1,343 research outputs found
Immediate and Delayed Response of Simulated Human Atrial Myocytes to Clinically-Relevant Hypokalemia
Although plasma electrolyte levels are quickly and precisely regulated in the mammalian cardiovascular system, even small transient changes in K+, Na+, Ca2+, and/or Mg2+ can significantly alter physiological responses in the heart, blood vessels, and intrinsic (intracardiac) autonomic nervous system. We have used mathematical models of the human atrial action potential (AP) to explore the electrophysiological mechanisms that underlie changes in resting potential (Vr) and the AP following decreases in plasma K+, [K+]o, that were selected to mimic clinical hypokalemia. Such changes may be associated with arrhythmias and are commonly encountered in patients (i) in therapy for hypertension and heart failure; (ii) undergoing renal dialysis; (iii) with any disease with acid-base imbalance; or (iv) post-operatively. Our study emphasizes clinically-relevant hypokalemic conditions, corresponding to [K+]o reductions of approximately 1.5 mM from the normal value of 4 to 4.5 mM. We show how the resulting electrophysiological responses in human atrial myocytes progress within two distinct time frames: (i) Immediately after [K+]o is reduced, the K+-sensing mechanism of the background inward rectifier current (IK1) responds. Specifically, its highly non-linear current-voltage relationship changes significantly as judged by the voltage dependence of its region of outward current. This rapidly alters, and sometimes even depolarizes, Vr and can also markedly prolong the final repolarization phase of the AP, thus modulating excitability and refractoriness. (ii) A second much slower electrophysiological response (developing 5–10 minutes after [K+]o is reduced) results from alterations in the intracellular electrolyte balance. A progressive shift in intracellular [Na+]i causes a change in the outward electrogenic current generated by the Na+/K+ pump, thereby modifying Vr and AP repolarization and changing the human atrial electrophysiological substrate. In this study, these two effects were investigated quantitatively, using seven published models of the human atrial AP. This highlighted the important role of IK1 rectification when analyzing both the mechanisms by which [K+]o regulates Vr and how the AP waveform may contribute to “trigger” mechanisms within the proarrhythmic substrate. Our simulations complement and extend previous studies aimed at understanding key factors by which decreases in [K+]o can produce effects that are known to promote atrial arrhythmias in human hearts
Na+ current expression in human atrial myofibroblasts: identity and functional roles
In the mammalian heart fibroblasts have important functional roles in both healthy conditions and diseased states. During pathophysiological challenges, a closely related myofibroblast cell population emerges, and can have distinct and significant roles.Recently, it has been reported that human atrial myofibroblasts can express a Na+ current, INa. Some of the biophysical properties and molecular features suggest that this INa is due to expression of Nav 1.5, the same Na+ channel α subunit that generates the predominant INa in myocytes from adult mammalian heart. In principle, expression of Nav 1.5 could give rise to regenerative action potentials in the fibroblasts/myofibroblasts. This would suggest an active as opposed to passive role for fibroblasts/myofibroblasts in both the ‘trigger’ and the ‘substrate’ components of cardiac rhythm disturbances.Our goals in this preliminary study were: (i) to confirm and extend the electrophysiological characterization of INa in a human atrial fibroblast/myofibroblast cell population maintained in conventional 2-D tissue culture; (ii) to identify key molecular properties of the α and β subunits of these Na+ channel(s); (iii) to define the biophysical and pharmacological properties of this INa ; (iv) to integrate the available multi-disciplinary data, and attempt to illustrate its functional consequences, using a mathematical model in which the human atrial myocyte is coupled via connexins to fixed numbers of fibroblasts/myofibroblasts in a syncytial arrangement.Our experimental findings confirm that a significant fraction (~40-50%) of these human atrial myofibroblasts can express INa. However, our results suggest that INa may be generated by Nav 1.9, Nav 1.2, and Nav 1.5. Our findings, when complemented with mathematical modeling, provide a background for re-evaluating pharmacological management of supraventricular rhythm disorders, e.g. persistent atrial fibrillation
