Sudden Death of Cardiac Origin and Psychotropic Drugs

Mortality rate is high in psychiatric patients versus general population. An important cause of this increased mortality is sudden cardiac death (SCD) as a major side-effect of psychotropic drugs. These SCDs generally result from arrhythmias occurring when the posology is high and may attain a toxic threshold but also at dosages within therapeutic range, in the presence of risk factors. There are three kinds of risk factors: physiological (e.g., low cardiac rate of sportsmen), physiopathological (e.g., hepatic insufficiency, hypothyroidism) and “therapeutic” (due to interactions between psychotropic drugs and other medicines). Association of pharmacological agents may increase the likelihood of SCDs either by (i) a pharmacokinetic mechanism (e.g., increased torsadogenic potential of a psychotropic drug when its destruction and/or elimination are compromised) or (ii) a pharmacodynamical mechanism (e.g., mutual potentiation of proarrhythmic properties of two drugs). In addition, some psychotropic drugs may induce sudden death in cases of pre-existing congenital cardiopathies such as (i) congenital long QT syndrome, predisposing to torsade de pointes that eventually cause syncope and sudden death. (ii) A Brugada syndrome, that may directly cause ventricular fibrillation due to reduced sodium current through Nav1.5 channels. Moreover, psychotropic drugs may be a direct cause of cardiac lesions also leading to SCD. This is the case, for example, of phenothiazines responsible for ischemic coronaropathies and of clozapine that is involved in the occurrence of myocarditis. The aims of this work are to delineate: (i) the risk of SCD related to the use of psychotropic drugs; (ii) mechanisms involved in the occurrence of such SCD; (iii) preventive actions of psychotropic drugs side effects, on the basis of the knowledge of patient-specific risk factors, documented from clinical history, ionic balance, and ECG investigation by the psychiatrist

Genetic associations of protein-coding variants in human disease.

Genome-wide association studies (GWAS) have identified thousands of genetic variants linked to the risk of human disease. However, GWAS have so far remained largely underpowered in relation to identifying associations in the rare and low-frequency allelic spectrum and have lacked the resolution to trace causal mechanisms to underlying genes1. Here we combined whole-exome sequencing in 392,814 UK Biobank participants with imputed genotypes from 260,405 FinnGen participants (653,219 total individuals) to conduct association meta-analyses for 744 disease endpoints across the protein-coding allelic frequency spectrum, bridging the gap between common and rare variant studies. We identified 975 associations, with more than one-third being previously unreported. We demonstrate population-level relevance for mutations previously ascribed to causing single-gene disorders, map GWAS associations to likely causal genes, explain disease mechanisms, and systematically relate disease associations to levels of 117 biomarkers and clinical-stage drug targets. Combining sequencing and genotyping in two population biobanks enabled us to benefit from increased power to detect and explain disease associations, validate findings through replication and propose medical actionability for rare genetic variants. Our study provides a compendium of protein-coding variant associations for future insights into disease biology and drug discovery

Effects of low [K+]o on the electrical activity of human cardiac ventricular and Purkinje cells: Human ventricular and Purkinje cells in low [K+]o

International audienceVentricular and Purkinje action potentials were recorded with a microelectrode in a strip of human papillary muscle. Lowering the K-content of the superfusing solution from 5.9 to 0.5 mmol.litre-1 at 37 degrees C hyperpolarised ventricular diastolic potential steadily as long as [K+]o was low (up to 70 min tested). Ventricular action potentials were transiently lengthened and then shortened. A positive inotropic effect was noted and attributed to Na-K pump inhibition since it was reversed by the addition of 2 mmol.litre-1 thallous chloride to the low [K+]o solution. Beyond 40 min, transient depolarisations and after-contractions were found. During the first minutes in low [K+]o, Purkinje diastolic potential was hyperpolarised and the action potential was lengthened at all levels of repolarisation. Afterwards, the Purkinje diastolic potential suddenly depolarised by 30 mV. Restoration of the control solution caused a slow repolarisation and then a sudden return of the diastolic potential to near control value. This was reproduced during drive (38 stim.min-1) and at rest. At the depolarised level of potential, stimulation elicited slow action potentials with diastolic slow depolarisation and spontaneous oscillations of potential appeared at rest. In Purkinje cells, increasing concentrations of tetrodotoxin from 10(-7) to 8 X 10(-6) mol.litre-1 in the control solution shifted the diastolic potential in negative direction by a few mV and shortened the action potential duration at all levels of repolarisation. The possible implications of these phenomena in the genesis of some cardiac arrhythmias are discussed

Localization of K(+) channels in the tubules of cardiomyocytes as suggested by the parallel decay of membrane capacitance, IK(1) and IK(ATP) during culture and by delayed IK(1) response to barium.: Inward Rectifier Currents and Cardiac T-tubules

