Fonction surrénalienne après bolus d'étomidate en chirurgie cardiaque : une étude rétrospective [Adrenal function after induction of cardiac surgery patients with etomidate: A retrospective study]

Objectif Un bolus unique d'étomidate inhibe une enzyme mitochondriale impliquée dans la synthèse du cortisol. Au sein de notre institution, tout patient candidat à une chirurgie cardiaque reçoit de l'étomidate à l'induction de l'anesthésie. L'objectif de cette étude a été de déterminer l'incidence des dysfonctions surrénaliennes chez les patients bénéficiant d'une chirurgie cardiaque et nécessitant de hautes doses de noradrénaline au cours de la période postopératoire. Type d'étude Étude rétrospective descriptive dans l'unité de réanimation d'un centre hospitalier universitaire. Patients et méthodes Soixante-trois patients admis en réanimation après chirurgie cardiaque nécessitant plus de 0,2μg/kg par minute de noradrénaline au cours des premières 48 heures postopératoires ont été étudiés. L'insuffisance surrénalienne absolue a été définie par un cortisol basal inférieur à 414nmo/l (15μg/dl), l'insuffisance surrénalienne relative par un cortisol basal entre 414nmo/l (15μg/dl) et 938nmo/l (34μg/dl) avec une augmentation de la cortisolémie (à 60 minutes après un test de stimulation par 250μg de corticotropine de synthèse) inférieure à 250nmo/l (9μg/dl). Résultats Quatorze patients (22 %) ont présenté une fonction surrénalienne normale, 10 (16 %) une insuffisance surrénalienne absolue et 39 (62 %) une insuffisance surrénalienne relative. Tous les patients ont reçu une substitution stéroïdienne, sans aucune différence d'évolution clinique entre les différents groupes. Conclusion L'incidence de l'insuffisance surrénalienne chez les patients qui ont reçu un bolus d'étomidate à l'induction, lors d'une chirurgie cardiaque avec circulation extracorporelle, et présenté une défaillance circulatoire postopératoire, est élevée.

Transient Ischemic Dilation (TID) ratio measurement during Rb-82 cardiac PET: Comparison between three different software packages.

Background: TIDratio indirectly reflects myocardial ischemia and is correlated with cardiacprognosis. We aimed at comparing the influence of three different softwarepackages for the assessment of TID using Rb-82 cardiac PET/CT. Methods: Intotal, data of 30 patients were used based on normal myocardial perfusion(SSS<3 and SRS<3) and stress myocardial blood flow 2mL/min/g)assessed by Rb-82 cardiac PET/CT. After reconstruction using 2D OSEM (2Iterations, 28 subsets), 3-D filtering (Butterworth, order=10, ωc=0.5), data were automatically processed, and then manually processed fordefining identical basal and apical limits on both stress and rest images.TIDratio were determined with Myometrix®, ECToolbox® and QGS®software packages. Comparisons used ANOVA, Student t-tests and Lin concordancetest (ρc). Results: All of the 90 processings were successfullyperformed. TID ratio were not statistically different between software packageswhen data were processed automatically (P=0.2) or manually (P=0.17). There was a slight, butsignificant relative overestimation of TID with automatic processing incomparison to manual processing using ECToolbox® (1.07 ± 0.13 vs 1.0± 0.13, P=0.001)and Myometrix® (1.07 ± 0.15 vs 1.01 ± 0.11, P=0.003) but not using QGS®(1.02 ±0.12 vs 1.05 ± 0.11, P=0.16). The best concordance was achieved between ECToolbox®and Myometrix® manual (ρc=0.67) processing.Conclusion: Using automatic or manual mode TID estimation was not significantlyinfluenced by software type. Using Myometrix® or ECToolbox®TID was significantly different between automatic and manual processing, butnot using QGS®. Software package should be account for when definingTID normal reference limits, as well as when used in multicenter studies. QGS®software seemed to be the most operator-independent software package, whileECToolbox® and Myometrix® produced the closest results.