The Resting Potential and K+ Currents in Primary Human Articular Chondrocytes
Human transplant programs provide significant opportunities for detailed in vitro assessments of physiological properties of selected tissues and cell types. We present a semi-quantitative study of the fundamental electrophysiological/biophysical characteristics of human chondrocytes, focused on K+ transport mechanisms, and their ability to regulate to the resting membrane potential, Em. Patch clamp studies on these enzymatically isolated human chondrocytes reveal consistent expression of at least three functionally distinct K+ currents, as well as transient receptor potential (TRP) currents. The small size of these cells and their exceptionally low current densities present significant technical challenges for electrophysiological recordings. These limitations have been addressed by parallel development of a mathematical model of these K+ and TRP channel ion transfer mechanisms in an attempt to reveal their contributions to Em. In combination, these experimental results and simulations yield new insights into: (i) the ionic basis for Em and its expected range of values; (ii) modulation of Em by the unique articular joint extracellular milieu; (iii) some aspects of TRP channel mediated depolarization-secretion coupling; (iv) some of the essential biophysical principles that regulate K+ channel function in “chondrons.” The chondron denotes the chondrocyte and its immediate extracellular compartment. The presence of discrete localized surface charges and associated zeta potentials at the chondrocyte surface are regulated by cell metabolism and can modulate interactions of chondrocytes with the extracellular matrix. Semi-quantitative analysis of these factors in chondrocyte/chondron function may yield insights into progressive osteoarthritis
In silico assessment of drug safety in human heart applied to late sodium current blockers
Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development
of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block
different channels, remains an important opportunity. Partial block of the late sodium current (INaL) has emerged as a
novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this
approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K+ current (IKr). The main goal
of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by
illustrating the impact of IKr/INaL ratio of steady-state block of drug candidates on “torsadogenic” biomarkers. The O’Hara
et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation,
reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated
using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of INaL and IKr were
evaluated. “Safety plots” were developed to illustrate the value of the specific biomarker for selected combinations of
IC50s for IKr and INaL of potential drugs. The reference biomarkers at baseline changed depending on the “drug” specificity
for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of INaL) yielded a biomarker data set that
is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic
potential of drugs and drug candidates in the human ventricle.This work was supported by (1) Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica, (2) Plan Avanza en el marco de la Accion Estrategica de Telecomunicaciones y Sociedad de la Informacion del Ministerio de Industria Turismo y Comercio of Spain (TSI-020100-2010-469), (3) Programa de Apoyo a la Investigacion y Desarrollo (PAID-06-11-2002) de la Universidad Politecnica de Valencia, (4) Programa Prometeo (PROMETEO/2012/030) de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana and (5) Gilead Sciences, Ltd.Trenor Gomis, BA.; Gomis-Tena Dolz, J.; Cardona Urrego, KE.; Romero Pérez, L.; Rajamani, S.; Belardinelli, L.; Giles, WR.... (2013). In silico assessment of drug safety in human heart applied to late sodium current blockers. Channels. 7(4):1-14. doi:10.4161/chan.24905S11474Maltsev, V. A., Silverman, N., Sabbah, H. N., & Undrovinas, A. I. (2007). Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variability. European Journal of Heart Failure, 9(3), 219-227. doi:10.1016/j.ejheart.2006.08.007Zaza, A., Belardinelli, L., & Shryock, J. C. (2008). Pathophysiology and pharmacology of the cardiac «late sodium current». Pharmacology & Therapeutics, 119(3), 326-339. doi:10.1016/j.pharmthera.2008.06.001Song, Y., Shryock, J. C., Wagner, S., Maier, L. S., & Belardinelli, L. (2006). Blocking Late Sodium Current Reduces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dysfunction. Journal of Pharmacology and Experimental Therapeutics, 318(1), 214-222. doi:10.1124/jpet.106.101832Milberg, P., Pott, C., Fink, M., Frommeyer, G., Matsuda, T., Baba, A., … Eckardt, L. (2008). Inhibition of the Na+/Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3. Heart Rhythm, 5(10), 1444-1452. doi:10.1016/j.hrthm.2008.06.017Jia, S., Lian, J., Guo, D., Xue, X., Patel, C., Yang, L., … Yan, G.-X. (2011). Modulation of the late sodium current by ATX-II and ranolazine affects the reverse use-dependence and proarrhythmic liability of IKrblockade. British Journal of Pharmacology, 164(2), 308-316. doi:10.1111/j.1476-5381.2010.01181.xUNDROVINAS, A. I., BELARDINELLI, L., UNDROVINAS, N. A., & SABBAH, H. N. (2006). Ranolazine Improves Abnormal Repolarization and Contraction in Left Ventricular Myocytes of Dogs with Heart Failure by Inhibiting Late Sodium Current. Journal of Cardiovascular Electrophysiology, 17(s1), S169-S177. doi:10.1111/j.1540-8167.2006.00401.xWu, L., Shryock, J. C., Song, Y., Li, Y., Antzelevitch, C., & Belardinelli, L. (2004). Antiarrhythmic Effects of Ranolazine in a Guinea Pig in Vitro Model of Long-QT Syndrome. Journal of Pharmacology and Experimental Therapeutics, 310(2), 599-605. doi:10.1124/jpet.104.066100MOSS, A. J., ZAREBA, W., SCHWARZ, K. Q., ROSERO, S., MCNITT, S., & ROBINSON, J. L. (2008). Ranolazine Shortens Repolarization in Patients with Sustained Inward Sodium Current Due to Type-3 Long-QT Syndrome. Journal of Cardiovascular Electrophysiology, 19(12), 1289-1293. doi:10.1111/j.1540-8167.2008.01246.xSong, Y., Shryock, J. C., Wu, L., & Belardinelli, L. (2004). Antagonism by Ranolazine of the Pro-Arrhythmic Effects of Increasing Late INa in Guinea Pig Ventricular Myocytes. Journal of Cardiovascular Pharmacology, 44(2), 192-199. doi:10.1097/00005344-200408000-00008Belardinelli, L., Liu, G., Smith-Maxwell, C., Wang, W.-Q., El-Bizri, N., Hirakawa, R., … Shryock, J. C. (2012). A Novel, Potent, and Selective Inhibitor of Cardiac Late Sodium Current Suppresses Experimental Arrhythmias. Journal of Pharmacology and Experimental Therapeutics, 344(1), 23-32. doi:10.1124/jpet.112.198887Banyasz, T., Koncz, R., Fulop, L., Szentandrassy, N., Magyar, J., & Nanasi, P. (2004). Profile of IKs During the Action Potential Questions the Therapeutic Value of IKs Blockade. Current Medicinal Chemistry, 11(1), 45-60. doi:10.2174/0929867043456304Hopenfeld, B. (2006). A mathematical analysis of the action potential plateau duration of a human ventricular myocyte. Journal of Theoretical Biology, 240(2), 311-322. doi:10.1016/j.jtbi.2005.09.021Maleckar, M. M., Greenstein, J. L., Giles, W. R., & Trayanova, N. A. (2009). Electrotonic Coupling between Human Atrial Myocytes and Fibroblasts Alters Myocyte Excitability and Repolarization. Biophysical Journal, 97(8), 2179-2190. doi:10.1016/j.bpj.2009.07.054Nygren, A., Fiset, C., Firek, L., Clark, J. W., Lindblad, D. S., Clark, R. B., & Giles, W. R. (1998). Mathematical Model of an Adult Human Atrial Cell. Circulation Research, 82(1), 63-81. doi:10.1161/01.res.82.1.63Viswanathan, P. (1999). Pause induced early afterdepolarizations in the long QT syndrome: a simulation study. Cardiovascular Research, 42(2), 530-542. doi:10.1016/s0008-6363(99)00035-8Wu, R., & Patwardhan, A. (2007). Effects of rapid and slow potassium repolarization currents and calcium dynamics on hysteresis in restitution of action potential duration. Journal of Electrocardiology, 40(2), 188-199. doi:10.1016/j.jelectrocard.2006.01.001Zaniboni, M. (2011). 3D current–voltage–time surfaces unveil critical repolarization differences underlying similar cardiac action potentials: A model study. Mathematical Biosciences, 233(2), 98-110. doi:10.1016/j.mbs.2011.06.008Zaniboni, M. (2012). Late Phase of Repolarization is Autoregenerative and Scales Linearly with Action Potential Duration in Mammals Ventricular Myocytes: A Model Study. IEEE Transactions on Biomedical Engineering, 59(1), 226-233. doi:10.1109/tbme.2011.2170987Zaniboni, M., Riva, I., Cacciani, F., & Groppi, M. (2010). How different two almost identical action potentials can be: A model study on cardiac repolarization. Mathematical Biosciences, 228(1), 56-70. doi:10.1016/j.mbs.2010.08.007Belardinelli, L., Antzelevitch, C., & Vos, M. A. (2003). Assessing predictors of drug-induced torsade de pointes. Trends in Pharmacological Sciences, 24(12), 619-625. doi:10.1016/j.tips.2003.10.002Shah, R. R., & Hondeghem, L. M. (2005). Refining detection of drug-induced proarrhythmia: QT interval and TRIaD. Heart Rhythm, 2(7), 758-772. doi:10.1016/j.hrthm.2005.03.023Hondeghem, L. M., Carlsson, L., & Duker, G. (2001). Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic. Circulation, 103(15), 2004-2013. doi:10.1161/01.cir.103.15.2004Mirams, G. R., Cui, Y., Sher, A., Fink, M., Cooper, J., Heath, B. M., … Noble, D. (2011). Simulation of multiple ion channel block provides improved early prediction of compounds’ clinical torsadogenic risk. Cardiovascular Research, 91(1), 53-61. doi:10.1093/cvr/cvr044Obiol-Pardo, C., Gomis-Tena, J., Sanz, F., Saiz, J., & Pastor, M. (2011). A Multiscale Simulation System for the Prediction of Drug-Induced Cardiotoxicity. Journal of Chemical Information and Modeling, 51(2), 483-492. doi:10.1021/ci100423zSuzuki, S., Murakami, S., Tsujimae, K., Findlay, I., & Kurachi, Y. (2008). In silico risk assessment for drug-induction of cardiac arrhythmia. Progress in Biophysics and Molecular Biology, 98(1), 52-60. doi:10.1016/j.pbiomolbio.2008.05.003Mirams, G. R., Davies, M. R., Cui, Y., Kohl, P., & Noble, D. (2012). Application of cardiac electrophysiology simulations to pro-arrhythmic safety testing. British Journal of Pharmacology, 167(5), 932-945. doi:10.1111/j.1476-5381.2012.02020.xSarkar, A. X., & Sobie, E. A. (2011). Quantification of repolarization reserve to understand interpatient variability in the response to proarrhythmic drugs: A computational analysis. Heart Rhythm, 8(11), 1749-1755. doi:10.1016/j.hrthm.2011.05.023CHANG, C., ACHARFI, S., WU, M., CHIANG, F., WANG, J., SUNG, T., & CHAHINE, M. (2004). A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardia. Cardiovascular Research, 64(2), 268-278. doi:10.1016/j.cardiores.2004.07.007Weirich, J., & Antoni, H. (1998). Rate-dependence of antiarrhythmic and proarrhythmic properties of class I and class III antiarrhythmic drugs. Basic Research in Cardiology, 93(0), s125-s132. doi:10.1007/s003950050236O’Hara, T., Virág, L., Varró, A., & Rudy, Y. (2011). Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation. PLoS Computational Biology, 7(5), e1002061. doi:10.1371/journal.pcbi.1002061Wu, L., Ma, J., Li, H., Wang, C., Grandi, E., Zhang, P., … Belardinelli, L. (2011). Late Sodium Current Contributes to the Reverse Rate-Dependent Effect of I
Kr
Inhibition on Ventricular Repolarization. Circulation, 123(16), 1713-1720. doi:10.1161/circulationaha.110.000661Banyasz, T., Barandi, L., Harmati, G., Virag, L., Szentandrassy, N., Marton, I., … P. Nanasi, P. (2011). Mechanism of Reverse Rate-Dependent Action of Cardioactive Agents. Current Medicinal Chemistry, 18(24), 3597-3606. doi:10.2174/092986711796642355Noble D, Tsien RW. The repolarization process of heart cells. In: DeMello WC, ed. Electrical Phenomena in the Heart. New York: Academic Press, 1972:133-161.Fink, M., Noble, D., Virag, L., Varro, A., & Giles, W. R. (2008). Contributions of HERG K+ current to repolarization of the human ventricular action potential. Progress in Biophysics and Molecular Biology, 96(1-3), 357-376. doi:10.1016/j.pbiomolbio.2007.07.011Goineau, S., Castagné, V., Guillaume, P., & Froget, G. (2012). The comparative sensitivity of three in vitro safety pharmacology models for the detection of lidocaine-induced cardiac effects. Journal of Pharmacological and Toxicological Methods, 66(1), 52-58. doi:10.1016/j.vascn.2012.06.001Wu, L., Guo, D., Li, H., Hackett, J., Yan, G.-X., Jiao, Z., … Belardinelli, L. (2008). Role of late sodium current in modulating the proarrhythmic and antiarrhythmic effects of quinidine. Heart Rhythm, 5(12), 1726-1734. doi:10.1016/j.hrthm.2008.09.008Diness, J. G., Hansen, R. S., Nissen, J. D., Jespersen, T., & Grunnet, M. (2009). Antiarrhythmic effect of IKr activation in a cellular model of LQT3. Heart Rhythm, 6(1), 100-106. doi:10.1016/j.hrthm.2008.10.020Laursen, M., Olesen, S.-P., Grunnet, M., Mow, T., & Jespersen, T. (2011). Characterization of cardiac repolarization in the Göttingen minipig. Journal of Pharmacological and Toxicological Methods, 63(2), 186-195. doi:10.1016/j.vascn.2010.10.001HONDEGHEM, L. M. (2006). Thorough QT/QTc Not So Thorough: Removes Torsadogenic Predictors from the T-Wave, Incriminates Safe Drugs, and Misses Profibrillatory Drugs. Journal of Cardiovascular Electrophysiology, 17(3), 337-340. doi:10.1111/j.1540-8167.2006.00347.xHondeghem, L. M., & Snyders, D. J. (1990). Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation, 81(2), 686-690. doi:10.1161/01.cir.81.2.686Bril, A. (1998). Combined potassium and calcium channel antagonistic activities as a basis for neutral frequency dependent increase in action potential duration: comparison between BRL-32872 and azimilide. Cardiovascular Research, 37(1), 130-140. doi:10.1016/s0008-6363(97)00216-2Jurkiewicz, N. K., & Sanguinetti, M. C. (1993). Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide. Circulation Research, 72(1), 75-83. doi:10.1161/01.res.72.1.75O’Hara, T., & Rudy, Y. (2012). Quantitative comparison of cardiac ventricular myocyte electrophysiology and response to drugs in human and nonhuman species. American Journal of Physiology-Heart and Circulatory Physiology, 302(5), H1023-H1030. doi:10.1152/ajpheart.00785.2011Stengl, M., Volders, P. G. A., Thomsen, M. B., Spatjens, R. L. H. M. G., Sipido, K. R., & Vos, M. A. (2003). Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes. The Journal of Physiology, 551(3), 777-786. doi:10.1113/jphysiol.2003.044040Shah, R. R. (2002). The significance of QT interval in drug development. British Journal of Clinical Pharmacology, 54(2), 188-202. doi:10.1046/j.1365-2125.2002.01627.xNuyens, D., Stengl, M., Dugarmaa, S., Rossenbacker, T., Compernolle, V., Rudy, Y., … Carmeliet, P. (2001). Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome. Nature Medicine, 7(9), 1021-1027. doi:10.1038/nm0901-1021Gautier, M., Zhang, H., & Fearon, I. M. (2008). Peroxynitrite formation mediates LPC-induced augmentation of cardiac late sodium currents. Journal of Molecular and Cellular Cardiology, 44(2), 241-251. doi:10.1016/j.yjmcc.2007.09.007Fearon, I. M., & Brown, S. T. (2004). Acute and chronic hypoxic regulation of recombinant hNav1.5 α subunits. Biochemical and Biophysical Research Communications, 324(4), 1289-1295. doi:10.1016/j.bbrc.2004.09.188Ward, C. A., & Giles, W. R. (1997). Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. The Journal of Physiology, 500(3), 631-642. doi:10.1113/jphysiol.1997.sp022048Saint, D. A. (2009). The cardiac persistent sodium current: an appealing therapeutic target? British Journal of Pharmacology, 153(6), 1133-1142. doi:10.1038/sj.bjp.0707492Zygmunt, A. C., Eddlestone, G. T., Thomas, G. P., Nesterenko, V. V., & Antzelevitch, C. (2001). Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle. American Journal of Physiology-Heart and Circulatory Physiology, 281(2), H689-H697. doi:10.1152/ajpheart.2001.281.2.h689Trenor, B., Cardona, K., Gomez, J. F., Rajamani, S., Ferrero, J. M., Belardinelli, L., & Saiz, J. (2012). Simulation and Mechanistic Investigation of the Arrhythmogenic Role of the Late Sodium Current in Human Heart Failure. PLoS ONE, 7(3), e32659. doi:10.1371/journal.pone.0032659Martin, R. L., McDermott, J. S., Salmen, H. J., Palmatier, J., Cox, B. F., & Gintant, G. A. (2004). The Utility of hERG and Repolarization Assays in Evaluating Delayed Cardiac Repolarization: Influence of Multi-Channel Block. Journal of Cardiovascular Pharmacology, 43(3), 369-379. doi:10.1097/00005344-200403000-00007Antzelevitch, C., Belardinelli, L., Zygmunt, A. C., Burashnikov, A., Di Diego, J. M., Fish, J. M., … Thomas, G. (2004). Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With Antiarrhythmic Properties. Circulation, 110(8), 904-910. doi:10.1161/01.cir.0000139333.83620.5dNoble, D. (2006). Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium-calcium overload. Heart, 92(suppl_4), iv1-iv5. doi:10.1136/hrt.2005.078782Scirica, B. M., Morrow, D. A., Hod, H., Murphy, S. A., Belardinelli, L., Hedgepeth, C. M., … Braunwald, E. (2007). Effect of Ranolazine, an Antianginal Agent With Novel Electrophysiological Properties, on the Incidence of Arrhythmias in Patients With Non–ST-Segment–Elevation Acute Coronary Syndrome. Circulation, 116(15), 1647-1652. doi:10.1161/circulationaha.107.724880Hoefen, R., Reumann, M., Goldenberg, I., Moss, A. J., O-Uchi, J., Gu, Y., … Lopes, C. M. (2012). In Silico Cardiac Risk Assessment in Patients With Long QT Syndrome. Journal of the American College of Cardiology, 60(21), 2182-2191. doi:10.1016/j.jacc.2012.07.053Silva, J. R., Pan, H., Wu, D., Nekouzadeh, A., Decker, K. F., Cui, J., … Rudy, Y. (2009). A multiscale model linking ion-channel molecular dynamics and electrostatics to the cardiac action potential. Proceedings