasopressin receptor antagonists on the hypothalamic-pituitary-adrenal axis in the rat.

Arginine-vasopressin (AVP) is regarded as a potent stimulator of pituitary adrenocorticotropin (ACTH) secretion and participates therefore in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis function in concert with the physiological activator of the axis, hypothalamic corticotropin-releasing hormone (CRH). We examined the effects of AVP and/or three synthetic V1b receptor antagonists on the activity of the HPA axis in vivo and in vitro in the rat. AVP was injected intravenously to Sprague-Dawley rats (1 microgram/rat) through an indwelling jugular catheter. AVP stimulated ACTH release, with maximal effect 10 min after injection. Intravenous injection of three V1b antagonists, [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-O-ethyltyrosine, 4-valine] arginine vasopressin (d(CH2)5[Tyr(Et2)]VAVP (WK 1-1), 9-desglycine[1-(beta-mercapto-beta,beta- cyclopentamethylenepropionic acid), 2-O-ethyltyrosine, 4-valine] arginine vasopressin desGly9d(CH2)5 [Tyr(Et2)]-VAVP (WK 3-6), and 9-desglycine [1-(beta-mercapto-beta,beta- cyclopentamethylenepropionic acid),2-D-(O-ethyl)tyrosine, 4-valine ] arginine vasopressin des Gly9d(CH2)5[D-Tyr(Et2)]VAVP (AO 3-21), prevented AVP-stimulated ACTH secretion. Explanted rat hypothalami incubated in vitro with graded concentrations of AVP (10(-14)-10(-5) M) secreted immunoreactive CRH (iCRH) in a concentration-dependent fashion. Maximal stimulatory effect occurred at the concentration of 10(-6) M. Incubation of hypothalami with WK 1-1, WK3-6, or AO 3-21 (10(-6) M) prevented AVP-stimulated iCRH secretion. Results suggest that AVP plays a relevant, multiple role in the activation of the HPA axis in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the calcium channel blockers, diltiazem and Ro 40-5967, on systemic haemodynamics and plasma noradrenaline levels in conscious dogs with pacing-induced heart failure.

1. Calcium channel blockers increase cardiovascular morbidity and mortality in patients with left ventricular dysfunction. These adverse effects are probably related to the negative inotropic effect of calcium channel blockers and/or a neurohormonal activation. 2. The present study was designed to examine, in conscious dogs, the acute haemodynamic and sympathetic effects of diltiazem and Ro 40-5967 (a novel calcium channel blocker) in the control state and in heart failure. 3. Thirteen dogs were instrumented with a micromanometer and an aortic catheter. After completion of experiments in the control state, heart failure was induced by right ventricular pacing (250 beats min-1, 3 weeks). Diltiazem and Ro 40-5967 were given intravenously (0.8 mg kg-1 and 1.0 mg kg-1 respectively). Cardiac output was measured by a thermodilution technique. 4. In the control state, both agents decreased similarly mean aortic pressure with significant increases in heart rate, cardiac output (both +1.0 l min-1 and P < 0.001) and plasma noradrenaline (both +55%) without changes in left ventricular dP/dtmax. In heart failure, for matched decreases in mean aortic pressure, neither diltiazem nor Ro 40-5967 changed heart rate significantly; diltiazem decreased cardiac output (-0.3 l min-1, P < 0.02) and dP/dtmax (-14%, P < 0.001) while Ro 40-5967 still increased cardiac output (+0.3 l min-1, P < 0.02) although the increased amount was smaller than in the control state. Plasma noradrenaline level was increased more during diltiazem infusion (+120%) than during Ro 40-5967 infusion (+38%, P < 0.001). 5. Diltiazem and Ro 40-5967 have similar haemodynamic and sympathetic effects in the control state.Heart failure alters haemodynamic and sympathetic responses to both calcium channel blockers but the magnitude of the alteration appears to be different. Diltiazem exerts a depressant effect on cardiac function which cannot be overcome by its vasodilator effect and sympathetic stimulation, while Ro 40-5967 has little effect on cardiac function. These data suggest that novel calcium channel blockers with less depressant effect may not be detrimental in heart failure.