When information can save lives: the duty to warn relatives about sudden cardiac death and environmental risks.

In certain cases of sudden death, forensic experts may discover during an investigation or autopsy that family members of the deceased are also at risk of harm-from genetic disease, for instance. But do they have a duty to warn them? Looking at similar duties of physicians and researchers to warn third parties of risk suggests they do.

Competition between beta-subunits of cardiac L-type calcium channels

Cardiac L-type Ca (CaV1.2) channels are composed of a pore forming CaV1.2-α1 subunit and auxiliary β- and α2δ-subunits. β-subunits are important not only for surface expression of the channel pore but also for modulation of channel gating properties. Different β-subunits differentially modulate channel activity (Hullin et al., PLOSone, 2007) and thus L-type Ca2+ channel gating is altered when β-subunit expression pattern is changed. In human heart failure increased activity of single ventricular L-type Ca2+-channels is associated with an increased expression of β2-subunits. Interestingly, induction of β2-subunit over-expression in hearts of transgenic mice resembled this heart failure phenotype of hyperactive single L-type Ca2+-channel channels (Beetz et al., Cardiovasc Res. 2009). We hypothesised that competition of less stimulating β-subunits (e.g. β1) with β-subunits causing strong channel stimulation (e.g. β2) might be a means to treat dysfunctional L-type Ca2+-channel activity. To test this hypothesis, we performed whole-cell and single-channel measurements employing recombinant CaV1.2 channels expressed in HEK293 cells together with both β- and β1a2b-subunits. Whole-cell analysis revealed no differences of maximum L-type Ca2+-current densities [pA/pF] with coexpression of either β1a-subunits (-52±3.8), β2b-subunits (-61.5±6.6) or the mixtures of β- and β1a2b-subunits with the plasmid transfection ratio of 2:1 (-60.2±1.6) and 1:1 (-56.7±2.6) respectively. However, steady state inactivation kinetics differed between particular β-subunit and the relative amount of β-subunit presence in the mixtures (β1a1a-subunit (-41.1±1.0), β2b-subunits (-35.1±1.1), mixture 2:1 (-40.3±1.5), and mixture 1:1 (-38.4±2.0); [mV]; p<0.05, students t-test). Using a novel single-channel analysis, switching of gating between β1-like and β2-like modes was monitored on a minute time-scale when both β-subunits were co-expressed in the same cells, but the larger amount of β1a-subunits is required for the effective switching of gating. Our results indicate a model of mutually exclusive binding and effective competition between several β-subunits suggesting that hyperactive channel gating mediated e.g. by β2-subunits can be normalized by β1-subunits. Therefore, competitive replacement between different L-type Ca2+-channel β-subunits might serve as a novel therapeutic strategy for e.g. heart failure.

Correction of through-plane deformation artifacts in stimulated echo acquisition mode cardiac imaging.

Attempts to use a stimulated echo acquisition mode (STEAM) in cardiac imaging are impeded by imaging artifacts that result in signal attenuation and nulling of the cardiac tissue. In this work, we present a method to reduce this artifact by acquiring two sets of stimulated echo images with two different demodulations. The resulting two images are combined to recover the signal loss and weighted to compensate for possible deformation-dependent intensity variation. Numerical simulations were used to validate the theory. Also, the proposed correction method was applied to in vivo imaging of normal volunteers (n = 6) and animal models with induced infarction (n = 3). The results show the ability of the method to recover the lost myocardial signal and generate artifact-free black-blood cardiac images.

A Heterozygous Deletion Mutation in the Cardiac Sodium Channel Gene SCN5A with Loss- and Gain-of-Function Characteristics Manifests as Isolated Conduction Disease, without Signs of Brugada or Long QT Syndrome.