International audienceAdult ventricular myocytes lose T-tubules over few days in culture, which causes the loss of about 60% of the cell membrane capacitance (Cm) (Mitcheson et al., 1996). In this study, we have measured, in whole-cell voltage-clamped rabbit right ventricular myocytes at 0, 1, 2 and 3-5 days of culture (nine to 20 myocytes at each age) in a defined Dulbecco's modified Eagle's medium, the value of Cm and the magnitudes of the background inward rectifier current (IK(1)) and of the 2,4-dinitrophenol-induced ATP-sensitive potassium current (IK(ATP)). Cm, IK(1) and IK(ATP) all had decreased significantly by 51, 83 and 88%, respectively after 4 days of culture. Analysis using a single exponential decay function of time gave time constants of, 2.6+/-0.2, 2.2+/-0.5 and 2.4+/-0.4 days, respectively. Linear regressions of IK(1) and IK(ATP) versus Cm had regression coefficients of 0.93 and 0. 98, respectively. These observations are consistent with a strong link of the decay of IK(1) and IK(ATP) currents to that of Cm. Furthermore, the time course of changes in IK(1) when an external blocker (100 microm BaCl(2)) was applied and washed by local perfusion (95% change in 50 ms) agrees with a model including a diffusion time constant of 300 ms. This value is consistent with the known kinetics of diffusion of divalent cations in the T-tubules. Taken together, these results could be explained by the localization of a major part of the IK(1) and IK(ATP) currents of ventricular cardiomyocytes in the T-tubules. As a consequence, transient accumulation of K(+) ions in cardiac T-tubules may take place and modulate excitation-contraction coupling

ARRHYTHMOGENIC EFFECT OF EXTRACELLULAR K+ -DEPLETION IS PREVENTED BY THE TRANSVERSE-AXIAL TUBULAR SYSTEM IN A VENTRICULAR CARDIAC CELL MODEL

International audienceIn this work, we studied the role of the transverse-axial tubular system (TAT-system) in arrythmogenesis of ventricular cardiac cells under conditions of simulated hypokalaemia (low [K+]e). We used the model of a mammalian ventricular myocyte that integrated the quantitative description of electrical activity of surface and tubular membranes and dynamic changes in intracellular ion concentrations. To maintain potassium homeostasis, an energy-dependent K+ extrusion pump was incorporated into the model. According to predictions provided by the model, the TAT-system protects the cell against arrhythmogenesis due to the enhancement of a potassium concentration gradient between tubular and extracellular spaces at low levels of [K+]e. The energy-dependent K+ extrusion pump maintains tubular [K+] at a level higher than the overall [K+]e. This makes the activation of tubular K+-conductances responsible for action potential repolarisation and resting voltage

Accounting for cardiac t-tubule increase with age and myocyte volume to improve measurements of its membrane area and ionic current densities

International audienceIn-silico models of cardiac myocytes allow simulating experiments in numbers on series of myocytes as well as on large populations of myocytes assembled in 3D structures. The simulated myocyte populations should have realistic values and statistical dispersions of biophysical parameters such as myocyte dimensions and volume and areas of the peripheral membrane and transverse-axial tubular system (TATS). Dependencies among these variables also have to be taken into account. In this work, we propose a quantitative representation of the changes in the fraction of membrane area in the TATS that integrates published dependencies with body weight (age) and size of rat ventricular cardiac myocytes while respecting the above constraints. Imposing a constant total membrane area-to-volume ratio appears to account for the increase of this fraction with myocyte size (i.e.: volume) within a given age group. The agreement of our results with published data was discussed and reasons for discrepancies were analysed. On the basis of our framework, strategies are proposed for minimizing the influence of non-random dispersion related to myocyte volume on measurements of the area of TATS and surface membrane compartments and of ionic current densities. The next step will be to quantitatively compare these strategies by evaluating the impact of myocyte morphological parameters and their dependencies, sample size, biases and errors, on the output of experiments

Modelling the cardiac transverse-axial tubular system.

International audienceThe transverse-axial tubular system (TATS) of cardiac ventricular myocytes is a complex network of tubules that arises as invaginations of the surface membrane; it appears to form a specialised region of cell membrane that is particularly important for excitation-contraction coupling. However, much remains unknown about the structure and role of the TATS. In this brief review we use experimental data and computer modelling to address the following key questions: (i) What fraction of the cell membrane is within the TATS? (ii) Is the composition of the TATS membrane the same as the surface membrane? (iii) How good is electrical coupling between the surface and TATS membranes? (iv) What fraction of each current is within the TATS? (v) How important is the complex structure of the TATS network? (vi) What is the effect of current inhomogeneity on lumenal ion concentrations? (vii) Does the TATS contribute to the functional changes observed in heart failure? Although there are many areas in which experimental evidence is lacking, computer models provide a method to assess and predict the possible function of the TATS; such models suggest that although the surface and TATS membranes are electrically well coupled, concentration of ion flux pathways within the TATS, coupled to restricted diffusion, may result in the ionic composition in the TATS lumen being different from that in the bulk extracellular space, and varying with activity and in pathological conditions

