10 research outputs found
Estudio de las modificaciones farmacológicas de los efectos electrofisiológicos producidos por el estiramiento local miocárdico a partir de técnicas dinámicas de cartografía eléctrica, en un modelo experimental de corazón aislado de conejo
La electrofisiología cardíaca permite el estudio de la actividad
eléctrica de regiones específicas del corazón y, por tanto, el análisis de las
modificaciones de sus características en regiones sometidas a cambios tales
como el estiramiento miocárdico agudo. El estiramiento miocárdico modifica
las propiedades electrofisiológicas de los cardiomiocitos, originando arritmias
cardíacas en diferentes situaciones patológicas. Los efectos mecánicos del
estiramiento inducen cambios relacionados con el calcio, y son varios los
mecanismos que han sido implicados, incluyendo un incremento de la entrada
de Na+ y la activación secuencial de los intercambiadores Na+/H+ y Na+/Ca2+
(modo inverso), ligados a eventos autocrino/paracrinos.
Esta Tesis Doctoral tiene como principal objetivo el estudio de la
posible participación de estos mecanismos en las respuestas electrofisiológicas
al estiramiento mediante el análisis de las modificaciones farmacológicas de
dichas respuestas.
Se han estudiado las modificaciones de las características de la
activación miocárdica durante la fibrilación ventricular (FV) y de las
propiedades electrofisiológicas miocárdicas inducidas por el estiramiento
miocárdico agudo en 44 corazones de conejo aislados y perfundidos en un
sistema Langendorff, utilizando electrodos múltiples epicárdicos y técnicas de
cartografía eléctrica, bajo condiciones control (n=9) y durante la perfusión del
antagonista de los receptores tipo 1 de angiotensina II losartán 1µM (n=8),
del antagonista de los receptores tipo A de endotelina BQ-123 0,1µM (n=9),
del inhibidor del intercambiador Na+/H+ 5-(N-ethyl-N-isopropyl)-amiloride
(EIPA) 1µM (n=9) y del inhibidor de la corriente tardía de Na+ ranolazina
5µM (n=9)Canto Serrano, ID. (2015). Estudio de las modificaciones farmacológicas de los efectos electrofisiológicos producidos por el estiramiento local miocárdico a partir de técnicas dinámicas de cartografía eléctrica, en un modelo experimental de corazón aislado de conejo [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/48544TESI
Effect of chronic exercise on myocardial electrophysiological heterogeneity and stability. Role of intrinsic cholinergic neurons: A study in the isolated rabbit heart
[EN] A study has been made of the effect of chronic exercise on myocardial electrophysiological heterogeneity and stability, as well as of the role of cholinergic neurons in these changes. Determinations in hearts from untrained and trained rabbits on a treadmill were performed. The hearts were isolated and perfused. A pacing electrode and a recording multielectrode were located in the left ventricle. The parameters determined during induced VF, before and after atropine (1 mu M), were: fibrillatory cycle length (VV), ventricular functional refractory period (FRPVF), normalized energy (NE) of the fibrillatory signal and its coefficient of variation (CV), and electrical ventricular activation complexity, as an approach to myocardial heterogeneity and stability. The VV interval was longer in the trained group than in the control group both prior to atropine (78 +/- 10 vs. 68 +/- 10 ms) and after atropine (76 +/- 8 vs. 67 +/- 10 ms). Likewise, FRPVF was longer in the trained group than in the control group both prior to and after atropine (53 +/- 8 vs. 42 +/- 7 ms and 50 +/- 6 vs. 40 +/- 6 ms, respectively), and atropine did not modify FRPVF. The CV of FRPVF was lower in the trained group than in the control group prior to atropine (12.5 +/- 1.5% vs. 15.1 +/- 3.8%) and, decreased after atropine (15.1 +/- 3.8% vs. 12.2 +/- 2.4%) in the control group. The trained group showed higher NE values before (0.40 +/- 0.04 vs. 0.36 +/- 0.05) and after atropine (0.37 +/- 0.04 vs. 0.34 +/- 0.06; p = 0.08). Training decreased the CV of NE both before (23.3 +/- 2% vs. 25.2 +/- 4%; p = 0.08) and after parasympathetic blockade (22.6 +/- 1% vs. 26.1 +/- 5%). Cholinergic blockade did not modify these parameters within the control and trained groups. Activation complexity was lower in the trained than in the control animals before atropine (34 +/- 8 vs. 41 +/- 5), and increased after atropine in the control group (41 +/- 5 vs. 48 +/- 9, respectively). Thus, training decreases the intrinsic heterogeneity of the myocardium, increases electrophysiological stability, and prevents some modifications due to muscarinic block.This research was supported by the Spanish Ministry of Education and Science, (DEP2007-73234-C03-01 to AMA), http://www.mecd.gob.es/portada-mecd/; and the Generalitat Valenciana (PROMETEO 2010/093 to FJC, and FPI/2008/003 to MZ), http://www.gva.es/va/inicio/presentacion; jsessionid=ydprbDQZTsCTz85W1Such-Miquel, L.; Brines-Ferrando, L.; Alberola, A.; Zarzoso Muñoz, M.; Chorro Gasco, FJ.; Guerrero-Martínez, JF.; Parra-Giraldo, G.... (2018). Effect of chronic exercise on myocardial electrophysiological heterogeneity and stability. Role of intrinsic cholinergic neurons: A study in the isolated rabbit heart. PLoS ONE. 13(12). https://doi.org/10.1371/journal.pone.0209085S1312Billman, G. E. (2002). Aerobic exercise conditioning: a nonpharmacological antiarrhythmic intervention. Journal of Applied Physiology, 92(2), 446-454. doi:10.1152/japplphysiol.00874.2001Billman, G. E. (2006). A comprehensive review and analysis of 25 years of data from an in vivo canine model of sudden cardiac death: Implications for future anti-arrhythmic drug development. Pharmacology & Therapeutics, 111(3), 808-835. doi:10.1016/j.pharmthera.2006.01.002Dor-Haim, H., Berenfeld, O., Horowitz, M., Lotan, C., & Swissa, M. (2013). Reduced Ventricular Arrhythmogeneity and Increased Electrical Complexity in Normal Exercised Rats. PLoS ONE, 8(6), e66658. doi:10.1371/journal.pone.0066658Hamer, M., & Stamatakis, E. (2008). Physical Activity and Cardiovascular Disease: Directions for Future Research. The Open Sports Sciences Journal, 1(1), 1-2. doi:10.2174/1875399x00801010001Powers, S. K., Smuder, A. J., Kavazis, A. N., & Quindry, J. C. (2014). Mechanisms of Exercise-Induced Cardioprotection. Physiology, 29(1), 27-38. doi:10.1152/physiol.00030.2013Hull, S. S., Vanoli, E., Adamson, P. B., Verrier, R. L., Foreman, R. D., & Schwartz, P. J. (1994). Exercise training confers anticipatory protection from sudden death during acute myocardial ischemia. Circulation, 89(2), 548-552. doi:10.1161/01.cir.89.2.548Hajnal, Á., Nagy, O., Litvai, Á., Papp, J., Parratt, J. R., & Végh, Á. (2005). Nitric oxide involvement in the delayed antiarrhythmic effect of treadmill exercise in dogs. Life Sciences, 77(16), 1960-1971. doi:10.1016/j.lfs.2005.02.015Such, L., Alberola, A. M., Such-Miquel, L., López, L., Trapero, I., Pelechano, F., … Chorro, F. J. (2008). Effects of chronic exercise on myocardial refractoriness: a study on isolated rabbit heart. Acta Physiologica, 193(4), 331-339. doi:10.1111/j.1748-1716.2008.01851.xZarzoso, M., Such-Miquel, L., Parra, G., Brines-Ferrando, L., Such, L., Chorro, F. J., … Alberola, A. (2011). The training-induced changes on automatism, conduction and myocardial refractoriness are not mediated by parasympathetic postganglionic neurons activity. European Journal of Applied Physiology, 112(6), 2185-2193. doi:10.1007/s00421-011-2189-4Billman, G. E. (2009). Cardiac autonomic neural remodeling and susceptibility to sudden cardiac death: effect of endurance exercise training. American Journal of Physiology-Heart and Circulatory Physiology, 297(4), H1171-H1193. doi:10.1152/ajpheart.00534.2009HAN, J., & MOE, G. K. (1964). Nonuniform Recovery of Excitability in Ventricular Muscle. Circulation Research, 14(1), 44-60. doi:10.1161/01.res.14.1.44Beaumont, E., Salavatian, S., Southerland, E. M., Vinet, A., Jacquemet, V., Armour, J. A., & Ardell, J. L. (2013). Network interactions within the canine intrinsic cardiac nervous system: implications for reflex control of regional