Carbon dioxide rebreathing method of cardiac output measurement during acute respiratory failure in patients with chronic obstructive pulmonary disease.

OBJECTIVE: To compare measurement of cardiac output by the CO2 rebreathing method vs. the thermodilution cardiac output technique in the setting of acute respiratory failure in patients with chronic obstructive pulmonary disease. DESIGN: Prospective, comparative study of two methods in a consecutive sample. SETTING: Intensive care unit. PATIENTS: Twenty-five patients with chronic obstructive pulmonary disease with acute respiratory failure were studied. The patients were being mechanically ventilated and monitored with systemic and pulmonary artery catheters. MEASUREMENTS AND MAIN RESULTS: Cardiac output was determined, using both the thermodilution technique and an indirect CO2 Fick method. Veno-arterial CO2 content difference was calculated from an estimated mixed venous PCO2 obtained by an equilibrium CO2 rebreathing method and measured PaCO2. PCO2 was converted to content using the equation of the CO2 dissociation curve described by McHardy. A wide range of cardiac output was studied. There was a significant correlation between thermodilution and CO2 rebreathing methods (r2 = .92, p < .001). The mean difference between thermodilution and CO2 rebreathing methods was -0.06 L/min/m2, standard deviation for the bias was 0.028 L/min/m2, and 95% confidence interval for the bias was -0.120 to -0.001 L/min/m2. CONCLUSION: Our results suggest that the CO2 rebreathing method may be a reliable non-invasive technique to determine cardiac output in mechanically ventilated patients with chronic obstructive pulmonary disease.

Increased hypothalamic [3H]flunitrazepam binding in hypothalamic-pituitary-adrenal axis hyporesponsive Lewis rats.

We have previously demonstrated that susceptibility of Lewis (LEW/N) rats to inflammatory disease, compared to relatively resistant Fischer (F344/N) rats, is related to deficient glucocorticoid counter-regulation of the immune response resulting from deficient corticotropin-releasing hormone (CRH) responsiveness to inflammatory and other stress mediators. The GABA/benzodiazepine receptor complex is an important negative modulator of CRH secretion and responsiveness to excitatory stimuli. In this study, we have examined in vitro binding of [3H]flunitrazepam to hypothalamic membrane preparations from LEW/N and F344/N rats. LEW/N rats had significantly more hypothalamic benzodiazepine binding sites (Bmax) than F344/N rats, but there were no differences in benzodiazepine binding affinities (Kd) between these two strains. The differences in benzodiazepine receptor number were consistent with the respective plasma corticosterone levels in the two strains, and with previous work indicating a negative correlation between corticosterone levels and benzodiazepine binding site number. Adrenalectomy of F344/N rats increased benzodiazepine binding to levels comparable to LEW/N animals and treatment of adrenalectomized F344/N rats with DEX resulted in lowering of benzodiazepine Bmax to levels that did not differ significantly from those of intact F344/N rats. There was no significant change in receptor number in either adrenalectomized or DEX-treated LEW/N rats. These findings suggest that basal benzodiazepine receptor differences between these strains may be partially related to strain differences in corticosterone levels, however that additional factors may contribute to maintenance of these differences in LEW/N rats. Since benzodiazepines attenuate hypothalamic CRH secretion through GABAergic inhibition, we suggest that strain differences in receptor number could also augment strain differences in hypothalamic-pituitary-adrenal axis function through differential sensitivity to GABA-mediated feedback.

Analytical expressions for the paraxial parameters of a single lens with a spherical distribution of refractive index.

The concept of isoindicial surfaces and position variables is used to develop analytical expressions for the effective focal length and back focal length of a single gradient lens with a spherical distribution of refractive index, where the square of the refractive index is a quadratic function of the distance from the center of symmetry.