of the National Academy of Sciences, 106(27), 11102-11106. doi:10.1073/pnas.0904505106STARMER, C. (1991). Lidocaine blockade of continuously and transiently accessible sites in cardiac sodium channels*1. Journal of Molecular and Cellular Cardiology, 23, 73-83. doi:10.1016/0022-2828(91)90026-iRudy, Y., & Silva, J. R. (2006). Computational biology in the study of cardiac ion channels and cell electrophysiology. Quarterly Reviews of Biophysics, 39(1), 57-116. doi:10.1017/s0033583506004227Clancy, C. E., Zhu, Z. I., & Rudy, Y. (2007). Pharmacogenetics and anti-arrhythmic drug therapy: a theoretical investigation. American Journal of Physiology-Heart and Circulatory Physiology, 292(1), H66-H75. doi:10.1152/ajpheart.00312.2006Zygmunt, A. C., Nesterenko, V. V., Rajamani, S., Hu, D., Barajas-Martinez, H., Belardinelli, L., & Antzelevitch, C. (2011). Mechanisms of atrial-selective block of Na+ channels by ranolazine: I. Experimental analysis of the use-dependent block. American Journal of Physiology-Heart and Circulatory Physiology, 301(4), H1606-H1614. doi:10.1152/ajpheart.00242.2011Nesterenko, V. V., Zygmunt, A. C., Rajamani, S., Belardinelli, L., & Antzelevitch, C. (2011). Mechanisms of atrial-selective block of Na+ channels by ranolazine: II. Insights from a mathematical model. American Journal of Physiology-Heart and Circulatory Physiology, 301(4), H1615-H1624. doi:10.1152/ajpheart.00243.2011Zemzemi, N., Bernabeu, M. O., Saiz, J., Cooper, J., Pathmanathan, P., Mirams, G. R., … Rodriguez, B. (2013). Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials. British Journal of Pharmacology, 168(3), 718-733. doi:10.1111/j.1476-5381.2012.02200.xHille B. Ionic Channels of Excitable Membranes. 2nd ed. Sunderland, MA: Sinauer Associates, 1992.Rajamani, S., Shryock, J. C., & Belardinelli, L. (2008). Rapid Kinetic Interactions of Ranolazine With HERG K+ Current. Journal of Cardiovascular Pharmacology, 51(6), 581-589. doi:10.1097/fjc.0b013e3181799690Rajamani, S., El-Bizri, N., Shryock, J. C., Makielski, J. C., & Belardinelli, L. (2009). Use-dependent block of cardiac late Na+ current by ranolazine. Heart Rhythm, 6(11), 1625-1631. doi:10.1016/j.hrthm.2009.07.042Bassingthwaighte, J., Hunter, P., & Noble, D. (2009). The Cardiac Physiome: perspectives for the future. Experimental Physiology, 94(5), 597-605. doi:10.1113/expphysiol.2008.044099Quinn, T. A., Granite, S., Allessie, M. A., Antzelevitch, C., Bollensdorff, C., Bub, G., … Delmar, M. (2011). Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): Standardised reporting for model reproducibility, interoperability, and data sharing. Progress in Biophysics and Molecular Biology, 107(1), 4-10. doi:10.1016/j.pbiomolbio.2011.07.001Glukhov, A. V., Fedorov, V. V., Lou, Q., Ravikumar, V. K., Kalish, P. W., Schuessler, R. B., … Efimov, I. R. (2010). Transmural Dispersion of Repolarization in Failing and Nonfailing Human Ventricle. Circulation Research, 106(5), 981-991. doi:10.1161/circresaha.109.204891MALTSEV, V., & UNDROVINAS, A. (2006). A multi-modal composition of the late Na+ current in human ventricular cardiomyocytes. Cardiovascular Research, 69(1), 116-127. doi:10.1016/j.cardiores.2005.08.015Drouin, E., Charpentier, F., Gauthier, C., Laurent, K., & Le Marec, H. (1995). Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: Evidence for presence of M cells. Journal of the American College of Cardiology, 26(1), 185-192. doi:10.1016/0735-1097(95)00167-xBerecki, G., Zegers, J. G., Bhuiyan, Z. A., Verkerk, A. O., Wilders, R., & Van Ginneken, A. C. G. (2006). Long-QT syndrome-related sodium channel mutations probed by the dynamic action potential clamp technique. The Journal of Physiology, 570(2), 237-250. doi:10.1113/jphysiol.2005.096578Maltsev, V. A., Silverman, N., Sabbah, H. N., & Undrovinas, A. I. (2007). Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variability. European Journal of Heart Failure, 9(3), 219-227. doi:10.1016/j.ejheart.2006.08.007Valdivia, C. R., Chu, W. W., Pu, J., Foell, J. D., Haworth, R. A., Wolff, M. R., … Makielski, J. C. (2005). Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. Journal of Molecular and Cellular Cardiology, 38(3), 475-483. doi:10.1016/j.yjmcc.2004.12.012Belardinelli, L. (2006). Inhibition of the late sodium current as a potential cardioprotective principle:
Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations
This is an open-access article distributed
under the terms of the Creative
Commons Attribution License (CC BY).