BACKGROUND: The SCN5A gene encodes for the α-subunit of the cardiac sodium channel NaV1.5, which is responsible for the rapid upstroke of the cardiac action potential. Mutations in this gene may lead to multiple life-threatening disorders of cardiac rhythm or are linked to structural cardiac defects. Here, we characterized a large family with a mutation in SCN5A presenting with an atrioventricular conduction disease and absence of Brugada syndrome. METHOD AND RESULTS: In a large family with a high incidence of sudden cardiac deaths, a heterozygous SCN5A mutation (p.1493delK) with an autosomal dominant inheritance has been identified. Mutation carriers were devoid of any cardiac structural changes. Typical ECG findings were an increased P-wave duration, an AV-block I° and a prolonged QRS duration with an intraventricular conduction delay and no signs for Brugada syndrome. HEK293 cells transfected with 1493delK showed strongly (5-fold) reduced Na(+) currents with altered inactivation kinetics compared to wild-type channels. Immunocytochemical staining demonstrated strongly decreased expression of SCN5A 1493delK in the sarcolemma consistent with an intracellular trafficking defect and thereby a loss-of-function. In addition, SCN5A 1493delK channels that reached cell membrane showed gain-of-function aspects (slowing of the fast inactivation, reduction in the relative fraction of channels that fast inactivate, hastening of the recovery from inactivation). CONCLUSION: In a large family, congregation of a heterozygous SCN5A gene mutation (p.1493delK) predisposes for conduction slowing without evidence for Brugada syndrome due to a predominantly trafficking defect that reduces Na(+) current and depolarization force.

A-Kinase Anchoring Protein Lbc Coordinates a p38 Activating Signaling Complex Controlling Compensatory Cardiac Hypertrophy.

In response to stress, the heart undergoes a remodeling process associated with cardiac hypertrophy that eventually leads to heart failure. A-kinase anchoring proteins (AKAPs) have been shown to coordinate numerous prohypertrophic signaling pathways in cultured cardiomyocytes. However, it remains to be established whether AKAP-based signaling complexes control cardiac hypertrophy and remodeling in vivo. In the current study, we show that AKAP-Lbc assembles a signaling complex composed of the kinases PKN, MLTK, MKK3, and p38α that mediates the activation of p38 in cardiomyocytes in response to stress signals. To address the role of this complex in cardiac remodeling, we generated transgenic mice displaying cardiomyocyte-specific overexpression of a molecular inhibitor of the interaction between AKAP-Lbc and the p38-activating module. Our results indicate that disruption of the AKAP-Lbc/p38 signaling complex inhibits compensatory cardiomyocyte hypertrophy in response to aortic banding-induced pressure overload and promotes early cardiac dysfunction associated with increased myocardial apoptosis, stress gene activation, and ventricular dilation. Attenuation of hypertrophy results from a reduced protein synthesis capacity, as indicated by decreased phosphorylation of 4E-binding protein 1 and ribosomal protein S6. These results indicate that AKAP-Lbc enhances p38-mediated hypertrophic signaling in the heart in response to abrupt increases in the afterload.

Neurological Prognostication after Cardiac Arrest and Therapeutic Hypothermia: a Prospective Validation Study