cardiac function. The Journal of Physiology, 591(18), 4515-4533. doi:10.1113/jphysiol.2013.259382Armour, J. A. (2008). Potential clinical relevance of the ‘little brain’ on the mammalian heart. Experimental Physiology, 93(2), 165-176. doi:10.1113/expphysiol.2007.041178Abramochkin, D. V., Nurullin, L. F., Borodinova, A. A., Tarasova, N. V., Sukhova, G. S., Nikolsky, E. E., & Rosenshtraukh, L. V. (2009). Non-quantal release of acetylcholine from parasympathetic nerve terminals in the right atrium of rats. Experimental Physiology, 95(2), 265-273. doi:10.1113/expphysiol.2009.050302CHORRO, F. J., CANOVES, J., GUERRERO, J., MAINAR, L., SANCHIS, J., SORIA, E., … LOPEZ-MERINO, V. (2000). Opposite Effects of Myocardial Stretch and Verapamil on the Complexity of the Ventricular Fibrillatory Pattern: An Experimental Study. Pacing and Clinical Electrophysiology, 23(11), 1594-1603. doi:10.1046/j.1460-9592.2000.01594.xSuch, L., Rodriguez, A., Alberola, A., Lopez, L., Ruiz, R., Artal, L., … Chorro, F. J. (2002). Intrinsic changes on automatism, conduction, and refractoriness by exercise in isolated rabbit heart. Journal of Applied Physiology, 92(1), 225-229. doi:10.1152/jappl.2002.92.1.225Duytschaever, M., Mast, F., Killian, M., Blaauw, Y., Wijffels, M., & Allessie, M. (2001). Methods for Determining the Refractory Period and Excitable Gap During Persistent Atrial Fibrillation in the Goat. Circulation, 104(8), 957-962. doi:10.1161/hc3401.093156Wijffels, M. C. E. F., Kirchhof, C. J. H. J., Dorland, R., & Allessie, M. A. (1995). Atrial Fibrillation Begets Atrial Fibrillation. Circulation, 92(7), 1954-1968. doi:10.1161/01.cir.92.7.1954Zaitsev, A. V., Berenfeld, O., Mironov, S. F., Jalife, J., & Pertsov, A. M. (2000). Distribution of Excitation Frequencies on the Epicardial and Endocardial Surfaces of Fibrillating Ventricular Wall of the Sheep Heart. Circulation Research, 86(4), 408-417. doi:10.1161/01.res.86.4.408Armour, J. A., Collier, K., Kember, G., & Ardell, J. L. (1998). Differential selectivity of cardiac neurons in separate intrathoracic autonomic ganglia. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 274(4), R939-R949. doi:10.1152/ajpregu.1998.274.4.r939Armour, J. A., & Hopkins, D. A. (1990). Activity of in vivo canine ventricular neurons. American Journal of Physiology-Heart and Circulatory Physiology, 258(2), H326-H336. doi:10.1152/ajpheart.1990.258.2.h326D’Souza, A., Bucchi, A., Johnsen, A. B., Logantha, S. J. R. J., Monfredi, O., Yanni, J., … Boyett, M. R. (2014). Exercise training reduces resting heart rate via downregulation of the funny channel HCN4. Nature Communications, 5(1). doi:10.1038/ncomms4775Sartiani, L., Romanelli, M., Mugelli, A., & Cerbai, E. (2015). Updates on HCN Channels in the Heart: Function, Dysfunction and Pharmacology. Current Drug Targets, 16(8), 868-876. doi:10.2174/1389450116666150531152047Herrmann, S., Layh, B., & Ludwig, A. (2011). Novel insights into the distribution of cardiac HCN channels: An expression study in the mouse heart. Journal of Molecular and Cellular Cardiology, 51(6), 997-1006. doi:10.1016/j.yjmcc.2011.09.005Welch, P. (1967). The use of fast Fourier transform for the estimation of power spectra: A method based on time averaging over short, modified periodograms. IEEE Transactions on Audio and Electroacoustics, 15(2), 70-73. doi:10.1109/tau.1967.116190
Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)
This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe
Estudio del envejecimiento y de la diabetes a partir de la determinación del consumo de glucosa mediante el análisis de imagen molecular. Desarrollo de una herramienta de cuantificación cerebral en rata
Se ha desarrollado una herramienta de cuantificación de imágenes moleculares adquiridas mediante PET, que permita el estudio del cerebro de rata. Se ha utilizado esta herramienta para el estudio de una población de ratas, determinando el consumo de glucosa en el cerebro de rata en el envejecimiento y la diabetes.Del Canto Serrano, I. (2010). Estudio del envejecimiento y de la diabetes a partir de la determinación del consumo de glucosa mediante el análisis de imagen molecular. Desarrollo de una herramienta de cuantificación cerebral en rata. http://hdl.handle.net/10251/11362Archivo delegad
Multiclass texture-based PI-RADS classification in multiparametric MRI: performance evaluation of the DWI sequence
Jaen-Lorites, JM.; Ruiz-España, S.; Piñeiro-Vidal, T.; Canto Serrano, ID.; Santabárbara, J.; Moratal, D. (2020). Multiclass texture-based PI-RADS classification in multiparametric MRI: performance evaluation of the DWI sequence. Springer Nature. 207-207. http://hdl.handle.net/10251/179211S20720
Estudio experimental de los efectos de EIPA, losartán y BQ-123 sobre las modificaciones electrofisiológicas inducidas por el estiramiento miocárdico
[ES] Introducción y objetivos
Se han implicado diversos mecanismos en la respuesta mecánica al estiramiento miocárdico, que incluyen la activación del intercambiador Na+/H+ por acciones autocrinas y paracrinas. Se estudia la participación de estos mecanismos en las respuestas electrofisiológicas al estiramiento agudo miocárdico mediante el análisis de los cambios inducidos con fármacos.
Métodos
Se analizan las modificaciones de la fibrilación ventricular inducidas por el estiramiento agudo miocárdico en corazones de conejo aislados y perfundidos utilizando electrodos múltiples epicárdicos y técnicas cartográficas. Se estudian 4 series: control (n = 9); durante la perfusión del antagonista de los receptores de la angiotensina II, losartán (1 ¿M, n = 8); durante la perfusión del bloqueador del receptor de la endotelina A, BQ-123 (0,1 ¿M, n = 9), y durante la perfusión del inhibidor del intercambiador Na+/H+, EIPA (5-[N-ethyl-N-isopropyl]-amiloride) (1 ¿M, n = 9).
Resultados
EIPA atenuó el aumento de la frecuencia dominante de la fibrilación producido por el estiramiento (control = 40,4%; losartán = 36% [no significativo]; BQ-123 = 46% [no significativo], y EIPA = 22% [p < 0,001]). Durante el estiramiento, la complejidad de los mapas de activación fue menor en la serie con EIPA (p < 0,0001) y también en esta serie fue mayor la concentración espectral de la arritmia (mayor regularidad): control = 18 ± 3%; EIPA = 26 ± 9% (p < 0,02); losartán = 18 ± 5% (no significativo), y BQ-123 = 18 ± 4% (no significativo).
Conclusiones
El inhibidor del intercambiador Na+/H+ EIPA atenúa los efectos electrofisiológicos responsables de la aceleración y del aumento de la complejidad de la fibrilación ventricular producidos por el estiramiento agudo miocárdico. Por el contrario, el antagonista de los receptores de la angiotensina II, losartán, y el del receptor A de la endotelina, BQ-123, no modifican estos efectos.[EN] Introduction and objectives
Mechanical response to myocardial stretch has been explained by various mechanisms, which include Na+/H+ exchanger activation by autocrine-paracrine system activity. Drug-induced changes were analyzed to investigate the role of these mechanisms in the electrophysiological responses to acute myocardial stretch.
Methods
Multiple epicardial electrodes and mapping techniques were used to analyze changes in ventricular fibrillation induced by acute myocardial stretch in isolated perfused rabbit hearts. Four series were studied: control (n = 9); during perfusion with the angiotensin receptor blocker losartan (1 ¿M, n = 8); during perfusion with the endothelin A receptor blocker BQ-123 (0.1 ¿M, n = 9), and during perfusion with the Na+/H+ exchanger inhibitor EIPA (5-[N-ethyl-N-isopropyl]-amiloride) (1 ¿M, n = 9).
Results
EIPA attenuated the increase in the dominant frequency of stretch-induced fibrillation (control = 40.4%; losartan = 36% [not significant]; BQ-123 = 46% [not significant]; and EIPA = 22% [P < .001]). During stretch, the activation maps were less complex (P < .0001) and the spectral concentration of the arrhythmia was greater (greater regularity) in the EIPA series: control = 18 (3%); EIPA = 26 (9%) (P < .02); losartan = 18 (5%) (not significant); and BQ-123 = 18 (4%) (not significant).