The use, distribution or reproduction in
other forums is permitted, provided the
original author(s) or licensor are credited
and that the original publication
in this journal is cited, in accordance
with accepted academic practice. No use,
distribution or reproduction is permitted
which does not comply with these
terms.Carbon monoxide (CO) that is produced in a number of different mammalian tissues is
now known to have significant effects on the cardiovascular system. These include: (i)
vasodilation, (ii) changes in heart rate and strength of contractions, and (iii) modulation
of autonomic nervous system input to both the primary pacemaker and the working
myocardium. Excessive CO in the environment is toxic and can initiate or mediate life
threatening cardiac rhythm disturbances. Recent reports link these ventricular arrhythmias
to an increase in the slowly inactivating, or “late” component of the Na+ current in
the mammalian heart. The main goal of this paper is to explore the basis of this
pro-arrhythmic capability of CO by incorporating changes in CO-induced ion channel
activity with intracellular signaling pathways in the mammalian heart. To do this, a quite
well-documented mathematical model of the action potential and intracellular calcium
transient in the human ventricular myocyte has been employed. In silico iterations based
on this model provide a useful first step in illustrating the cellular electrophysiological
consequences of CO that have been reported from mammalian heart experiments.
Specifically, when the Grandi et al. model of the human ventricular action potential is
utilized, and after the Na+ and Ca2+ currents in a single myocyte are modified based on
the experimental literature, early after-depolarization (EAD) rhythm disturbances appear,
and important elements of the underlying causes of these EADs are revealed/illustrated.
Our modified mathematical model of the human ventricular action potential also provides
a convenient digital platform for designing future experimental work and relating these
changes in cellular cardiac electrophysiology to emerging clinical and epidemiological data
on CO toxicity.In Valencia, this work was supported by: (i) VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica from the Ministerio de Economia y Competitividad of Spain (TIN2012-37546-0O3-01) and the European Commission (European Regional Development Funds-ERDF-FEDER)., (ii) Plan Avanza en el marco de la Accion Estrategica de Telecomunicaciones y Sociedad de la Informacion del Ministerio de Industria Turismo y Comercio of Spain (TSI-020100-2010-469), (iii) Programa deApoyo a la Investigacion y Desarrollo (PAID-06-11-2002) de la Universitat Politecnica de Valencia, (iv) Programa Prometeo (PROMETEO/2012/030) de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana, and (v) GileadSciences, Ltd. Wayne Giles acknowledges receipt of financial support in the form of a salary award (Medical Scientist) from Alberta Innovates-Health Solutions, and operating funding from the Canadian Institutes for Health Research and the Heart and Stroke Foundation of Alberta.Trénor Gomis, BA.; Cardona-Urrego, KE.; Saiz Rodríguez, FJ.; Rajamani, S.; Belardinelli, L.; Giles, WR. (2013). Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations. Frontiers in Physiology. 4:1-11. https://doi.org/10.3389/fphys.2013.00282S111
Ischemic stroke risk, smoking, and the genetics of inflammation in a biracial population: the stroke prevention in young women study
<p>Abstract</p> <p>Background</p> <p>Although cigarette smoking is a well-established risk factor for vascular disease, the genetic mechanisms that link cigarette smoking to an increased incidence of stroke are not well understood. Genetic variations within the genes of the inflammatory pathways are thought to partially mediate this risk. Here we evaluate the association of several inflammatory gene single nucleotide polymorphisms (SNPs) with ischemic stroke risk among young women, further stratified by current cigarette smoking status.</p> <p>Methods</p> <p>A population-based case-control study of stroke among women aged 15–49 identified 224 cases of first ischemic stroke (47.3% African-American) and 211 age-comparable control subjects (43.1% African-American). Several inflammatory candidate gene SNPs chosen through literature review were genotyped in the study population and assessed for association with stroke and interaction with smoking status.</p> <p>Results</p> <p>Of the 8 SNPs (across 6 genes) analyzed, only <it>IL6 </it>SNP rs2069832 (allele C, African-American frequency = 92%, Caucasian frequency = 55%) was found to be significantly associated with stroke using an additive model, and this was only among African-Americans (age-adjusted: OR = 2.2, 95% CI = 1.0–5.0, p = 0.049; risk factor adjusted: OR = 2.5, 95% CI = 1.0–6.5, p = 0.05). When stratified by smoking status, two SNPs demonstrated statistically significant gene-environment interactions. First, the T allele (frequency = 5%) of <it>IL6 </it>SNP rs2069830 was found to be protective among non-smokers (OR = 0.30, 95% CI = 0.11–.082, p = 0.02), but not among smokers (OR = 1.63, 95% CI = 0.48–5.58, p = 0.43); genotype by smoking interaction (p = 0.036). Second, the C allele (frequency = 39%) of <it>CD14 </it>SNP rs2569190 was found to increase risk among smokers (OR = 2.05, 95% CI = 1.09–3.86, p = 0.03), but not among non-smokers (OR = 0.93, 95% CI = 0.62–1.39, p = 0.72); genotype by smoking interaction (p = 0.039).