Introduction: Clinical examination and electroencephalography study (EEG) have been recommended to predict functional recovery in comatose survivors of cardiac arrest (CA), however their prognostic value in patients treated with induced hypothermia (IH) has not been evaluated. Hypothesis: We aimed to validate the prognostic ability of clinical examination and EEG in predicting outcome of patients with coma after CA treated with IH and sought to derive a score with high predictive value for poor functional outcome in this setting. Methods: We prospectively studied 100 consecutive comatose survivors of CA treated with IH. Repeated neurological examination and EEG were performed early after passive rewarming and off sedation. Mortality was assessed at hospital discharge, and functional outcome at 3 to 6 months with Cerebral Performance Categories (CPC), and was dichotomized as good (CPC 1-2) vs. poor (CPC 3-5). Independent predictors of outcome were identified by multivariable logistic regression and used to assess the prognostic value of a Reproducible Electro-clinical Prognosticators of Outcome Score (REPOS). Results: Patients (20/100) with good outcome had all a reactive EEG background. Incomplete recovery of brainstem reflexes, myoclonus, time to return of spontaneous circulation (ROSC) > 25 min, and unreactive EEG background were all independent predictors of death and severe disability, and were added to construct the REPOS. Using a cut-off of 0 or 1 variables for good vs. 2 to 4 for poor outcome, the REPOS had a positive predictive value of 1.00 (95% CI: 0.92-1.00), a negative predictive value of 0.43 (95% CI: 0.29-0.58) and an accuracy of 0.81 for poor functional recovery at 3 to 6 months. Conclusions: In comatose survivors of CA treated with IH, a prognostic score, including clinical and EEG examination, was highly predictive of death and poor functional outcome at 3 to 6 months. Lack of EEG background reactivity strongly predicted poor neurological recovery after CA. Our findings show that clinical and electrophysiological studies are effective in predicting long-term outcome of comatose survivors after CA and IH, and suggest that EEG improves early prognostic assessment in the setting of therapeutic cooling.

Deep hypothermia and rewarming alters glutamate levels and glycogen content in cultured astrocytes.

BACKGROUND: Deep hypothermia has been associated with an increased incidence of postoperative neurologic dysfunction after cardiac surgery in children. Recent studies suggest an excitotoxic mechanism involving overstimulation of glutamate receptors. Extracellular glutamate uptake occurs primarily by astrocytes. Astrocytes also store glycogen, which may be used to sustain the energy-consuming glutamate uptake. Extracellular glutamate and glycogen content were studied during temperature changes mimicking cardiopulmonary bypass in vivo. METHODS: Primary cultures of cerebral cortical astrocytes were used in a specially designed incubator allowing continuous changes of temperature and ambient gas concentrations. The sequence of events was as follows: normothermia, rapid cooling (2.8 degrees C/min) followed by 60 min of deep hypothermia (15 degrees C), followed by rewarming (3.0 degrees C/min) and subsequent 5 h of mild hyperthermia (38.5 degrees C). Two different conditions of oxygenation were studied: (1) normoxia (25% O2, 70% N2, 5% CO2); or (2) hyperoxia (95% O2, 5% CO2). The extracellular glutamate concentrations and intracellular glycogen levels were measured at nine time points. RESULTS: One hundred sixty-two cultures were studied in four independent experiments. The extracellular concentration of glutamate in the normoxic group increased significantly from 35+/-10 nM/mg protein at baseline up to 100+/-15 nM/mg protein at the end of 5 h of mild hyperthermia (P < 0.05). In contrast, extracellular glutamate levels did not vary from control in the hyperoxic group. Glycogen levels decreased significantly from 260+/-85 nM/mg protein at baseline to < 25+/-5 nM/mg protein at the end of 5 h in the normoxic group (P < 0.05) but returned to control levels after rewarming in the hyperoxic group. No morphologic changes were observed in either group. CONCLUSION: The extracellular concentration of glutamate increases, whereas the intracellular glycogen content decreases when astrocytes are exposed to a sequence of deep hypothermia and rewarming. This effect of hypothermia is prevented when astrocytes are exposed to hyperoxic conditions.

For better or worse: Associations between the experience of negative life events and positive and negative sibling relationship characteristics

Using Dutch data (N = 6630), this article examines how sibling relationships (including full biological, half- and adopted siblings) differed for persons who experienced a negative life event (divorce, physical illness, psychological problems, addiction, problems with the law, victimization of abuse or financial problems) and those who did not. Results showed that people who experienced serious negative life events in the past often had less active, less supportive and more strained sibling ties. The group that experienced a physical illness formed an exception, showing more supportive and active sibling ties, but also higher levels of conflict. Results suggest inequality between persons who have experienced negative life events and those who have not in terms of access to positive and supportive sibling relationships.