Conclusions
The Na+/H+ exchanger inhibitor EIPA attenuated the electrophysiological effects responsible for the acceleration and increased complexity of ventricular fibrillation induced by acute myocardial stretch. The angiotensin II receptor antagonist losartan and the endothelin A receptor blocker BQ-123 did not modify these effects.This study was funded by the Spanish Department of Science (Instituto de Salud Carlos III): projects FIS PS09/02417, FIS PI12/00407, and RETIC "RIC" RD12/0042/0048, and Generalitat Valenciana: project PROMETEO 2010/093Chorro, FJ.; Canto Serrano, ID.; Brines, L.; Such-Miquel, L.; Calvo Saiz, CJ.; Soler, C.; Zarzoso, M.... (2015). Experimental Study of the Effects of EIPA, Losartan, and BQ-123 on Electrophysiological Changes Induced by Myocardial Stretch. Revista Española de Cardiología. 68(12):1101-1110. https://doi.org/10.1016/j.rec.2014.12.023S11011110681
Effects of S-Nitrosoglutathione on Electrophysiological Manifestations of Mechanoelectric Feedback
[EN] Electromechanical coupling studies have described the intervention of nitric oxide and S-nitrosylation processes in Ca2+ release induced by stretch, with heterogeneous findings. On the other hand, ion channel function activated by stretch is influenced by nitric oxide, and concentration-dependent biphasic effects upon several cellular functions have been described. The present study uses isolated and perfused rabbit hearts to investigate the changes in mechanoelectric feedback produced by two different concentrations of the nitric oxide carrier S-nitrosoglutathione. Epicardial multielectrodes were used to record myocardial activation at baseline and during and after left ventricular free wall stretch using an intraventricular device. Three experimental series were studied: (a) control (n=10); (b) S-nitrosoglutathione 10 mu M (n=11); and (c) S-nitrosoglutathione 50 mu M (n=11). The changes in ventricular fibrillation (VF) pattern induced by stretch were analyzed and compared. S-nitrosoglutathione 10 mu M did not modify VF at baseline, but attenuated acceleration of the arrhythmia (15.6 +/- 1.7 vs. 21.3 +/- 3.8Hz; p<0.0001) and reduction of percentile 5 of the activation intervals (42 +/- 3 vs. 38 +/- 4ms; p<0.05) induced by stretch. In contrast, at baseline using the 50 mu M concentration, percentile 5 was shortened (38 +/- 6 vs. 52 +/- 10ms; p<0.005) and the complexity index increased (1.77 +/- 0.18 vs. 1.27 +/- 0.13; p<0.0001). The greatest complexity indices (1.84 +/- 0.17; p<0.05) were obtained during stretch in this series. S-nitrosoglutathione 10 mu M attenuates the effects of mechanoelectric feedback, while at a concentration of 50 mu M the drug alters the baseline VF pattern and accentuates the increase in complexity of the arrhythmia induced by myocardial stretch.Carlos III Health Institute/FEDER funds (Spanish Ministry of Economy and Competitiveness): Grants FIS PI12/00407, PI15/01408, PIE15/00013, and RETIC “RIC” RD12/0042/0048. Generalitat Valenciana: Grant PROMETEO FASE II 2014/037.Such-Miquel, L.; Canto Serrano, ID.; Zarzoso Muñoz, M.; Brines-Ferrando, L.; Soler, C.; Parra-Giraldo, G.; Guill Ibáñez, A.... (2018). Effects of S-Nitrosoglutathione on Electrophysiological Manifestations of Mechanoelectric Feedback. Cardiovascular Toxicology. 18(6):520-529. https://doi.org/10.1007/s12012-018-9463-1S520529186Tamargo, J., Caballero, R., Gómez, R., & Delpón, E. (2010). Cardiac electrophysiological effects of nitric oxide. Cardiovascular Research, 87, 593–600.Gonzalez, D. R., Treuer, A., Sun, Q. A., Stamler, J. S., & Hare, J. M. (2009). S-nitrosylation of cardiac ion channels. Journal of Cardiovascular Pharmacology, 54, 188–195.Treuer, A. V., & Gonzalez, D. R. (2015). Nitric oxide synthases, S-nitrosylation and cardiovascular health: From molecular mechanisms to therapeutic opportunities. Molecular Medicine Reports, 11, 1555–1565.Beigi, F., Gonzalez, D. R., Minhas, K. M., Sun, Q. A., Foster, M. W., Khan, S. A., Treuer, A. V., Dulce, R. A., Harrison, R. W., Saraiva, R. M., Premer, C., Schulman, I. H., Stamler, J. S., & Hare, J. M. (2012). Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function. Proceedings of the National Academy of Sciences of the United States of America, 109, 4314–4319.Broniowska, K. A., Diers, A. R., & Hogg, N. (2013). S-nitrosoglutathione. Biochimica et Biophysica Acta, 1830, 3173–3181.Zaman, K., Palmer, L. A., Doctor, A., Hunt, J. F., & Gaston, B. (2004). Concentration-dependent effects of endogenous S-nitrosoglutathione on gene regulation by specificity proteins Sp3 and Sp1. The Biochemical Journal, 380, 67–74.Janse, M. J., Coronel, R., Wilms-Schopman, F. J. G., & de Groot, J. R. (2003). Mechanical effects on arrhythmogenesis: From pipette to patient. Progress in Biophysics and Molecular Biology, 82, 187–195.Quinn, T. A., & Kohl, P. (2016). Rabbit models of cardiac mechano-electric and mechano-mechanical coupling. Progress in Biophysics and Molecular Biology, 121, 110–122.Vila-Petroff, M., Kim, S. H., Pepe, S., Dessy, C., Marbán, E., Balligand, J. L., & Sollott, S. J. (2001). Endogenous nitric oxide mechanisms mediate the stretch-dependency of Ca2+ release in cardiomyocytes. Nature Cell Biology, 3, 867–873.Leite-Moreira, A. M., Neves, J. S., Almeida-Coelho, J., Neiva-Sousa, M., & Leite-Moreira, A. F. (2016). On the study of the role of NO-mediated pathways in the myocardial response to acute stretch. Nitric Oxide: Biology and Chemistry, 53, 1–3.Peyronnet, R., Nerbonne, J. M., & Kohl, P. (2016). Cardiac mechano-gated ion channels and arrhythmias. Circulation Research 118, 311–329.Fischmeister, R., Castro, L., Abi-Gerges, A., Rochais, F., & Vandecasteele, G. (2005). Species- and tissue-dependent effects of NO and cyclic GMP on cardiac ion channels. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology 142, 136–143.Kazanski, V. E., Kamkin, A. G., Makarenko, E. Y., Lysenko, N. N., Sutiagin, P. V., Bo, T., & Kiseleva, I. S. (2010). Role of nitric oxide in activity control of mechanically gated ionic channels in cardiomyocytes: NO-donor study. Bulletin of Experimental Biology and Medicine, 150, 1–5.Dyachenko, V., Rueckschloss, U., & Isenberg, G. (2009). Modulation of cardiac mechanosensitive ion channels involves superoxide, nitric oxide and peroxynitrite. Cell Calcium, 45, 55–64.Chorro, F. J., Trapero, I., Guerrero, J., Such, L. M., Canoves, J., Mainar, L., Ferrero, A., Blasco, E., Sanchis, J., Millet, J., Tormos, A., Bodí, V., & Alberola, A. (2005). Modification of ventricular fibrillation activation patterns induced by local stretching. Journal of Cardiovascular Electrophysiology, 16, 1087–1096.Chorro, F. J., Trapero, I., Such-Miquel, L., Pelechano, F., Mainar, L., Cánoves, J., Tormos, A., Alberola, A., Hove-Madsen, L., Cinca, J., & Such, L. (2009). Pharmacological modifications of the stretch-induced effects on ventricular fibrillation in perfused rabbit-hearts. American Journal of Physiology Heart and Circulatory Physiology, 297, H1860–H1869.Brines, L., Such-Miquel, L., Gallego, D., Trapero, I., Del Canto, I., Zarzoso, M., Soler, C., Pelechano, F., Cánoves, J., Alberola, A., Such, L., & Chorro, F. J. (2012). Modifications of mechanoelectric feedback induced by 2,3-butanedione monoxime and blebbistatin in Langendorff-perfused rabbit hearts. Acta Physiologica, 206, 29–41.Chorro, F. J., del Canto, I., Brines, L., Such-Miquel, L., Calvo, C., Soler, C., Zarzoso, M., Trapero, I., Tormos, Á, & Such, L. (2015). Experimental study of the effects of EIPA, losartan and BQ-123 on electrophysiological changes induced by myocardial stretch. Revista Espanola de Cardiologia, 68, 1101–1110.Chorro, F. J., del Canto, I., Brines, L., Such-Miquel, L., Calvo, C., Soler, C., Parra, G., Zarzoso, M., Trapero, I., Tormos, A., Alberola, A., & Such, L. (2015). Ranolazine attenuates the electrophysiological effects of myocardial stretch in Langendorff-perfused rabbit hearts. Cardiovascular Drugs and Therapy, 29, 231–241.Kelly, R. A., Balligand, J. L., & Smith, T. W. (1996). Nitric oxide and cardiac function. Circulation Research, 79, 363–380.Kojda, G., & Kottenberg, K. (1999). Regulation of basal myocardial function by NO. Cardiovascular Research, 41, 514–523.Massion, P. B., Feron, O., Dessy, C., & Balligand, J. L. (2003). Nitric