</p> <p>Conclusion</p> <p>This study demonstrates that inflammatory gene SNPs are associated with early-onset ischemic stroke among African-American women (<it>IL6</it>) and that cigarette smoking may modulate stroke risk through a gene-environment interaction (<it>IL6 and CD14</it>). Our finding replicates a prior study showing an interaction with smoking and the C allele of <it>CD14 </it>SNP rs2569190.</p
A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current
[EN] Background: The QT interval is a phase of the cardiac cycle that corresponds to action potential duration (APD) including cellular repolarization (T-wave). In both clinical and experimental settings, prolongation of the QT interval of the electrocardiogram (ECG) and related proarrhythmia have been so strongly associated that a prolonged QT interval is largely accepted as surrogate marker for proarrhythmia. Accordingly, drugs that prolong the QT interval are not considered for further preclinical development resulting in removal of many promising drugs from development. While reduction of drug interactions with hERG is an important goal, there are promising means to mitigate hERG block. Here, we examine one possibility and test the hypothesis that selective inhibition of the cardiac late Na current (I-NaL) by the novel compound GS-458967 can suppress proarrhythmic markers.
Methods and results: New experimental data has been used to calibrate INaL in the Soltis-Saucerman computationally based model of the rabbit ventricular action potential to study effects of GS-458967 on INaL during the rabbit ventricular AP. We have also carried out systematic in silico tests to determine if targeted block of INaL would suppress proarrhythmia markers in ventricular myocytes described by TRIaD: Triangulation, Reverse use dependence, beat-to-beat Instability of action potential duration, and temporal and spatial action potential duration Dispersion.
Conclusions: Our computer modeling approach based on experimental data, yields results that suggest that selective inhibition of INaL modifies all TRIaD related parameters arising from acquired Long-QT Syndrome, and thereby reduced arrhythmia risk. This study reveals the potential for adjunctive pharmacotherapy via targeted block of INaL to mitigate proarrhythmia risk for drugs with significant but unintended off-target hERG blocking effects.The National Institutes of Health R01 HL128537-01 (CEC), U01 HL126273-01 (CEC) and R01HL128170-02 (CEC).Yang, P.; El-Bizri, N.; Romero Pérez, L.; Giles, W.; Rajamani, S.; Belardinelli, L.; Clancy, CE. (2016). A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current. Journal of Molecular and Cellular Cardiology. 99:151-161. https://doi.org/10.1016/j.yjmcc.2016.08.011S1511619
Adverse childhood experiences and prescription drug use in a cohort study of adult HMO patients
<p>Abstract</p> <p>Background</p> <p>Prescription drugs account for approximately 11% of national health expenditures. Prior research on adverse childhood experiences (ACEs), which include common forms of child maltreatment and related traumatic stressors, has linked them to numerous health problems. However, data about the relationship of these experiences to prescription drug use are scarce.</p> <p>Method</p> <p>We used the ACE Score (an integer count of 8 different categories of ACEs) as a measure of cumulative exposure to traumatic stress during childhood. We prospectively assessed the relationship of the Score to prescription drug use in a cohort of 15,033 adult HMO patients (mean follow-up: 6.1 years) and assessed mediation of this relationship by documented ACE-related health and social problems.</p> <p>Results</p> <p>Nearly 1.2 million prescriptions were recorded; prescriptions rates increased in a graded fashion as the ACE Score increased (p for trend < 0.0001). Compared to persons with an ACE Score of 0, persons with a Score ≥ 5 had rates increased by 40%; graded relationships were seen for all age groups (18–44, 45–64, and 65–89 years) (p for trend < 0.01). Graded relationships were observed for the risk of being in the upper decile of number of classes of drugs used; persons with scores of ≥ 5 had this risk increased 2-fold. Adjustment for ACE-related health problems reduced the strength of the associations by more than 60%.</p> <p>Conclusion</p> <p>ACEs substantially increase the number of prescriptions and classes of drugs used for as long as 7 or 8 decades after their occurrence. The increases in prescription drug use were largely mediated by documented ACE-related health and social problems.</p
- …