Differential Modulation of I-K and I-Ca,I-L Channels in High-Fat Diet-Induced Obese Guinea Pig Atria

[EN] Obesity mechanisms that make atrial tissue vulnerable to arrhythmia are poorly understood. Voltage-dependent potassium (I-K, I-Kur, and I-K1) and L-type calcium currents (I-Ca,I- L) are electrically relevant and represent key substrates for modulation in obesity. We investigated whether electrical remodeling produced by high-fat diet (HFD) alone or in concert with acute atrial stimulation were different. Electrophysiology was used to assess atrial electrical function after short-term HFD-feeding in guinea pigs. HFD atria displayed spontaneous beats, increased I-K (I-Kr + I-Ks) and decreased I-Ca,I- L densities. Only with pacing did a reduction in I-Kur and increased I-K1 phenotype emerge, leading to a further shortening of action potential duration. Computer modeling studies further indicate that the measured changes in potassium and calcium current densities contribute prominently to shortened atrial action potential duration in human heart. Our data are the first to show that multiple mechanisms (shortened action potential duration, early after depolarizations and increased incidence of spontaneous beats) may underlie initiation of supraventricular arrhythmias in obese guinea pig hearts. These results offer different mechanistic insights with implications for obese patients harboring supraventricular arrhythmias.This study was supported by an AHA (13SDG16850065 to AA), NIH (R01 HL147044 to AA), and Programa Prometeu de la Conselleria d Educació, Formació I Ocupació de la Generalitat Valenciana, award number PROMETEU/2016/088.Martínez-Mateu, L.; Saiz Rodríguez, FJ.; Aromolaran, A. (2019). Differential Modulation of I-K and I-Ca,I-L Channels in High-Fat Diet-Induced Obese Guinea Pig Atria. Frontiers in Physiology. 10:1-18. https://doi.org/10.3389/fphys.2019.01212S11810Abed, H. S., & Wittert, G. A. (2013). Obesity and atrial fibrillation. Obesity Reviews, 14(11), 929-938. doi:10.1111/obr.12056Angelin, B., Olivecrona, H., Reihnér, E., Rudling, M., Ståhlberg, D., Eriksson, M., … Einarsson, K. (1992). Hepatic cholesterol metabolism in estrogen-treated men. Gastroenterology, 103(5), 1657-1663. doi:10.1016/0016-5085(92)91192-7Aoki, Y., Hatakeyama, N., Yamamoto, S., Kinoshita, H., Matsuda, N., Hattori, Y., & Yamazaki, M. (2012). Role of ion channels in sepsis-induced atrial tachyarrhythmias in guinea pigs. British Journal of Pharmacology, 166(1), 390-400. doi:10.1111/j.1476-5381.2011.01769.xAromolaran, A. S., & Boutjdir, M. (2017). Cardiac Ion Channel Regulation in Obesity and the Metabolic Syndrome: Relevance to Long QT Syndrome and Atrial Fibrillation. Frontiers in Physiology, 8. doi:10.3389/fphys.2017.00431Aromolaran, A. S., Colecraft, H. M., & Boutjdir, M. (2016). High-fat diet-dependent modulation of the delayed rectifier K + current in adult guinea pig atrial myocytes. Biochemical and Biophysical Research Communications, 474(3), 554-559. doi:10.1016/j.bbrc.2016.04.113Aromolaran, A. S., Subramanyam, P., Chang, D. D., Kobertz, W. R., & Colecraft, H. M. (2014). LQT1 mutations in KCNQ1 C-terminus assembly domain suppress IKs using different mechanisms. Cardiovascular Research, 104(3), 501-511. doi:10.1093/cvr/cvu231Ashrafi, R., Yon, M., Pickavance, L., Yanni Gerges, J., Davis, G., Wilding, J., … Boyett, M. (2016). Altered Left Ventricular Ion Channel Transcriptome in a High-Fat-Fed Rat Model of Obesity: Insight into Obesity-Induced Arrhythmogenesis. Journal of Obesity, 2016, 1-12. doi:10.1155/2016/7127898Bai, J., Gladding, P. A., Stiles, M. K., Fedorov, V. V., & Zhao, J. (2018). Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells. Scientific Reports, 8(1). doi:10.1038/s41598-018-33958-yBarana, A., Matamoros, M., Dolz-Gaitón, P., Pérez-Hernández, M., Amorós, I., Núñez, M., … Caballero, R. (2014). Chronic Atrial Fibrillation Increases MicroRNA-21 in Human Atrial Myocytes Decreasing L-Type Calcium Current. Circulation: Arrhythmia and Electrophysiology, 7(5), 861-868. doi:10.1161/circep.114.001709Bar�, I., & Escande, D. (1989). A Ca2+-activated K+ current in guinea-pig atrial myocytes. Pfl�gers Archiv European Journal of Physiology, 414(S1), S168-S168. doi:10.1007/bf00582286Bar�, I., & Escande, D. (1989). A long lasting Ca2+ -activated outward current in guinea-pig atrial myocytes. Pfl�gers Archiv European Journal of Physiology, 415(1), 63-71. doi:10.1007/bf00373142Bhuyan, R., & Seal, A. (2016). Dynamics and modulation studies of human voltage gated Kv1.5 channel. Journal of Biomolecular Structure and Dynamics, 35(2), 380-398. doi:10.1080/07391102.2016.1144528Boden, G., She, P., Mozzoli, M., Cheung, P., Gumireddy, K., Reddy, P., … Ruderman, N. (2005). Free Fatty Acids Produce Insulin Resistance and Activate the Proinflammatory Nuclear Factor- B Pathway in Rat Liver. Diabetes, 54(12), 3458-3465. doi:10.2337/diabetes.54.12.3458Bosch, R. F., Schneck, A. C., Csillag, S., Eigenberger, B., Gerlach, U., Brendel, J., … Kühlkamp, V. (2003). Effects of the chromanol HMR 1556 on potassium currents in atrial myocytes. Naunyn-Schmiedeberg’s Archives of Pharmacology, 367(3), 281-288. doi:10.1007/s00210-002-0672-5BOUTJDIR, M., HEUZEY, J. Y., LAVERGNE, T., CHAUVAUD, S., GUIZE, L., CARPENTIER, A., & PERONNEAU, P. (1986). Inhomogeneity of Cellular Refractoriness in Human Atrium: Factor of Arrhythmia?. Pacing and Clinical Electrophysiology, 9(6), 1095-1100. doi:10.1111/j.1540-8159.1986.tb06676.xBrundel, B. J. J. M., Van Gelder, I. C., Henning, R. H., Tieleman, R. G., Tuinenburg, A. E., Wietses, M., … Crijns, H. J. G. M. (2001). Ion Channel Remodeling Is Related to Intraoperative Atrial Effective Refractory Periods in Patients With Paroxysmal and Persistent Atrial Fibrillation. Circulation, 103(5), 684-690. doi:10.1161/01.cir.103.5.684Bünemann, M., Liliom, K., Brandts, B. K., Pott, L., Tseng, J. L., Desiderio, D. M., … Tigyi, G. (1996). A novel membrane receptor with high affinity for lysosphingomyelin and sphingosine 1-phosphate in atrial myocytes. The EMBO Journal, 15(20), 5527-5534. doi:10.1002/j.1460-2075.1996.tb00937.xCaballero, R., de la Fuente, M. G., Gómez, R., Barana, A., Amorós, I., Dolz-Gaitón, P., … Delpón, E. (2010). In Humans, Chronic Atrial Fibrillation Decreases the Transient Outward Current and Ultrarapid Component of the Delayed Rectifier Current Differentially on Each Atria and Increases the Slow Component of the Delayed Rectifier Current in Both. Journal of the American College of Cardiology, 55(21), 2346-2354. doi:10.1016/j.jacc.2010.02.028Caillier, B., Pilote, S., Patoine, D., Levac, X., Couture, C., Daleau, P., … Drolet, B. (2012). Metabolic syndrome potentiates the cardiac action potential-prolonging action of drugs: A possible ‘anti-proarrhythmic’ role for amlodipine. Pharmacological Research, 65(3), 320-327. doi:10.1016/j.phrs.2011.11.015Chiu, H.-C., Kovacs, A., Ford, D. A., Hsu, F.