oxide and cardiac function: Ten years after, and continuing. Circulation Research, 93, 388–398.Shah, A. M., & MacCarthy, P. A. (2000). Paracrine and autocrine effects of nitric oxide on myocardial function. Pharmacology & Therapeutics, 86, 49–86.Zhang, Y. H., Dingle, L., Hall, R., & Casadei, B. (2009). The role of nitric oxide and reactive oxygen species in the positive inotropic response to mechanical stretch in the mammalian myocardium. Biochimica et Biophysica Acta, 1787, 811–817.Chorro, F. J., Ibañez-Catalá, X., Trapero, I., Such-Miquel, L., Pelechano, F., Cánoves, J., Mainar, L., Tormos, A., Cerdá, J. M., Alberola, A., & Such, L. (2013). Ventricular fibrillation conduction through an isthmus of preserved myocardium between radiofrequency lesions. Pacing and Clinical Electrophysiology, 36, 286–298.Gaston, B., Reilly, J., Drazen, J. M., Fackler, J., Ramdev, P., Arnelle, D., Mullins, M. E., Sugarbaker, D. J., Chee, C., Singel, D. J., Loscalzo, J., & Stamler, J. (1993). Endogenous nitrogen oxides and bronchodilator S-nitrosothiols in human airways. Proceedings of the National Academy of Sciences of the United States of America, 90, 10957–10961.Radomski, M. W., Rees, D. D., Dutra, A., & Moncada, S. (1992). S-nitroso-glutathione inhibits platelet activation in vitro and in vivo. British Journal of Pharmacology, 107, 745–749.Zaman, K., McPherson, M., Vaughan, J., Hunt, J., Mendes, F., Gaston, B., & Palmer, L. A. (2001). S-nitrosoglutathione increases cystic fibrosis transmembrane regulator maturation. Biochemical and Biophysical Research Communications, 284, 65–70.Zaman, K., Carraro, S., Doherty, J., Henderson, E. M., Lendermon, E., Liu, L., Verghese, G., Zigler, M., Ross, M., Park, M., Palmer, L. A., Doctor, A., Stamler, J. S., & Gaston, B. (2006). S-nitrosylating agents: A novel class of compounds that increase cystic fibrosis transmembrane conductance regulator expression and maturation in epithelial cells. Molecular Pharmacology, 70, 1435–1442.Kaposzta, Z., Baskerville, P. A., Madge, D., Fraser, S., Martin, J. F., & Markus, H. S. (2001). L-arginine and S-nitrosoglutathione reduce embolization in humans. Circulation, 103, 2371–2375.Kaposzta, Z., Clifton, A., Molloy, J., Martin, J. F., & Markus, H. S. (2002). S-nitrosoglutathione reduces asymptomatic embolization after carotid angioplasty. Circulation, 106, 2057–3062.Everett, T. R., Wilkinson, I. B., Mahendru, A. A., McEniery, C. M., Garner, S., Goodall, A. H., & Lees, C. C. (2014). S-nitrosoglutathione improves haemodynamics in early-onset pre-eclampsia. British Journal of Clinical Pharmacology, 78, 660–669.Everett, T. R., Wilkinson, I. B., & Lees, C. C. (2017). Pre-eclampsia: The potential of GSNO reductase inhibitors. Current Hypertension Reports, 19, 1–7.Oppenheim, A., & Schafer, R. (1975). Digital signal processing. Englewood Cliffs: Prentice Hall.Such-Miquel, L., Chorro, F. J., Guerrero, J., Trapero, I., Brines, L., Zarzoso, M., Parra, G., Soler, C., del Canto, I., Alberola, A., & Such, L. (2013). Evaluation of the complexity of myocardial activation during ventricular fibrillation. An experimental study. Revista Espanola de Cardiologia, 66, 177–184.Erickson, J. R., Nichols, C. B., Uchinoumi, H., Stein, M., Bossuyt, J., & Bers, D. M. (2015). S-nitrosylation induces both autonomous activation and inhibition of calcium/calmodulin-dependent protein kinase IIδ. Journal of Biological Chemistry, 290, 25646–25656.Gómez, R., Caballero, R., Barana, A., Amorós, I., Calvo, E., López, J. A., Klein, H., Vaquero, M., Osuna, L., Atienza, F., Almendral, J., Pinto, A., Tamargo, J., & Delpón, E. (2009). Nitric oxide increases cardiac IK1 by nitrosylation of cysteine 76 of Kir2.1 channels. Circulation Research, 105, 383–392.Sun, J., Yamaguchi, N., Xu, L., Eu, J. P., Stamler, J. S., & Meissner, G. (2008). Regulation of the cardiac muscle ryanodine receptor by O2 tension and S-nitrosoglutathione. Biochemistry, 47, 13985–13990.Xu, L., Eu, J. P., Meissner, G., & Stamler, J. S. (1998). Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation. Science, 279, 234–237.Zahradnikova, A., Minarovic, I., Venema, R. C., & Meszaros, L. G. (1997). Inactivation of the cardiac ryanodine receptor calcium release channel by nitric oxide. Cell Calcium, 22, 447–454.Kirstein, M., Rivet-Bastide, M., Hatem, S., Bénardeau, A., Mercadier, J. J., & Fischmeister, R. (1995). Nitric Oxide regulates the calcium current in isolated human atrial myocytes. Journal of Clinical Investigation, 95, 794–802.Rivet-Bastide, M., Vandecasteele, G., Hatem, S., Verde, I., Bénardeau, A., Mercadier, J. J., & Fischmeister, R. (1997). cGMP-stimulated cyclic nucleotide phosphodiesterase regulates the basal calcium current in human atrial myocytes. Journal of Clinical Investigation, 99, 2710–2718.Lim, G., Venetucci, L., Eisner, D. A., & Casadei, B. (2008). Does nitric oxide modulate cardiac ryanodine receptor function? Implications for excitation–contraction coupling. Cardiovascular Research, 77, 256–264.Ling, L., Hui, Y., Bing, G., Xin, H., Jing, W., & Jin-Cheng, L. (2015). Nitric oxide donor, NOC7, reveals dose dependently and cGMP pathway independently biphasic effects on contractile force of isolated rat heart after global ischemia. International Journal of Clinical and Experimental Pathology, 8, 3843–3849.Cingolani, H. E., Ennis, I. L., Aiello, E. A., & Pérez, N. G. (2011). Role of autocrine/paracrine mechanisms in response to myocardial strain. Pflugers Archiv European Journal of Physiology, 462, 29–38.Youm, J. B., Han, J., Kim, N., Zhang, Y. H., Kim, E., Joo, H., Leem, C. H., Kim, S. J., Cha, K. A., Earm, Y. E., & Leem, C. H. (2006). Role of stretch-activated channels on the stretch-induced changes of rat atrial myocytes. Progress in Biophysics and Molecular Biology, 90, 186–206.von Lewinski, D., Stumme, B., Maier, L. S., Luers, C., Bers, D. M., & Pieske, B. (2003). Stretch-dependent slow force response in isolated rabbit myocardium is Na+ dependent. Cardiovascular Research, 57, 1052–1061.Calaghan, S. C., Belus, A., & White, E. (2003). Do stretch-induced changes in intracellular calcium modify the electrical activity of cardiac muscle? Progress in Biophysics and Molecular Biology, 82, 91–95.Zhang, Y. H., Dingle, L., Hall, R., & Casadei, B. (2009). The role of nitric oxide and reactive oxygen species in the positive inotropic response to mechanical stretch in the mammalian myocardium. Biochimica Biophysica Acta, 1787, 811–817.Sag, C. M., Wagner, S., & Maier, L. S. (2013). Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes. Free Radical Biology and Medicine, 63, 338–349.Janvier, N. C., & Boyett, M. R. (1996). The role of Na-Ca exchange current in the cardiac action potential. Cardiovascular Research, 32, 69–84.Kovács, M., Kiss, A., Gönczi, M., Miskolczi, G., Seprényl, G., Kaszaki, J., Kohr, M. J., Murphy, E., & Vegh, A. (2015). Effect of sodium nitrite on ischaemia and reperfusion-induced arrhythmias in anaesthetized dogs: Is protein S-nitrosylation involved? PLoS ONE, 10(4), e0122243 (eCollection 2015). https://doi.org/10.1371/journal.pone.0122243
Effects of the inhibition of late sodium current by GS967 on stretch-induced changes in cardiac electrophysiology