Changes in action potentials and intracellular ionic homeostasis in a ventricular cell model related to a persistent sodium current in SCN5A mutations underlying LQT3

International audienceIn LQT3 patients, SCN5A mutations induce ultraslow inactivation of a small fraction of the hNav1.5 current, i.e. persistent Na+ current (I pNa). We explored the time course of effects of such a change on the intracellular ionic homeostasis in a model of guinea-pig cardiac ventricular cell [Pasek,M., Simurda,J., Orchard,C.H., Christe,G., 2007b. A model of the guinea-pig ventricular cardiomyocyte incorporating a transverse–axial tubular system. Prog. Biophys. Mol. Biol., this issue]. Sudden addition of IpNa prevented action potential (AP) repolarization when its conductance (gpNa) exceeded 0.12% of the maximal conductance of fast INa (gNa). With gpNa at 0.1% gNa, the AP duration at 90% repolarization (APD90) was initially lengthened to 2.6-fold that in control. Under regular stimulation at 1 Hz it shortened progressively to 1.37-fold control APD90,and intracellular [Na+]i increased by 6% with a time constant of 106 s. Further increasing gpNa to 0.2% gNa caused an immediate increase in APD90 to 5.7-fold that in control, which decreased to 2.2-fold that in control in 30 s stimulation at 1 Hz. At this time diastolic [Na+]i and [Ca2+]i were, respectively, 34% and 52% higher than in control and spontaneous erratic SR Ca release occurred. In the presence of IpNa causing 46% lengthening of APD90, the model cell displayed arrhythmogenic behaviour when external [K+] was lowered to 5 mM from an initial value at 5.4 mM. By contrast,when K+ currents IKr and IKs were lowered in the model cell to produce the same lengthening of APD90, no proarrhythmic behaviour was observed, even when external [K+] was lowered to 2.5 mM

Effect of Ion Concentration Changes in the Limited Extracellular Spaces on Sarcolemmal Ion Transport and Ca2+ Turnover in a Model of Human Ventricular Cardiomyocyte

We have developed a computer model of human cardiac ventricular myocyte (CVM), including t-tubular and cleft spaces with the aim of evaluating the impact of accumulation-depletion of ions in restricted extracellular spaces on transmembrane ion transport and ionic homeostasis in human CVM. The model was based on available data from human CVMs. Under steady state, the effect of ion concentration changes in extracellular spaces on [Ca2+]i-transient was explored as a function of critical fractions of ion transporters in t-tubular membrane (not documented for human CVM). Depletion of Ca2+ and accumulation of K+ occurring in extracellular spaces slightly affected the transmembrane Ca2+ flux, but not the action potential duration (APD90). The [Ca2+]i-transient was reduced (by 2%–9%), depending on the stimulation frequency, the rate of ion exchange between t-tubules and clefts and fractions of ion-transfer proteins in the t-tubular membrane. Under non-steady state, the responses of the model to changes of stimulation frequency were analyzed. A sudden increase of frequency (1–2.5 Hz) caused a temporal decrease of [Ca2+] in both extracellular spaces, a reduction of [Ca2+]i-transient (by 15%) and APD90 (by 13 ms). The results reveal different effects of activity-related ion concentration changes in human cardiac t-tubules (steady-state effects) and intercellular clefts (transient effects) in the modulation of membrane ion transport and Ca2+ turnover

Brain Death Does Not Change Epicardial Action Potentials and Their Response to Ischemia–Reperfusion in Open-chest Pigs

International audienceBackground: It is debated whether brain death (BD) causes transient functional ischemia. Here we used monophasic action potential (AP) recording, as a sensitive means to assess, during BD, (i) whether ischemia was present, (ii) the effect of BD on a subsequent ischemia-reperfusion challenge. Methods: Period 1: BD was induced (BD group, six pigs) or not (sham maneuver, C group, six pigs) and effects were followed up for 3 hours. Period 2: LAD ligation ischemia was applied for 20 min to all hearts, and was followed by 60-min reperfusion. Results: Period 1: plasma norepinephrine was 3.1, 6.3 and 5 fold larger in BD versus C at respectively 1, 120 and 180 minutes and systolic blood pressure was larger by 26% at 1 min and 35% at 120 minutes. The arterio-venous difference in lactate was similar or lower in BD versus C. In both groups, at all times, AP had rectangular plateau shape and the action potential duration (APD 50) followed a linear relationship to the RR interval (R 2 = 0.89 and 0.73, slope = 0.42±0.02 and 0.46±0.06 in BD and C respectively). Period 2: ischemia caused a similar (50%) APD shortening in BD and C. Restoration of APD upon reperfusion was complete in both groups. Conclusions: These data suggest that BD does not cause direct cardiac ischemia and does not change the response of the heart to subsequent ischemia-reperfusion challenge