-F., Garcia, R., Herrero, P., … Schaffer, J. E. (2001). A novel mouse model of lipotoxic cardiomyopathy. Journal of Clinical Investigation, 107(7), 813-822. doi:10.1172/jci10947Christ, T., Boknik, P., Wöhrl, S., Wettwer, E., Graf, E. M., Bosch, R. F., … Dobrev, D. (2004). L-Type Ca2+Current Downregulation in Chronic Human Atrial Fibrillation Is Associated With Increased Activity of Protein Phosphatases. Circulation, 110(17), 2651-2657. doi:10.1161/01.cir.0000145659.80212.6aCourtemanche, M., Ramirez, R. J., & Nattel, S. (1998). Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model. American Journal of Physiology-Heart and Circulatory Physiology, 275(1), H301-H321. doi:10.1152/ajpheart.1998.275.1.h301Czick, M. E., Shapter, C. L., & Silverman, D. I. (2016). Atrial Fibrillation: The Science behind Its Defiance. Aging and Disease, 7(5), 635. doi:10.14336/ad.2016.0211Dan, G.-A., & Dobrev, D. (2018). Antiarrhythmic drugs for atrial fibrillation: Imminent impulses are emerging. IJC Heart & Vasculature, 21, 11-15. doi:10.1016/j.ijcha.2018.08.005Daoud, E. G., Knight, B. P., Weiss, R., Bahu, M., Paladino, W., Goyal, R., … Morady, F. (1997). Effect of Verapamil and Procainamide on Atrial Fibrillation–Induced Electrical Remodeling in Humans. Circulation, 96(5), 1542-1550. doi:10.1161/01.cir.96.5.1542De Sensi, F., Costantino, S., Limbruno, U., & Paneni, F. (2019). Atrial fibrillation in the cardiometabolic patient. Minerva Medica, 110(2). doi:10.23736/s0026-4806.18.05882-2Dey, S., DeMazumder, D., Sidor, A., Foster, D. B., & O’Rourke, B. (2018). Mitochondrial ROS Drive Sudden Cardiac Death and Chronic Proteome Remodeling in Heart Failure. Circulation Research, 123(3), 356-371. doi:10.1161/circresaha.118.312708Diness, J. G., Sørensen, U. S., Nissen, J. D., Al-Shahib, B., Jespersen, T., Grunnet, M., & Hansen, R. S. (2010). Inhibition of Small-Conductance Ca 2+ -Activated K + Channels Terminates and Protects Against Atrial Fibrillation. Circulation: Arrhythmia and Electrophysiology, 3(4), 380-390. doi:10.1161/circep.110.957407Djoussé, L., Benkeser, D., Arnold, A., Kizer, J. R., Zieman, S. J., Lemaitre, R. N., … Ix, J. H. (2013). Plasma Free Fatty Acids and Risk of Heart Failure. Circulation: Heart Failure, 6(5), 964-969. doi:10.1161/circheartfailure.113.000521Ehrlich, J. R., Ocholla, H., Ziemek, D., Rütten, H., Hohnloser, S. H., & Gögelein, H. (2008). Characterization of Human Cardiac Kv1.5 Inhibition by the Novel Atrial-selective Antiarrhythmic Compound AVE1231. Journal of Cardiovascular Pharmacology, 51(4), 380-387. doi:10.1097/fjc.0b013e3181669030Feng, J., Yue, L., Wang, Z., & Nattel, S. (1998). Ionic Mechanisms of Regional Action Potential Heterogeneity in the Canine Right Atrium. Circulation Research, 83(5), 541-551. doi:10.1161/01.res.83.5.541Fernandez, M. L., Conde, A. K., Ruiz, L. R., Montano, C., Ebner, J., & McNamara, D. J. (1995). Carbohydrate type and amount alter intravascular processing and catabolism of plasma lipoproteins in guinea pigs. Lipids, 30(7), 619-626. doi:10.1007/bf02536998Fretts, A. M., Mozaffarian, D., Siscovick, D. S., Djousse, L., Heckbert, S. R., King, I. B., … Lemaitre, R. N. (2014). Plasma Phospholipid Saturated Fatty Acids and Incident Atrial Fibrillation: The Cardiovascular Health Study. Journal of the American Heart Association, 3(3). doi:10.1161/jaha.114.000889Gaborit, N., Steenman, M., Lamirault, G., Le Meur, N., Le Bouter, S., Lande, G., … Demolombe, S. (2005). Human Atrial Ion Channel and Transporter Subunit Gene-Expression Remodeling Associated With Valvular Heart Disease and Atrial Fibrillation. Circulation, 112(4), 471-481. doi:10.1161/circulationaha.104.506857Garnvik, L. E., Malmo, V., Janszky, I., Wisløff, U., Loennechen, J. P., & Nes, B. M. (2018). Physical activity modifies the risk of atrial fibrillation in obese individuals: The HUNT3 study. European Journal of Preventive Cardiology, 25(15), 1646-1652. doi:10.1177/2047487318784365Gaspo, R., Bosch, R. F., Talajic, M., & Nattel, S. (1997). Functional Mechanisms Underlying Tachycardia-Induced Sustained Atrial Fibrillation in a Chronic Dog Model. Circulation, 96(11), 4027-4035. doi:10.1161/01.cir.96.11.4027Goette, A., Honeycutt, C., & Langberg, J. J. (1996). Electrical Remodeling in Atrial Fibrillation. Circulation, 94(11), 2968-2974. doi:10.1161/01.cir.94.11.2968González de la Fuente, M., Barana, A., Gómez, R., Amorós, I., Dolz-Gaitón, P., Sacristán, S., … Delpón, E. (2012). Chronic atrial fibrillation up-regulates β1-Adrenoceptors affecting repolarizing currents and action potential duration. Cardiovascular Research, 97(2), 379-388. doi:10.1093/cvr/cvs313Grandi, E., Dobrev, D., & Heijman, J. (2019). Computational modeling: What does it tell us about atrial fibrillation therapy? International Journal of Cardiology, 287, 155-161. doi:10.1016/j.ijcard.2019.01.077Grandi, E., Pandit, S. V., Voigt, N., Workman, A. J., Dobrev, D., Jalife, J., & Bers, D. M. (2011). Human Atrial Action Potential and Ca2+Model. Circulation Research, 109(9), 1055-1066. doi:10.1161/circresaha.111.253955HADIAN, D., ZIPES, D. P., OLGIN, J. E., & MILLER, J. M. (2002). Short-Term Rapid Atrial Pacing Produces Electrical Remodeling of Sinus Node Function in Humans. Journal of Cardiovascular Electrophysiology, 13(6), 584-586. doi:10.1046/j.1540-8167.2002.00584.xHeijman, J., Guichard, J.-B., Dobrev, D., & Nattel, S. (2018). Translational Challenges in Atrial Fibrillation. Circulation Research, 122(5), 752-773. doi:10.1161/circresaha.117.311081Huang, H., Amin, V., Gurin, M., Wan, E., Thorp, E., Homma, S., & Morrow, J. P. (2013). Diet-induced obesity causes long QT and reduces transcription of voltage-gated potassium channels. Journal of Molecular and Cellular Cardiology, 59, 151-158. doi:10.1016/j.yjmcc.2013.03.007Hume, J. R., & Uehara, A. (1985). Ionic basis of the different action potential configurations of single guinea-pig atrial and ventricular myocytes. The Journal of Physiology, 368(1), 525-544. doi:10.1113/jphysiol.1985.sp015874INOUE, M., INOUE, D., ISHIBASHI, K., SAKAI, R., OMORI, I., YAMAHARA, Y., … NAKAGAWA, M. (1993). Effects of Pilsicainide on the Atrial Fibrillation Threshold in Guinea Kg Atria. A Comparative Study with Disopyramide, Lidocaine and Flecainide. Japanese Heart Journal, 34(3), 301-312. doi:10.1536/ihj.34.301Inoue, D., Shirayama, T., Omori, I., Inoue, M., Sakai, R., Ishibashi, K., … Nakagawa, M. (1993). Electrophysiological effects of flecainide acetate on stretched guinea pig left atrial muscle fibers. Cardiovascular Drugs and Therapy, 7(3), 373-378. doi:10.1007/bf00880161Iwasaki, Y., Nishida, K., Kato, T., & Nattel, S. (2011). Atrial Fibrillation Pathophysiology. Circulation, 124(20), 2264-2274. doi:10.1161/circulationaha.111.019893Jensen, M. D., Ryan, D. H., Apovian, C. M., Ard, J. D., Comuzzie, A. G., Donato, K. A., … Yanovski, S. Z. (2013). 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults. Circulation, 129(25 suppl 2), S102-S138. doi:10.1161/01.cir.0000437739.71477.eeJi, Y., Varkevisser, R., Opacic, D., Bossu, A., Kuiper, M., Beekman, J. D. M., … van der Heyden, M. A. G. (2017). The inward rectifier current inhibitor PA-6 terminates atrial fibrillation and does not cause ventricular arrhythmias in goat and dog models. British Journal of Pharmacology, 174(15), 2576-2590. doi:10.1111/bph.13869Kanner, S. A., Jain, A., & Colecraft, H. M. (2018). Development of a High-Throughput Flow Cytometry Assay to Monitor Defective Trafficking and Rescue of Long QT2 Mutant hERG Channels. Frontiers in Physiology, 9. doi:10.3389/fphys.2018.00397Killeen, M. J., Sabir, I. N., Grace, A. A., & Huang, C. L.