[EN] PurposeMechanical stretch increases sodium and calcium entry into myocytes and activates the late sodium current. GS967, a triazolopyridine derivative, is a sodium channel blocker with preferential effects on the late sodium current. The present study evaluates whether GS967 inhibits or modulates the arrhythmogenic electrophysiological effects of myocardial stretch.MethodsAtrial and ventricular refractoriness and ventricular fibrillation modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts (n=28) using epicardial multiple electrodes and high-resolution mapping techniques under control conditions and during the perfusion of GS967 at different concentrations (0.03, 0.1, and 0.3M).ResultsOn comparing ventricular refractoriness, conduction velocity and wavelength obtained before stretch had no significant changes under each GS967 concentration while atrial refractoriness increased under GS967 0.3M. Under GS967, the stretch-induced changes were attenuated, and no significant differences were observed between before and during stretch. GS967 0.3M diminished the normal stretch-induced changes resulting in longer (less shortened) atrial refractoriness (13826ms vs 95 +/- 9ms; p<0.01), ventricular refractoriness (155 +/- 18ms vs 124 +/- 16 ms; p<0.01) and increments in spectral concentration (23 +/- 5% vs 17 +/- 2%; p<0.01), the fifth percentile of ventricular activation intervals (46 +/- 8ms vs 31 +/- 3ms; p<0.05), and wavelength of ventricular fibrillation (2.5 +/- 0.5cm vs 1.7 +/- 0.3cm; p<0.05) during stretch. The stretch-induced increments in dominant frequency during ventricular fibrillation (control=38%, 0.03M=33%, 0.1M=33%, 0.3M=14%; p<0.01) and the stretch-induced increments in arrhythmia complexity index (control=62%, 0.03M=41%, 0.1M=32%, 0.3M=16%; p<0.05) progressively decreased on increasing the GS967 concentration.Conclusions GS967 attenuates stretch-induced changes in cardiac electrophysiology.This work was supported by the Spanish Ministry of Economy and Competiveness (Carlos III Health Institute)/European Regional Development Fund (FEDER) (Grants FIS PI12/00407, PI15/01408, PIE15/00013, CB16/11/00486) and by the Generalitat Valenciana (Grant PROMETEO FASE II 2014/037).Canto Serrano, ID.; Santamaría, L.; Genovés, P.; Such-Miquel, L.; Arias-Mutis, ÓJ.; Zarzoso Muñoz, M.; Soler, C.... (2018). Effects of the inhibition of late sodium current by GS967 on stretch-induced changes in cardiac electrophysiology. Cardiovascular Drugs and Therapy. 32(5):413-425. https://doi.org/10.1007/s10557-018-6822-xS413425325Kondratev D, Christ A, Gallitelli MF. Inhibition of the Na+-H+ exchanger with cariporide abolishes stretch-induced calcium but not sodium accumulation in mouse ventricular myocytes. Cell Calcium. 2005;37:69–80.Cingolani HE, Perez NG, Cingolani OH, Ennis IL. The Anrep effect: 100 years later. Am J Physiol Heart Circ Physiol. 2013;304:H175–82.Von Lewinski D, Stumme B, Maier LS, Luers C, Bers DM, Pieske B. Stretch-dependent slow force response in isolated rabbit myocardium is Na+ dependent. Cardiovasc Res. 2003;57:1052–61.Quinn TA, Kohl P. Rabbit models of cardiac mechano-electric and mechano-electric and mechano-mechanical coupling. Prog Biophys Mol Biol. 2016;121:110–22.Kim D. Novel cation-selective mechanosensitive ion channel in the atrial cell membrane. Circ Res. 1993;72:225–31.Beyder A, Rae JL, Bernard C, Strege PR, Sachs F, Farrugia G. Mechanosensitivity of Nav1.5, a voltage-sensitive sodium channel. J Physiol. 2010;588:4969–85.Peyronnet R, Nerbonne JM, Kohl P. Cardiac mechano-gated ion channels and arrhythmias. Circ Res. 2016;118:311–29.Sag CM, Wagner S, Maier LS. Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes. Free Radic Biol Med. 2013;63:338–49.Prosser BL, Ward CW, Lederer WJ. X-ROS signaling is enhanced and graded by cyclic cardiomyocyte stretch. Cardiovasc Res. 2013;98:307–14.Patlak JB, Ortiz M. Slow currents through single sodium channels of the adult rat heart. J Gen Physiol. 1985;86:89–104.Maltsev VA, Undrovinas A. Late sodium current in failing heart: friend or foe? Prog Biophys Mol Biol. 2008;96:421–51.Wei XH, Yu SD, Ren L, Huang SH, Yang QM, Wang P, et al. Inhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions. Sci Rep. 2017;7:981.Yao L, Fan P, Jiang Z, Viatchenko-Karpinski S, Wu Y, Kornyeyev D, et al. Nav1.5-dependent persistent Na+ influx activates CaMKII in rat ventricular myocytes and N1325S mice. Am J Physiol Cell Physiol. 2011;301:C577–86.Ma J, Luo A, Wu L, Wan W, Zhang P, Ren Z, et al. Calmodulin kinase II and protein kinase C mediate the effect of increased intracellular calcium to augment late sodium current in rabbit ventricular myocytes. Am J Physiol Cell Physiol. 2012;302:C1141–51.Antzelevitch C, Burashnikov A, Sicouri S, Belardinelli L. Electrophysiological basis for the antiarrhythmic actions of ranolazine. Heart Rhythm. 2011;8:1281–90.Verrier RL, Kumar K, Nieminen T, Belardinelli L. Mechanisms of ranolazine’s dual protection against atrial and ventricular fibrillation. Europace. 2013;15:317–24.Chorro FJ, del Canto I, Brines L, Such-Miquel L, Calvo C, Soler C, et al. Ranolazine attenuates the electrophysiological effects of myocardial stretch in Langendorff perfused rabbit hearts. Cardiovasc Drugs Ther. 2015;29:231–41.Belardinelli L, Liu G, Smith-Maxwell C, Wang WQ, el-Bizri N, Hirakawa R, et al. A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias. J Pharmacol Exp Ther. 2013;344:23–32.Sicouri S, Belardinelli L, Antzelevitch C. Antiarrhytmic effects of the highly selective late sodium channel current blocker GS-458967. Heart Rhyhm. 2013;10:1036–43.Koltun DO, Parkhill EQ, Elzein E, Kobayashi T, Notte GT, Kalla R, et al. Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (late INai) of the cardiac NaV 1.5 channel with improved efficacy and potency relative to ranolazine. Bioorg Med Chem Lett. 2016;26:3202–6.Bonatti R, Silva AF, Batatinha JA, Sobrado LF, Machado AD, Varone BB, et al. Selective late sodium current blockade with GS-458967 markedly reduces ischemia-induced atrial and ventricular repolarization alternans and ECG heterogeneity. Heart Rhythm. 2014;11:1827–35.Alves Bento AS, Bacic D, Saran Carneiro J, Nearing BD, Fuller H, Justo FA, et al. Selective late INa inhibition by GS-458967 exerts parallel suppression of catecholamine-induced hemodynamically significant ventricular tachycardia and T-wave alternans in an intact porcine model. Heart Rhyhm. 2015;12:2508–14.Carneiro JS, Bento AS, Bacic D, Nearing BD, Rajamani S, Belardinelli L, et al. The selective cardiac late sodium current inhibitor GS-458967 suppresses autonomically triggered atrial fibrillation in an intact porcine model. J Cardiovasc Electrophysiol. 2015;26:1364–9.Chorro FJ, Trapero I, Guerrero J, Such LM, Canoves J, Mainar L, et al. Modification of ventricular fibrillation activation patterns induced by local stretching. J Cardiovasc Electrophysiol. 2005;16:1087–96.Chorro FJ, Trapero I, Such-Miquel L, Pelechano F, Mainar L, Cánoves J, et al. Pharmacological modifications of the stretch-induced effects of ventricular fibrillation in perfused rabbit-hearts. Am J Physiol Heart Circ Physiol. 2009;297:H1860–9.Such-Miquel L, Chorro FJ, Guerrero J, Trapero I, Brines L, Zarzoso M, et al. Evaluation of the complexity of myocardial activation during ventricular fibrillation. An experimental study. Rev Esp Cardiol. 2013;66:177–84.Burashnikov A, Di Diego JM, Robert J, Goodrow RJ, Belardinelli L, Antzelevitch C. Atria are more sensitive than ventricles to GS-458967-induced inhibition of late sodium current. J Cardiovasc Pharmacol Ther. 2015;20:501–8.Weiss JN, Chen PS, Qu Z, Karagueuzian HS, Garfinkel A. Ventricular fibrillation: how do we stop the waves from breaking? Circ Res. 2000;87:1103–7.Del Canto I, Such-Miquel L, Brines L, Soler C, Zarzoso M, Calvo C, et al. Effects of JTV-519 on stretch-induced manifestations of mechanoelectric feedback. Clin Exp Pharmacol Physiol. 2016;43:1062–70.Pezhouman A, Madahian S, Stepanyan H, Ghukasyan H, Qu Z, Belardinelli L, et al. Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts. Heart Rhythm. 2014;11:492–501.Potet F, Vanoye CG, George AL. Use-dependent block of human cardiac sodium channels by GS967. Mol Pharmacol. 2016;90:52–60.Chorro FJ, Canto ID, Brines L, Such-Miquel L, Calvo C, Soler C, et al. Experimental study of the effects of EIPA, losartan, and BQ-123 on electrophysiological changes induced by myocardial stretch. Rev Esp Cardiol. 2015;68:1101–10.Ravelli F, Allessie MA. Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart. Circulation. 1997;96:1686–95.Reiter MJ, Synhorst DP, Mann DE. Electrophysiological effects of acute ventricular dilatation in the isolated rabbit heart. Circ Res. 1988;62:554–62.Chorro FJ, Egea S, Mainar L, Cánoves J, Sanchis J, Llavador E, et al. Acute modifications in the wavelength of the atrial excitation process induced by stretching. An experimental study. Rev Esp Cardiol. 1998;51:874–83.Iribe G, Jin H, Kaihara K, Naruse K. Effects of axial stretch on sarcolemmal BKCa channels in post-hatch chick ventricular myocytes. Exp Physiol. 2010;95:699–711.Calaghan SC, Belus A, White E. Do stretch-induced changes in intracellular calcium modify the electrical activity of cardiac muscle? Progr Biophys Mol Biol. 2003;82:81–95.Zhao HC, Agula H, Zhang W, Wang F, Sokabe M, Li LM. Membrane stretch and cytoplasmic Ca2+ independently modulate stretch-activated BK channel activity. J. Biomechanics. 2010;43:3015–9.Isenberg G, Kazanski V, Kondratev D, Gallitelli MF, Kiseleva I, Kamkin A. Differential effects of stretch and compression on membrane currents and [Na+]c in ventricular myocytes. Progr Biophys. Mol Biol. 2003;82:43–56.Kelly D, Mackenzie L, Hunter P, Smaill B, Saint DA. Gene expression of stretch-activated channels and mechanoelectric feedback in the heart. Clin Exp Pharmacol Physiol. 2006;33:642–8.Decher N, Kiper AK, Rinné S. Stretch-activated potassium currents in the heart: focus on TREK-1 and arrhythmias. Progr Biophys Mol Biol. 2017;130:223–32.Carmeliet E. Action potential duration, rate of stimulation, and intracellular sodium. J Cariovasc Electrophysiol. 2006;17(Suppl. I):S2–7.Wu L, Ma J, Li H, Wang C, Grandi E, Zhang P, et al. Late sodium current contributes to the reverse rate-dependent effect of Ikr inhibition on ventricular repolarization. Circulation. 2011;123:1713–20.Despa S, Bers DM. Na+ transport in the normal and failing heart—remember the balance. J Mol Cell Cardiol. 2013;61:2–10.Burashnikov A. Late INa inhibition as an antiarrhythmic strategy. J Cardiovasc Pharmacol. 2017;70:159–67.Zygmunt AC, Nesterenko VV, Rajamani S, Hu D, Barajas-Martinez H, Belardinelli L, et al. Mechanisms of atrial-selective block of Na+ channels by ranolazine: I. Experimental analysis of the use-dependent block. Am J Physiol Heart Circ Physiol. 2011;301:H1606–14.Kornyeyev D, El-Bizri N, Hirakawa R, Nguyen S, Viatchenko-Karpinski S, Yao L, et al. Contribution of the late sodium current to intracellular sodium and calcium overload in rabbit ventricular myocytes treated by anemone toxin. Am J Physiol Heart Circ Physiol. 2016;310:H426–35.Janvier NC, Boyett MR. The role of Na-Ca exchange current in the cardiac action potential. Cardiovasc Res. 1996;32:69–84.Karagueuzian HS, Pezhouman A, Angelini M, Olcese R. Enhanced late Na and Ca currents as effective antiarrhythmic drug targets. Front Pharmacol. 2017;8Remme CA, Bezzina CR. Sodium channel (Dys) function and cardiac arrhythmias. Cardiovasc Ther. 2010;28:287–94.Scirica BM, Morrow DA, Hod H, Murphy SA, Belardinelli L, Hedgepeth CM, et al. 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: results from the metabolic efficiency with ranolazine for less ischemia in non ST-elevation acute coronary syndrome thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation. 2007;116:1647–52.Shenasa M, Assadi H, Heidary S, Ranolazine SH. Electrophysiologic effect, efficacy, and safety in patients with cardiac arrhythmias. Card Electrophysiol Clin. 2016;8:467–79.Yu S, Li G, Huang CLH, Lei M, Wu L. Late sodium current associated cardiac electrophysiological and mechanical dysfunction. Pflugers Arch - Eur J Physiol. 2018;470:461–9.Gong M, Zhang Z, Fragakis N, Korantzopoulos P, Letsas KP, Li G, et al. Role of ranolazine in the prevention and treatment of atrial fibrillation: a meta-analysis of randomized clinical trials. Heart Rhythm. 2017;14:3–11
Recommended from our members
7th Drug hypersensitivity meeting: part two
Table of contents Poster walk 11: miscellaneous drug hypersensitivity 2 (P92–P94, P96–P101) P92 16 years of experience with proton pump inhibitors (PPIs) Javier Dionicio Elera, Cosmin Boteanu, Maria Aranzazu Jimenez Blanco, Rosario Gonzalez-Mendiola, Irene Carrasco García, Antonio Alvarez, Jose Julio Laguna Martinez P93 Allergy evaluation of quinolone induced adverse reactions Jaume Martí Garrido, Carla Torán Barona, Carolina Perales Chorda, Ramón López Salgueiro, Miguel Díaz Palacios, Dolores Hernández Fernández De Rojas P94 Bupropion-induced acute urticaria and angioedema, a case report Emre Ali Acar, Ayse Aktas, Aylin Türel Ermertcan, Peyker Temiz P96 Delayed type hypersensitivity and study of cross-reactivity between proton-pump inhibitors Chien-Yio Lin, Chung-Yee Rosaline Hui, Ya-Ching Chang, Chih-Hsun Yang, Wen-Hung Chung P97 Diagnostic work-up in suspected hypersensitivity to proton-pump inhibitors: looking at cross-reactivity Fabrícia Carolino, Diana Silva, Eunice Dias De Castro, Josefina R. Cernadas P98 Management of infusion-related hypersensitivity reactions to enzyme replacement therapy for lysosomal diseases Luis Felipe Ensina, Carolina Aranda, Ines Camelo Nunes, Alex Lacerda, Ana Maria Martins, Ekaterini Goudouris, Marcia Ribeiro, José Francisco Da Silva Franco, Leandra Queiroz, Dirceu Solé P99 Management of insulin allergy with continuous subcutaneous insulin infusion Ceyda Tunakan Dalgiç, Aytül Zerrin Sin, Fatma Düsünür Günsen, Gökten Bulut, Fatma Ömür Ardeniz, Okan Gülbahar, Emine Nihal Mete Gökmen, Ali Kokuludag P100 Off-label use of icatibant for management of serious angioedema associated with angiotensin inhibitors Ana M. Montoro De Francisco, Talía Mª De Vicente Jiménez, Adriana M. Mendoza Parra, Angella M. Burgos Pimentel, Amelia García Luque P101 Thiocolchicoside anaphylaxis: an unusual suspect? Luis Amaral, Fabricia Carolino, Leonor Carneiro Leão, Eunice Castro, Josefina Cernadas Poster walk 12: betalactam hypersensitivity (P102–P111) P102 A curious delayed reading: a case report of a β-lactam allergy in a child Nicole Pinto, Joana Belo, João Marques, Pedro Carreiro-Martins, Paula Leiria-Pinto P103 Betalactam-induced hypersensitivity: a 10-years’ experience Amel Chaabane, Haifa Ben Romdhane, Nadia Ben Fredj, Zohra Chadly, Naceur A. Boughattas, Karim Aouam P104 Cefazolin hypersensitivity: towards optimized diagnosis Astrid P. Uyttebroek, Chris H. Bridts, Antonino Romano, Didier G. Ebo, Vito Sabato P105 Clavulanic acid allergy: two cases report Anabela Lopes, Joana Cosme, Rita Aguiar, Tatiana Lourenço, Maria-João Paes, Amélia Spínola-Santos, Manuel Pereira-Barbosa P106 Diagnosis of betalactam allergy in an allergy department Cíntia Rito Cruz, Rute Pereira Dos Reis, Elza Tomaz, Ana Paula Pires, Filipe Inácio P107 Diagnostic work-up of 410 patients with suspicion of betalactam antibiotic hypersensitivity Filipe Benito-Garcia, Inês Mota, Magna Correia, Ângela Gaspar, Marta Chambel, Susana Piedade, Mário Morais-Almeida P108 Immediate selective hypersensitivity reactions to clavulanic acid Alla Nakonechna, Yurij Antipkin, Tetiana Umanets, Fernando Pineda, Francisca Arribas, Volodymyr Lapshyn P109 Prevalence and incidence of penicillin hypersensitivity reactions in Colombia Pablo Andrés Miranda, Bautista De La Cruz Hoyos P110 Selective sensitization to amoxicilin and clavulanic acid Jose Julio Laguna Martinez, Aranzazu Jimenez Blanco, Javier Dionicio Elera, Cosmin Boteanu, Rosario Gonzalez-Mendiola, Marta Del Pozo P111 Infliximab-specific T cells are detectable also in treated patients who have not developed anti-drug antibodies Alessandra Vultaggio, Francesca Nencini, Sara Pratesi, Andrea Matucci, Enrico Maggi Poster walk 13: biologicals, local anesthetics, others (P112–P118) P112 A case report of allergic immediate systemic reaction to adalimumab and certolizumab Ceyda Tunakan Dalgiç, Fatma Düsünür Günsen, Gökten Bulut, Fatma Ömür Ardeniz, Okan Gülbahar, Emine Nihal Mete Gökmen, Aytül Zerrin Sin, Ali Kokuludag P113 Allergy to local anesthetics: negative predictive value of skin tests Ivana Cegec, Danica Juricic Nahal, Viktorija Erdeljic Turk, Matea Radacic Aumiler, Ksenija Makar Ausperger, Iva Kraljickovic, Iveta Simic P114 Cutaneous adverse reactions of molecular targeted agents: a retrospective analysis in 150 patients in our department Yukie Yamaguchi, Tomoya Watanabe, Megumi Satoh, Tomohiko Tanegashima, Kayoko Oda, Hidefumi Wada, Michiko Aihara P115 Generalized paralysis induced by local lidocaine injection Jaechun Jason Lee, Jay Chol Choi, Hwa Young Lee P116 Hypersensitivity to local anaesthetics: a 10 year review Rosa-Anita Rodrigues Fernandes, Emília Faria, Joana Pita, Nuno Sousa, Carmelita Ribeiro, Isabel Carrapatoso, Ana Todo Bom P117 Local anaesthetics: a rare culprit in hypersensitivity reactions Ana Rodolfo, Eunice Dias-Castro, Josefina Cernadas P118 Stevens–Johnson syndrome in clinical practice: a variant of clinical course Marina Voronova Poster walk 14: RCM (P119–P128) P119 13 cases of severe anaphylactic