-H. (2008). Dispersions of repolarization and ventricular arrhythmogenesis: Lessons from animal models. Progress in Biophysics and Molecular Biology, 98(2-3), 219-229. doi:10.1016/j.pbiomolbio.2008.10.008Killeen, M. J., Thomas, G., Sabir, I. N., Grace, A. A., & Huang, C. L.-H. (2008). Mouse models of human arrhythmia syndromes. Acta Physiologica, 192(4), 455-469. doi:10.1111/j.1748-1716.2007.01822.xKoivumäki, J. T., Korhonen, T., & Tavi, P. (2011). Impact of Sarcoplasmic Reticulum Calcium Release on Calcium Dynamics and Action Potential Morphology in Human Atrial Myocytes: A Computational Study. PLoS Computational Biology, 7(1), e1001067. doi:10.1371/journal.pcbi.1001067LAU, C.-P., TSE, H.-F., SIU, C.-W., & GBADEBO, D. (2012). Atrial Electrical and Structural Remodeling: Implications for Racial Differences in Atrial Fibrillation. Journal of Cardiovascular Electrophysiology, 23, s36-s40. doi:10.1111/jce.12022Leopoldo, A. S., Lima-Leopoldo, A. P., Sugizaki, M. M., Nascimento, A. F. do, de Campos, D. H. S., Luvizotto, R. de A. M., … Cicogna, A. C. (2011). Involvement of L-type calcium channel and serca2a in myocardial dysfunction induced by obesity. Journal of Cellular Physiology, 226(11), 2934-2942. doi:10.1002/jcp.22643Lima-Leopoldo, A. P., Leopoldo, A. S., Silva, D. C. T., Nascimento, A. F. do, Campos, D. H. S. de, Luvizotto, R. de A. M., … Cicogna, A. C. (2013). Influence of Long-Term Obesity on Myocardial Gene Expression. Arquivos Brasileiros de Cardiologia, 100(3). doi:10.5935/abc.20130045Lima-Leopoldo, A. P., Sugizaki, M. M., Leopoldo, A. S., Carvalho, R. F., Nogueira, C. R., Nascimento, A. F., … Cicogna, A. C. (2008). Obesity induces upregulation of genes involved in myocardial Ca2+ handling. Brazilian Journal of Medical and Biological Research, 41(7), 615-620. doi:10.1590/s0100-879x2008000700011Liu, T., Takimoto, E., Dimaano, V. L., DeMazumder, D., Kettlewell, S., Smith, G., … O’Rourke, B. (2014). Inhibiting Mitochondrial Na + /Ca 2+ Exchange Prevents Sudden Death in a Guinea Pig Model of Heart Failure. Circulation Research, 115(1), 44-54. doi:10.1161/circresaha.115.303062Mancarella, S., Yue, Y., Karnabi, E., Qu, Y., El-Sherif, N., & Boutjdir, M. (2008). Impaired Ca2+ homeostasis is associated with atrial fibrillation in the α1D L-type Ca2+ channel KO mouse. American Journal of Physiology-Heart and Circulatory Physiology, 295(5), H2017-H2024. doi:10.1152/ajpheart.00537.2008Mangoni, M. E., Couette, B., Bourinet, E., Platzer, J., Reimer, D., Striessnig, J., & Nargeot, J. (2003). Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity. Proceedings of the National Academy of Sciences, 100(9), 5543-5548. doi:10.1073/pnas.0935295100Martinez-Mateu, L., Romero, L., Ferrer-Albero, A., Sebastian, R., Rodríguez Matas, J. F., Jalife, J., … Saiz, J. (2018). Factors affecting basket catheter detection of real and phantom rotors in the atria: A computational study. PLOS Computational Biology, 14(3), e1006017. doi:10.1371/journal.pcbi.1006017Matafome, P., & Seiça, R. (2017). Function and Dysfunction of Adipose Tissue. Obesity and Brain Function, 3-31. doi:10.1007/978-3-319-63260-5_1Matsimra, H., & Ehara, T. (1997). Selective Enhancement of the Slow Component of Delayed Rectifier K+Current in Guinea-Pig Atrial Cells by External ATP. The Journal of Physiology, 503(1), 45-54. doi:10.1111/j.1469-7793.1997.045bi.xMichael, G., Xiao, L., Qi, X.-Y., Dobrev, D., & Nattel, S. (2008). Remodelling of cardiac repolarization: how homeostatic responses can lead to arrhythmogenesis. Cardiovascular Research, 81(3), 491-499. doi:10.1093/cvr/cvn266Mickelson, A. V., & Chandra, M. (2017). Hypertrophic cardiomyopathy mutation in cardiac troponin T (R95H) attenuates length-dependent activation in guinea pig cardiac muscle fibers. American Journal of Physiology-Heart and Circulatory Physiology, 313(6), H1180-H1189. doi:10.1152/ajpheart.00369.2017Nakaya, H., Furusawa, Y., Ogura, T., Tamagawa, M., & Uemura, H. (2000). Inhibitory effects of JTV-519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea-pig hearts. British Journal of Pharmacology, 131(7), 1363-1372. doi:10.1038/sj.bjp.0703713Nattel, S. (2002). New ideas about atrial fibrillation 50 years on. Nature, 415(6868), 219-226. doi:10.1038/415219aNattel, S., & Dobrev, D. (2017). Controversies About Atrial Fibrillation Mechanisms. Circulation Research, 120(9), 1396-1398. doi:10.1161/circresaha.116.310489Nattel, S., & Harada, M. (2014). Atrial Remodeling and Atrial Fibrillation. Journal of the American College of Cardiology, 63(22), 2335-2345. doi:10.1016/j.jacc.2014.02.555Nerbonne, J. M., & Kass, R. S. (2005). Molecular Physiology of Cardiac Repolarization. Physiological Reviews, 85(4), 1205-1253. doi:10.1152/physrev.00002.2005Ni, H., Whittaker, D. G., Wang, W., Giles, W. R., Narayan, S. M., & Zhang, H. (2017). Synergistic Anti-arrhythmic Effects in Human Atria with Combined Use of Sodium Blockers and Acacetin. Frontiers in Physiology, 8. doi:10.3389/fphys.2017.00946O’Connell, R. P., Musa, H., Gomez, M. S. M., Avula, U. M., Herron, T. J., Kalifa, J., & Anumonwo, J. M. B. (2015). Free Fatty Acid Effects on the Atrial Myocardium: Membrane Ionic Currents Are Remodeled by the Disruption of T-Tubular Architecture. PLOS ONE, 10(8), e0133052. doi:10.1371/journal.pone.0133052OCHI, R., MOMOSE, Y., OYAMA, K., & GILES, W. (2006). Sphingosine-1-phosphate effects on guinea pig atrial myocytes: Alterations in action potentials and K+ currents. Cardiovascular Research, 70(1), 88-96. doi:10.1016/j.cardiores.2006.01.010O’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.00785.2011Osadchii, O. E. (2012). Electrophysiological determinants of arrhythmic susceptibility upon endocardial and epicardial pacing in guinea-pig heart. Acta Physiologica, 205(4), 494-506. doi:10.1111/j.1748-1716.2012.02428.xPatoine, D., Levac, X., Pilote, S., Drolet, B., & Simard, C. (2013). Decreased CYP3A Expression and Activity in Guinea Pig Models of Diet-Induced Metabolic Syndrome: Is Fatty Liver Infiltration Involved? Drug Metabolism and Disposition, 41(5), 952-957. doi:10.1124/dmd.112.050641Paulino, E. C., Ferreira, J. C. B., Bechara, L. R., Tsutsui, J. M., Mathias, W., Lima, F. B., … Negrão, C. E. (2010). Exercise Training and Caloric Restriction Prevent Reduction in Cardiac Ca 2+ -Handling Protein Profile in Obese Rats. Hypertension, 56(4), 629-635. doi:10.1161/hypertensionaha.110.156141Pérez-Hernández, M., Matamoros, M., Barana, A., Amorós, I., Gómez, R., Núñez, M., … Caballero, R. (2015). Pitx2c increases in atrial myocytes from chronic atrial fibrillation patients enhancingIKsand decreasingICa,L. Cardiovascular Research, 109(3), 431-441. doi:10.1093/cvr/cvv280A, P., H, C., MC, F., L, B., JN, W., & HS, K. (2018). Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Eff

Radio-frequency heating of the cornea: theoretical model and in vitro experiments

[EN] We present a theoretical model for the study of cornea heating with radio-frequency currents. This technique is used to reshape the cornea to correct refractive disorders. Our numerical model has allowed the study of the temperature distributions in the cornea and to estimate the dimensions of the lesion. The model incorporates a fragment of cornea, aqueous humor, and the active electrode placed on the cornea surface. The finite element method has been used to calculate the temperature distribution in the cornea by solving a coupled electric-thermal problem. We analyzed by means of computer simulations the effect of: a) temperature influence on the tissue electrical conductivity; b) the dispersion of the biological characteristics; c) the anisotropy of the cornea thermal conductivity; d) the presence of the tear film; and e) the insertion depth of the active electrode in the cornea, and the results suggest that these effects have a significant influence on the temperature distributions and thereby on the lesion dimensions. However, the cooling of the aqueous humor in the endothelium or the realistic value of the cornea curvature did not have a significant effect on the temperature distributions. An experimental model based on the lesions created in rabbit eyes has been used in order to compare the theoretical and experimental results. There is a tendency toward the agreement between experimental and theoretical results, although we have observed that the theoretical model overestimates the lesion dimension.Berjano, E.; Saiz Rodríguez, FJ.; Ferrero Corral, JM. (2002). Radio-frequency heating of the cornea: theoretical model and in vitro experiments. IEEE Transactions on Biomedical Engineering. 49(3):196-205. doi:10.1109/10.983453S19620549