reactions due to radiocontrast media Jaume Martí Garrido, Ramon Lopez Salgueiro, Diana Kury Valle, Verónica Pacheco Coronel, Carolina Perales Chordá, Dolores Hernandez Fernandez De Rojas P120 Anaphylactic shock after administration of iodinated contrast medium during cardiac catheterization Roselle Catherine Yu Madamba, Marta Ferrer, Maria Jose Goikoetxea, Carmen D’Amelio, Amalia Bernad, Olga Vega, Gabriel Gastaminza P121 Anaphylactic shock and cardiac arrest induced by gadolinium-based contrast agents Beatriz Pola Bibián, Marina Lluncor Salazar, Gemma Vilà Nadal, Ana María Fiandor Roman, Javier Dominguez Ortega, Miguel Gonzalez Muñoz, Santiago Quirce Gancedo, Maria Rosario Cabañas Moreno P122 Anaphylaxis to gadobenate and cross-reactivity to other gadolinium-based contrast agents in two patients Kathrin Scherer Hofmeier P123 Anaphylaxis to glatiramer acetate in a patient with multiple sclerosis Fabrícia Carolino, Vladyslava Barzylovych, Josefina R. Cernadas P124 Delayed hypersensitivity reaction to radiocontrast media Fabrícia Carolino, Diana Silva, Leonor Leão, Josefina R. Cernadas P125 Drug reaction with eosinophilia and systemic symptoms induced by iodixanol Gemma Vilà-Nadal, Beatriz Pola, Marina Lluncor, Ana Fiandor, Teresa Bellón, Javier Domínguez, Santiago Quirce P126 Electronic consultation support system for radiocontrast media hypersensitivity changes clinician’s behavior Min-Suk Yang, Sun-Sin Kim, Sae-Hoon Kim, Hye-Ryun Kang, Heung-Woo Park, Sang-Heon Cho, Kyung-Up Min, Yoon-Seok Chang P127 Hypersensitivity reactions to iodinated contrast media: skin testing and follow-up Danica Juricic Nahal, Ivana Cegec, Viktorija Erdeljic Turk, Iva Kraljickovic, Matea Radacic Aumiler, Ksenija Makar Ausperger, Iveta Simic P128 Would iodine allergy exist? Clémence Delahaye, Jenny Flabbee, Julie Waton, Olivia Bauvin, Annick Barbaud Poster walk 15: MPE/type 4 (P129–P137) P129 Delayed hypersensitivity cutaneous reactions: a case/control study from a tunisian database Karim Aouam, Najah Ben Fadhel, Zohra Chadly, Nadia Ben Fredj, Naceur A. Boughattas, Amel Chaabane P130 Delayed hypersensitivity reactions to cephalosporins: a review of seven cases Joana Cosme, Anabela Lopes, Amélia Spínola-Santos, Manuel Pereira-Barbosa P131 Diclofenac induced allergic contact dermatitis: case series of four patients Sandra Jerkovic Gulin, Anca Chiriac P132 Late-onset maculopapular rash to irbesartan Bárbara Kong Cardoso, Elza Tomaz, Regina Viseu, Filipe Inácio P133 Nonimmediate hypersensitivity reactions to betalactams: a retrospective analysis Ana Moreira, Susana Cadinha, Ana Castro Neves, Patricia Barreira, Daniela Malheiro, J. P. Moreira Da Silva P134 Occupational airborne contact dermatitis to omeprazole Ružica Jurakic-Toncic, Suzana Ljubojevic, Petra Turcic P135 Ornidazole-induced fixed drug eruption confirmed by positive patch test on a residual pigmented lesion Liesbeth Gilissen, Sara Huygens, An Goossens P136 Repeated delayed reaction induced by amoxicillin and amoxicillin clavulanate Inmaculada Andreu, Ramon Lopez-Salgueiro, Alicia Martinez Romero, Pau Gomez Cabezas P137 Systemic photosensitivity from fenofibrate in a patient photo-sensitized to ketoprofen Liesbeth Gilissen, An Goossens Poster walk 16: HLA genetics (P138–P146) P138 A copy number variation in ALOX5 and PTGER1 is associated with nonsteroidal anti-inflammatory drugs induced urticaria and/or angioedema Pedro Ayuso Parejo, Maria Del Carmen Plaza-Serón, Inmaculada Doña, Natalia Blanca López, Carlos Flores, Luisa Galindo, Ana Molina, James Richard Perkins, Jose Antonio Cornejo-García, José Augusto García-Agúndez, Elena García-Martín, Paloma Campo, María Gabriela Canto, Miguel Blanca P139 Association of galectin-3 (LGALS3) single nucleotide polymorphisms with non-steroidal anti-inflammatory drugs-induced urticaria/angioedema José Antonio Cornejo-Garcia, Inmaculada Doña, Rosa María Guéant-Rodríguez, Natalia Blanca-López, María Carmen Plaza-Serón, Raquel Jurado-Escobar, Esther Barrionuevo, María Salas, María Luisa Galindo, Gabriela Canto, Miguel Blanca, Jean-Louis Guéant P140 Detection of T cell responses to ticlopidine using peripheral blood mononuclear cells from HLA-A*33:03+ healthy donors Toru Usui, Arun Tailor, Lee Faulkner, John Farrell, Ana Alfirevic, B. Kevin Park, Dean J. Naisbitt P141 Epistasis approaches to identify novel genes potentially involved in NSAIDs hypersensitivity James Richard Perkins, Jose Antonio Cornejo García, Oswaldo Trelles, Inmaculada Doña, Esther Barrionuevo, María Salas, María Auxiliadora Guerrero, Miguel Blanca, Alex Upton P142 Genetic predisposition of cold medicine related SJS/TEN with severe ocular complications Mayumi Ueta, Hiromi Sawai, Chie Sotozono, Katushi Tokunaga, Shigeru Kinoshita P143 HLA-B*13:01 and dapsone induced hypersensitivity in Thai population Chonlaphat Chonlaphat Sukasem, Patompong Satapornpong, Therdpong Tempark, Pawinee Rerknimitr, Kulprapat Pairayayutakul, Jettanong Klaewsongkram P144 HLA-B*15:02 alleles and lamotrigine-induced cutaneous adverse drug reactions in Thai Chonlaphat Sukasem, N. Koomdee, T. Jantararoungtong, S. Santon, A. Puangpetch, U. Intusoma, W. Tassaneeyakul, V. Theeramoke P145 HLA-B*38:01 and HLA-A*24:02 allele frequencies in Spanish patients with lamotrigine-induced SCARs Teresa Bellón, Elena Ramirez, Alberto Manuel Borobia, Hoi Tong, Jose Luis Castañer, Francisco José De Abajo P146 Overrepresentation of a class II HLA haplotype in severe hypersensitivity type I reactions to carboplatin Violeta Régnier Galvao, Rebecca Pavlos, Elizabeth Mckinnon, Kristina Williams, Alicia Beeghly-Fadiel, Alec Redwood, Elizabeth Phillips, Mariana Castells Poster walk 17: in vivo diagnosis + sIgE (P147–P154) P147 Absence of specific Ig-e against beta-lactams 9 months after an allergic reaction to amoxicillin-clavulanic acid Elisa Boni, Marina Russello, Marina Mauro P148 Drug provocation tests in suspected opioid allergy Kok Loong Ue, Krzysztof Rutkowski P149 Improvement to the specific IgE cut-off in the assess of β-lactamic allergy Victor Soriano Gomis, Jorge Frances Ferre, Angel Esteban Rodriguez, Vicente Cantó Reig, Javier Fernandez Sanchez P150 Initial false negative specific IgE to gelatin in a patient with gelatin-induced anaphylaxis Christine Breynaert, Erna Van Hoeyveld, Rik Schrijvers P151 Inmediate reactions to beta-lactam antibiotics: pattern of skin test response over the time Jose Julio Laguna Martinez, Rosario Gonzalez Mendiola, Javier Dionicio Elera, Cosmin Boteanu, Aranzazu Jimenez Blanco, Marta Del Pozo, Raquel Fuentes Irigoyen P152 New fluorescent dendrimeric antigens for the evaluation of dendritic cell maturation as a test to detect allergy reactions to amoxicillin Daniel Collado, Yolanda Vida, Francisco Najera, Ezequiel Perez-Inestrosa, Pablo Mesa-Antunez, Cristobalina Mayorga, María José Torres, Miguel Blanca P153 Positive skin test or positive specific IgE to penicillin does not predict penicillin allergy Line K. Tannert, Charlotte G. Mortz, Per Stahl Skov, Carsten Bindslev-Jensen P154 Significance of skin testing and in vitro-analysis of neuromuscular blocking agents in diagnosis of perioperative drug hypersensitivity: evaluation of a negative control population Wolfgang Pfützner, Hannah Dörnbach, Johanna Visse, Michele Rauber, Christian Möbs Poster walk 18: in vitro/ex vivo (P155–P158, P160–P164) P155 Diagnostic value of the lymphocyte toxicity assay (LTA) and the in vitro platelet toxicity assay (IPTA) for β-lactam allergy Abdelbaset A. Elzagallaai, Lindsey Chow, Awatif M. Abuzgaia, Michael J. Rieder P156 Enzyme linked immunospot assay used in the diagnosis of severe cutaneous adverse reactions to antimicrobials Alec Redwood, Jason Trubiano, Rebecca Pavlos, Emily Woolnough, Kaija Stautins, Christina Cheng, Elizabeth Phillips P157 Evaluation of in vitro diagnostic methods for identifying the culprit drugs in drug hypersensitivity Kenichi Kato, Hiroaki Azukizawa, Takaaki Hanafusa, Ichiro Katayama P158 Ex-vivo expanded skin-infiltrating T cells from severe drug eruptions are reactive with causative drugs: a possible novel method for determination of causative drugs Toshiharu Fujiyama, Hideo Hashizume, Takatsune Umayahara, Taisuke Ito, Yoshiki Tokura P160 In vitro release