Simulation Study of the Arrhythmogenic Effects of Two Missense Mutations in Human Atrial Fibrillation

[EN] Genetic mutations affecting genes encoding for ion channel protein structures have been associated with the presence of atrial fibrillation (AF) in healthy individuals. The aim of this study is to model and simulate the effects of two gain-of-function mutations found in literature, T895M and T436M, and affecting the rapid delayed rectifier potassium current. Courtemanche human atrial model has been chosen to reproduce myocytes behaviour and an optimization algorithm has been employed to fit model parameters to experimental data. Single cell and tissue patch simulations have been performed to study the effects of the two mutations in control, paroxysmal and permanent AF conditions, both in right and left atrium. 0D simulations revealed that both mutations cause an increase in IKr current, leading to action potential duration shortening and flattening of restitution curves, especially in presence of the mutation T895M. Initiation of a re-entrant activity in 2D simulations were possible both in case of T895M and T436M. The study reports the arrhythmogenicity of the two mutants and reveals T895M having a stronger effect with respect to T436M, in particular in control rather than in paroxysmal and permanent AF conditions. Differences in the dynamics of the two mutations highlight the importance of a patient-specific approach in planning targeted drug therapies.I acknowledge this work to the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie gran agreement No.766082 and to Generalitat Valenciana, Prometeo programme 2020/043Belletti, R.; Martínez-Mateu, L.; Romero Pérez, L.; Saiz Rodríguez, FJ. (2020). Simulation Study of the Arrhythmogenic Effects of Two Missense Mutations in Human Atrial Fibrillation. IEEE. 1-4. https://doi.org/10.22489/CinC.2020.420S1

Computational Study of the Effect of Electrode Polarity on Neural Activation Related to Paresthesia Coverage in Spinal Cord Stimulation Therapy

[EN] Objective: Using computer simulation, we investigated the effect of electrode polarity on neural activation in spinal cord stimulation and propose a new strategy to maximize the activating area in the dorsal column (DC) and, thus, paresthesia coverage in clinical practice. Materials and Methods: A new three-dimensional spinal cord model at the T10 vertebral level was developed to simulate neural activation induced by the electric field distribution produced by different typical four-contact electrode polarities in single- and dual-lead stimulation. Our approach consisted of the combination of a finite element model of the spinal cord developed in COMSOL Multiphysics and a nerve fiber model implemented in MATLAB. Five evaluation parameters were evaluated, namely, the recruitment ratio, the perception and discomfort thresholds, and the activating area and depth. The results were compared quantitatively. Results: The dual-guarded cathode presents the maximum activating area and depth in single- and dual-lead stimulation. However, the lowest value of the ratio between the perception threshold in DC and the perception threshold in the dorsal root (DR) is achieved when the guarded cathode is programmed. Although the two versions of bipolar polarity (namely bipolar 1 and bipolar 2) produce higher activating area and depth than the guarded cathode, they are suitable for producing DR stimulation. Similarly, dual-lead stimulation is likely to activate DR fibers because the electrodes are closer to these fibers. Conclusions: The results suggest that the activating area in the DC is maximized by using the dual-guarded cathode both in single- and dual-lead stimulation modes. However, DC nerve fibers are preferentially stimulated when the guarded cathode is used. According to these results, the new electrode programming strategy that we propose for clinical practice first uses the dual-guarded cathode, but, if the DR nerve fibers are activated, it then uses guarded cathode polarity.The authors thank Virginie Callot for providing us with all the spinal cord measurements from her research group’s study. The authors would like also to thank Surgicen S.L. for providing financial assistanceDurá, JL.; Solanes, C.; De Andrés, J.; Saiz Rodríguez, FJ. (2019). Computational Study of the Effect of Electrode Polarity on Neural Activation Related to Paresthesia Coverage in Spinal Cord Stimulation Therapy. Neuromodulation: Technology at the Neural Interface. 22(3):269-279. https://doi.org/10.1111/ner.1290926927922

Far-field contributions in multi-electrodes atrial recordings blur distinction between anatomical and functional reentries and may cause imaginary phase singularities A computational study

[EN] Background Atrial fibrillation (AF) is the most common cardiac arrhythmia and the most important cause of embolic stroke, requiring new technologies for its better understanding and therapies. Recent approaches to map the electrical activity during AF with multi-electrode systems aim at localizing patient-specific ablation targets of reentrant patterns. However, there is a critical need to determine the accuracy of those mapping systems. We performed computer simulations as a numerical approach of systematically evaluating the influence of far-field sources on the electrical recordings and detection of rotors. Methods We constructed 2 computer models of atrial tissue: (i) a 2D sheet model with varying non-active cells area in its center, and (ii) a whole realistic 3D atrial model. Phase maps were built based on the Hilbert transform of the unipolar electrograms recorded by virtual 2D and 3D multi-electrode systems and rotors were tracked through phase singularities detections. Results Analysis of electrograms recorded away from the 2D atrial model shows that the larger the distance between an electrode and the tissue model, the stronger the far-field sources contribution to the electrogram is. Importantly, even if an electrode is positioned in contact with the tissue, the electrogram contains significant contributions from distal sources that blur the distinction between anatomical and functional reentries. Moreover, when mapping the 3D atrial model, remote activity generated false phase singularities at locations without local reentrant excitation patterns. Conclusions Far-field contributions to electrograms during AF reduce the accuracy of detecting and interpreting reentrant activity.This work was supported in part by Programa Prometeu de la Conselleria d'Educacio, Formacio I Ocupacio de la Generalitat Valenciana, award number PROMETEU/2016/088; Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2013-2016 del Ministerio de Economia, Industria y Competitividad of Spain, Agencia Estatal de Investigacion and the European Commission (European Regional Development Funds - ERDF -FEDER), award number DPI2016-75799-R; The National Heart, Lung, and Blood Institute grant ROl-HL118304; the Gelman Award from the Cardiovascular Division at the University of Michigan; and the Coulter Program Award from the Dept. of Biomed Eng. at the University of Michigan.Martínez-Mateu, L.; Romero Pérez, L.; Saiz Rodríguez, FJ.; Berenfeld, O. (2019). Far-field contributions in multi-electrodes atrial recordings blur distinction between anatomical and functional reentries and may cause imaginary phase singularities A computational study. Computers in Biology and Medicine. 108:276-287. https://doi.org/10.1016/j.compbiomed.2019.02.022S27628710

What is the role of frequency on neural activation in tonic stimulation in SCS therapy? A computational study on sensoty Ab nerve fibers

[EN] The investigation of the effect of the stimulation parameters by computational modeling helps to understand the electrical response of specific neural elements in Spinal Cord Stimulation (SCS) therapy for chronic pain treatment. While the effect of the amplitude, the pulse width, and the electrode configuration on neural activation has been widely studied and is well-established in tonic stimulation, how frequency influences neural activation remains unclear. Thus, the aim of this work is to study the effect of frequency on the electrical response of sensory A beta neurons in tonic stimulation. Our approach consisted of the development of a new nerve fiber model from the combination of two previous models used in SCS modeling (the Wesselink-Holsheimer-Boom model and the Richardson-McIntyre-Grill model B). We simulate the action potential and the gates probabilities evolution of a 12.8 mu m fiber diameter at different pulse frequencies (50, 350, 600, 800, and 1000 Hz). We also simulated the firing rate of two nerve fiber diameters (5.7 and 12.8 mu m) in function of pulse frequency (from 1 to 1400 Hz) at different pulse widths (100, 300, and 500 mu s). In the range of 2-1000 Hz, the firing rate of a 12.8 mu m-diameter nerve fiber can be maximized by utilizing a 350 Hz, 300 mu s-stimulus. Frequencies above 350 Hz reduce half to one-third the firing rate, and 1000 Hz-stimulus overrides the electrical activity of the sensory nerve fiber. Small fibers (5.7 mu m-diameter) present lower firing rate values than large fibers (12.8 mu m-diameter). High values of pulse width decrease the firing rate of the nerve fibers as well as the range of frequencies that could be used to stimulate. According to the results, the frequency could have a considerable implication on the modulation of the firing rate of a nerve fiber. Thus, the frequency could play an important role to select and increase the activity of specific neural elements of the spinal cord in SCS therapy.Solanes, C.; Durá, JL.; De Andrés, J.; Saiz Rodríguez, FJ. (2021). What is the role of frequency on neural activation in tonic stimulation in SCS therapy? A computational study on sensoty Ab nerve fibers. IEEE Access. 9:107446-107461. https://doi.org/10.1109/ACCESS.2021.3099986S107446107461

Effect of Lead Position and Polarity on Paresthesia Coverage in Spinal Cord Stimulation Therapy: A Computational Study

[EN] Objectives: The effect of lead placement and programming strategies on spinal cord stimulation (SCS) therapy has been widely studied; however, there is a need to optimize these parameters to favor dorsal column (DC) over dorsal root (DR) stimulation in complex pain treatment. This study aimed to determine the optimal lateral distance between two leads and the effect of transverse stimulation using a mathematical model. Materials and Methods: A three-dimensional computational SCS and a nerve fiber model were used to determine the effect of the lateral distance between two leads at the same vertebral level T8 and the effect of the addition of anodes with two parallel leads at T8 and three different lateral distances on the model-based results (perception thresholds, activated DC fiber area and depth, and position of the first stimulated fiber). Results: With two parallel leads programmed with symmetrical polarities, the maximal DC fiber area stimulated was found for a lateral distance of 5 mm. The results also show a higher preference for DR stimulation as the lateral distance increased. The addition of positive contacts at the same level of active contacts in the second lead produces a displacement of the first stimulated fiber laterally. Conclusions: A lateral distance of 5 mm shows a DC stimulated fiber area greater than when leads are placed contiguously. The addition of anodes creates an effect whereby the area of paresthesia is not displaced to the midline, but in the opposite direction. This may be useful when the leads are too close and stimulation of one of the sides is compromised.Dura, JL.; Solanes, C.; De Andres, J.; Saiz Rodríguez, FJ. (2022). Effect of Lead Position and Polarity on Paresthesia Coverage in Spinal Cord Stimulation Therapy: A Computational Study. Neuromodulation: Technology at the Neural Interface. 25(5):680-692. https://doi.org/10.1016/j.neurom.2021.12.01368069225