of IL-2, IL-5 and IL-13 in diagnosis of patients with delayed-type nickel hypersensitivity Mira Silar, Mihaela Zidarn, Helena Rupnik, Peter Korosec P161 Single cell analysis of drug responsive T cells; identification of candidate drug reactive T cell receptors in abacavir and carbamazepine hypersensitivity Alec James Redwood, Kaija Strautins, Katie White, Abha Chopra, Katherine Konvinse, Shay Leary, Rebecca Pavlos, Simon Mallal, Elizabeth Phillips P162 Specificity and sensitivity of LTT in DRESS: analysis of agreement with the Spanish pharmacovigilance system probability algorithm Rosario Cabañas, Elena Ramirez, Ana María Fiandor, Teresa Bellón P163 The role of interleukin-22 in β-lactam hypersensitivity Andrew Sullivan, Paul Whitaker, Daniel Peckham, B. Kevin Park, Dean J. Naisbitt P164 Vancomycin-specific T cell responses and teicoplanin cross-reactivity Wei Yann Haw, Marta E. Polak, Carolann Mcguire, Michael R. Ardern-Jones Poster walk 19: BAT and biomarkers (P165–P173) P165 A combination of early biomarkers useful for the prediction of severe ADRs Yumi Aoyama, Tetsuo Shiohara P166 Basophil activation test in the diagnostic approach of reactions during general anaesthesia Ana Moreira, Susana Cadinha, Patrícia Barreira, Ana Castro Neves, Daniela Malheiro, Sara Correia, J. P. Moreira Da Silva P167 IL-10 can be related to successful desensitization Asli Gelincik, Semra Demir, Fatma Sen, Hamza Ugur Bozbey, Muge Olgac, Derya Unal, Raif Coskun, Bahauddin Colakoglu, Suna Buyuozturk, Esin Çatin-Aktas, Gunnur Deniz P168 Immediate reactions to proton pump inhibitors: value of basophil activation test Maria Salas, Jose Julio Laguna, Esther Barrionuevo, J. Dionicio, Tahia Fernandez, R. Gonzalez-Mendiola, I. Olazabal, Maria Dolores Ruiz, Miguel Blanca, Cristobalina Mayorga, Maria José Torres P169 Improvement of the elevated tryptase criterion to discriminate IgE from non-IgE mediated allergic reactions Gabriel Gastaminza, Alberto Lafuente, Carmen D’Amelio, Amalia Bernad, Olga Vega, Roselle Catherine Madamba, M. Jose Goikoetxea, Marta Ferrer, Jorge Núñez P170 Low expression of Tim-3 could serve as a biomarker for control and diagnose maculopapular exanthema induced by drugs Tahia Diana Fernández, Inmaculada Doña, Francisca Palomares, Rubén Fernández, Maria Salas, Esther Barrionuevo, Maria Isabel Sanchez, Miguel Blanca, Maria José Torres, Cristobalina Mayorga P171 Role of basophil activation test using two different activation markers for the diagnosis of allergy to fluoroquinolones Esther Barrionuevo, Tahía Fernandez, Arturo Ruiz, Adriana Ariza, Maria Salas, Inmaculada Doña, Ana Molina, Miguel Blanca, Maria Jose Torres, Cristobalina Mayorga P172 The importance of basophil activation test in anaphylaxis due to celecoxib Amalia Bernad Alonso, Carmen D’Amelio Garófalo, Olga Vega Matute, Marta Ferrer Puga, María José Goikoetxea Lapresa, Roselle Catherine Yu Madamba, Gabriel Gastaminza Lasarte P173 The role of basophil activation test in the diagnosis of immediate type drug hypersensitivity to betalactam antibiotics Antonia Thinnes, Hans F. Merk, Jens Malte Baron, Martin Leverkus, Galina Balakirski Poster walk 20: TCR recognition, cellular (P174–P183) P174 Characterisation of the effect of co-inhibitory signalling on the activation of drug-derived antigen-specific T-cells Andrew Gibson, Monday Ogese, Lee Faulkner, B. Kevin Park, Dean J. Naisbitt P175 Characterization of drug hapten-specific T cell responses in piperacillin hypersensitive patients Zaid Al-Attar, Fiazia Yaseen, Xiaoli Meng, Rozalind Jenkins, Paul Whitaker, Daniel Peckham, Lee Faulkner, John Farrel, Kevin Park, Dean Naisbitt P176 Characterization of the response of T-cells to telaprevir and its metabolite in normal volunteers Zaid Al-Attar, Khetam Alhilali, Yanni Xue, John Farrell, Lee Faulkner, Kevin Park, Dean Naisbitt P177 Characterization of the T cell receptor signatures of drug-responsive T cells Patricia Illing, Nicole Mifsud, Heidi Fettke, Jeffrey Lai, Rebecca Ho, Patrick Kwan, Anthony Purcell P178 Defining the signals between hepatocytes and immune cells in idiosyncratic drug-induced liver injury (DILI) Monday O. Ogese, Lee Faulkner, B. Kevin Park, Catherine Betts, Dean J. Naisbitt P179 Development of novel chemicals that do not bind to HLA-B*57:01 or activate CD8 + T-cells through modification of the 6-amino cyclopropyl group of abacavir Paul Thomson, John Farrell, Mohammad Alhaidari, Neill Berry, Paul M. O’Neill, B. Kevin Park, Dean J. Naisbitt P180 Generation and characterization of dapsone- and nitroso-dapsone-specific T-cell clones using lymphocytes from healthy volunteers Abdulaziz Alzahrani, Monday O. Ogese, John Farrell, Lee Faulkner, Andrew Gibson, Arun Tailor, B. Kevin Park, Dean J. Naisbitt P181 Identification of benzylpenicillin-hapten peptides responsible for naïve T-cell activation and immunization of allergic patients to penicillin Marie Eliane Azoury, Lucia Fili, Rami Bechara, Noémie Scornet, Cathy Nhim, Richard Weaver, Nancy Claude, Delphine Joseph, Bernard Maillere, Paola Parronchi, Marc Pallardy P182 Massive expansion of clonotypic and polycytotoxic CD8+ T cells in toxic epidermal necrolysis Axel Patrice Villani, Aurore Rozières, Benoît Bensaïd, Mathilde Tardieu, Floriane Albert, Virginie Mutez, Tugba Baysal, Marc Pallardy, Janet Maryanski, Jean-François Nicolas, Osami Kanagawa, Marc Vocanson P183 Pharmaco-immunological synapse of HLA-drug-TCR in SCAR Shuen-Iu Hung Poster walk 21: new in vitro methods, haptens, etc. (P184–P194) P184 Amoxicillin-clavulanate forms distinct multiple haptenic structures on human serum albumin in patients Xiaoli Meng, Arun Tailor, Caroline J. Harrison, Rosalind E. Jenkins, Paul Whitaker, Neil S. French, Dean J. Naisbitt, B. Kevin Park P185 Dendrimeric antigens for studying the influence of penicillin determinants orientation on IgE recognition Maria Isabel Montañez, Cristobalina Mayorga, Francisco Najera, Adriana Ariza, Tahia D. Fernandez, Maria Salas, Angela Martin-Serrano, Miguel Blanca, Ezequiel Perez-Inestrosa, Maria Jose Torres P186 Dendrimeric antigens on solid supports: designed materials for IgE quantification Yolanda Vida, Maria Isabel Montañez, Noemi Molina, Daniel Collado, Francisco Najera, Adriana Ariza, Maria Jose Torres, Cristobalina Mayorga, Ezequiel Perez-Inestrosa P187 Development of a screening assay for drug hypersensitivity using naïve T cells from donors with seven different HLA class I risk alleles Lee Faulkner, Sally Wood, Ana Alfirevic, Munir Pirmohamed, Dean J. Naisbitt, B. Kevin Park P188 Different patterns of recognition of structures derived from amoxicillin by IgE antibodies from patients with immediate hypersensitivity reactions to betalactams Adriana Ariza, Cristobalina Mayorga, María Isabel Montañez, María Salas, Inmaculada Doña, Ángela Martín-Serrano, Ezequiel Pérez-Inestrosa, Dolores Pérez-Sala, Miguel Blanca, Antonio E. Guzmán, María José Torres P189 High-resolution typing of HLA polymorphism and T-cell receptor repertoire for severe adverse drug reactions based on the cost-effective next-generation sequencing approaches Tai-Ming Ko, Yuan-Tsong Chen, Jer-Yuarn Wu P190 Identification and fate of intracellular proteins haptenated by amoxicillin Francisco J. Sánchez-Gómez, Juan M. González-Morena, Yolanda Vida, Ezequiel Pérez-Inestrosa, Miguel Blanca, María J. Torres, Dolores Pérez-Sala P191 In vitro detection of terbinafine protein adducts Arun Tailor, Toru Usui, Yanni Xue, Xiaoli Meng, Dean J. Naisbitt, B. Kevin Park P192 MicroRNAs dysregulation in PBMCs from drug hypersensitivity patients during drug challenge in vitro Alejandra Monroy Arreola, Jesus Agustin Badillo Corona, Silvia Mendez Flores, Judith Dominguez Cherit, Dean J. Naisbitt, Noe Valentin Duran Figueroa, Jose Luis Castrejon Flores P193 NSAIDs-exacerbated cutaneous disease: high throughput gene expression profiling José Antonio Cornejo-García, James Perkins, Natalia Blanca-López, Diana Pérez-Alzate, Raquel Jurado-Escobar, Inmaculada Doña, Gador Bogas, María J. Torres, Gabriela Canto, Miguel Blanca P194 Utility of skin tests in non-immediate reactions to amoxicillin Luis Mario Tubella Marti, Fernando Pineda De La Losa, Francisca Arribas Poves, Jaime Tubella Lopez, Teodora Lopez Santiag