Automatic modeling of dynamic drug-hERG channel interactions using three voltage protocols and machine learning techniques: A simulation study

[EN] Background: Assessment of drug cardiac safety is critical in the development of new compounds and is commonly addressed by evaluating the half-maximal blocking concentration of the potassium human ether-à-go-go related gene (hERG) channels. However, recent works have evidenced that the modelling of drug-binding dynamics to hERG can help to improve early cardiac safety assessment. Our goal is to de- velop a methodology to automatically generate Markovian models of the drug-hERG channel interactions. Methods: The training and the test sets consisted of 20800 and 5200 virtual drugs, respectively, dis- tributed into 104 groups with different affinities and kinetics to the conformational states of the chan- nel. In our system, drugs may bind to any state (individually or simultaneously), with different degrees of preference for a conformational state and the change of the conformational state of the drug bound channels may be restricted or allowed. To model such a wide range of possibilities, 12 Markovian chains are considered. Our approach uses the response of the drugs to our three previously developed voltage clamp protocols, which enhance the differences in the probabilities of occupying a certain conformational state of the channel (open, closed and inactivated). The computing tool is comprised of a classifier and a parameter optimizer and uses linear interpolation, support vector machines and a simplex method for function minimization. Results: We propose a novel methodology that automatically generates dynamic drug models using Markov model formulations and that elucidates the states where the drug binds and unbinds and the preferential binding state using data obtained from simple voltage clamp protocols that captures the preferential state-dependent binding properties, the relative affinities, trapping and non-trapping dynam- ics and the onset of I Kr block. Overall, the tool correctly predicted the class of 92.04% of the drugs and the model provided by the tool accurately fitted the response of the target compound, the mean accu- racy being 97.53%. Moreover, generation of the dynamic model of an I Kr blocker from its response to our voltage clamp protocols usually takes less than an hour on a common desktop computer. Conclusion: Our methodology could be very useful to model and simulate dynamic drug¿hERG channel interactions. It would contribute to the improvement of the preclinical assessment of the proarrhythmic risk of drugs that inhibit I Kr and the efficacy of antiarrhythmic I Kr blockers.This work was the Spanish Ministerio de Ciencia, Innovacion y Universidades [grant "Formacion de Profesorado Universitario" FPU19/02200; grant PID2019-104356RB-C41 funded by MCIN/AEI/10.13039/50110 0 011033 ]; the European Union's Horizon 2020 research and innovation program [grant agreement No 101016496 (SimCardioTest)]; and the Direccion General de Politica Cientifica de la Generalitat Valenciana [grant PROMETEO/2020/043]. Patenting of the proposed system/software is under considerationEscobar-Ropero, F.; Gomis-Tena Dolz, J.; Saiz Rodríguez, FJ.; Romero Pérez, L. (2022). Automatic modeling of dynamic drug-hERG channel interactions using three voltage protocols and machine learning techniques: A simulation study. Computer Methods and Programs in Biomedicine. 226:1-10. https://doi.org/10.1016/j.cmpb.2022.10714811022

Optimisation of ultrasound liver perfusion through a digital reference object and analysis tool

[EN] Background Conventional ultrasound (US) provides important qualitative information, although there is a need to evaluate the influence of the input parameters on the output signal and standardise the acquisition for an adequate quantitative perfusion assessment. The present study analyses how the variation in the input parameters influences the measurement of the perfusion parameters. Methods A software tool with simulator of the conventional US signal was created, and the influence of the different input variables on the derived biomarkers was analysed by varying the image acquisition configuration. The input parameters considered were the dynamic range, gain, and frequency of the transducer. Their influence on mean transit time (MTT), the area under the curve (AUC), maximum intensity (MI), and time to peak (TTP) parameters as outputs of the quantitative perfusion analysis was evaluated. A group of 13 patients with hepatocarcinoma was analysed with both a commercial tool and an in-house developed software. Results The optimal calculated inputs which minimise errors while preserving images¿ readability consisted of gain of 15¿dB, dynamic range of 60¿dB, and frequency of 1.5¿MHz. The comparison between the in-house developed software and the commercial software provided different values for MTT and AUC, while MI and TTP were highly similar. Conclusion Input parameter selection introduces variability and errors in US perfusion parameter estimation. Our results may add relevant insight into the current knowledge of conventional US perfusion and its use in lesions characterisation, playing in favour of optimised standardised parameter configuration to minimise variability.Alberich-Bayarri, Á.; Tomás-Cucarella, J.; Torregrosa-Lloret, A.; Saiz Rodríguez, FJ.; Martí-Bonmatí, L. (2019). Optimisation of ultrasound liver perfusion through a digital reference object and analysis tool. European Radiology Experimental. 3:1-10. https://doi.org/10.1186/s41747-019-0086-5S1103Parker JM, Weller MW, Feinstein LM et al (2013) Safety of ultrasound contrast agents in patients with known or suspected cardiac shunts. Am J Cardiol 112:1039–1045.Dhamija E, Paul SB (2014) Role of contrast enhanced ultrasound in hepatic imaging. Trop Gastroenterol 35:141–151.Wang XY, Kang LK, Lan CY (2014) Contrast-enhanced ultrasonography in diagnosis of benign and malignant breast lesions. Eur J Gynaecol Oncol 35:415–420.Wang S, Yang W, Zhang H, Xu Q, Yan K (2015) The role of contrast-enhanced ultrasound in selection indication and improveing diagnosis for transthoracic biopsy in peripheral pulmonary and mediastinal lesions. Biomed Res Int 2015:231782.Green MA, Mathias CJ, Willis LR, et al (2007) Assessment of Cu-ETS as a PET radiopharmaceutical for evaluation of regional renal perfusion. Nucl Med Biol 34:247–255.Daghini E, Primak AN, Chade AR, et al (2007) Assessment of renal hemodynamics and function in pigs with 64-section multidetector CT: comparison with electron-beam CT. Radiology 243:405–412.Martin DR, Sharma P, Salman K, et al (2008) Individual kidney blood flow measured with contrast-enhanced first-pass perfusion MR imaging. Radiology 246:241–248.Tang MX, Mulvana H, Gauthier T, et al (2011) Quantitative contrast-enhanced ultrasound imaging: a review of sources of variability. Interface Focus 1:520–539.Gauthier TP, Averkiou MA, Leen EL (2011) Perfusion quantification using dynamic contrast-enhanced ultrasound: the impact of dynamic range and gain on time-intensity curves. Ultrasonics 51:102–106.Möller I, Janta I, Backhaus M, et al (2017) The 2017 EULAR standardised procedures for ultrasound imaging in rheumatology. Ann Rheum Dis. 76:1974–1979.Pitre-Champagnat S, Coiffier B, Jourdain L, Benatsou B, Leguerney I, Lassau N (2017) Toward a standardization of ultrasound scanners for dynamic contrast-enhanced ultrasonography: methodology and phantoms. Ultrasound Med Biol. https://doi.org/10.1016/j.ultrasmedbio.2017.06.032Shunichi S, Hiroko I, Fuminori M, Waki H (2009) Definition of contrast enhancement phases of the liver using a perfluoro-based microbubble agent, perflubutane microbubbles. Ultrasound Med Biol 35:1819–1827. doiFairbank WM Jr, Scully MO (1977) A new noninvasive technique for cardiac pressure measurement: resonant scattering of ultrasound from bubbles. IEEE Trans Biomed Eng 24:107–110.Malm S, Frigstad S, Helland F, Oye K, Slordahl S, Skjarpe T (2005) Quantification of resting myocardial blood flow velocity in normal humans using real-time contrast echocardiography. A feasibility study. Cardiovasc Ultrasound 3:16.Arditi M, Frinking PJ, Zhou X, Rognin NG (2006) A new formalism for the quantification of tissue perfusion by the destruction-replenishment method in contrast ultrasound imaging. IEEE Trans Ultrason Ferroelectr Freq Control 53:1118–1129.Savic RM, Jonker DM, Kerbusch T, Karlsson MO (2007) Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn 34:711–726.Averkiou M, Lampaskis M, Kyriakopoulou K, et al (2010) Quantification of tumor microvascularity with respiratory gated contrast enhanced ultrasound for monitoring therapy. Ultrasound Med Biol 36:68–77.Kuenen MP, Mischi M, Wijkstra H (2011) Contrast-ultrasound diffusion imaging for localization of prostate cancer. IEEE Trans Med Imaging 30:1493–1502.Garcia D, Le Tarnec L, Muth S, Montagnon E, Porée J, Cloutier G(2013) Stolt’s f-k migration for plane wave ultrasound imaging. IEEE Trans Ultrason Ferroelectr Freq Control 60:1853–1867.Brands J, Vink H, Van Teeffelen JW (2011) Comparison of four mathematical models to analyze indicator-dilution curves in the coronary circulation. Med Biol Eng Comput 49:1471–1479.Zhou JH, Cao LH, Zheng W, Liu M, Han F, Li AH (2011) Contrast-enhanced gray-scale ultrasound for quantitative evaluation of tumor response to chemotherapy: preliminary results with a mouse hepatoma model. AJR Am J Roentgenol 196:W13-17.Wei K, Jayaweera AR, Firoozan S, Linka A, Skyba DM, Kaul S (1998) Quantification of myocardial blood flow with ultrasoundinduced destruction of microbubbles administered as a constant venous infusion. Circulation 97:473–483Riascos P, Velasco-Medina J (2005) Efectos Biológicos y Consideraciones de Seguridad en Ultrasonido. Available via https://www.yumpu.com/es/document/view/15350629/efectos-biologicos-y-consideraciones-de-seguridad-en-ultrasonidode Jong N, ten Cate FJ, Vletter WB, Roelandt JR (1993) Quantification of transpulmonary echocontrast effects. Ultrasound Med Biol 19:279–288Quaia E (2011) Assessment of tissue perfusion by contrast-enhanced ultrasound. Eur Radiol 21:604–615

Omnipolar EGM Voltage Mapping for Atrial Fibrosis Identification Evaluated with an Electrophysiological Model

[EN] Atrial fibrillation (AF) is the most spread heart arrhythmia, whose mechanisms are not completely clear yet. Catheter ablation is a standard treatment, which isolates the area involved in the arrhythmia. Intracardiac electrograms (EGMs) are used to better understand the AF mechanisms and to find appropriate ablation sites. Bipolar EGMs (b-EGMs) are often employed, but their amplitude and shape depend on catheter orientation, limiting reliability. To avoid this uncertainty, an approach insensitive to catheter orientation, referred as Omnipolar EGM (OP-EGM) method, has been introduced, which uses an estimation of the electric field within a group of electrodes, referred as clique. In this work, we compare different mapping approaches based on b-EGMs and OPEGM signals in simulation including fibrosis, so to evaluate their ability to detect fibrosis and reproduce the spatial distribution of the voltage. Maps have been computed using two clique configurations (square and triangular), introducing or not a previous time alignment of the bEGMs. OP-EGM signals have been obtained by projecting the electric field along directions of its maximal excursion and its principal components. Results show that both cliques configurations present good performance, in terms of fibrosis detection and correlation with the reference voltage maps. In addition, the proposed alignment of b-EGMS improves maps based on OP-EGM signals, especially when square cliques are used.This work is part of a project that has received funding from the European Union¿s Horizon 2020 research and innovation program under the Marie Sk¿odowska-Curie grant agreement No 766082 (MY-ATRIA).Riccio, J.; Alcaine, A.; Rocher-Ventura, S.; Laguna, P.; Saiz Rodríguez, FJ.; Martínez, JP. (2021). Omnipolar EGM Voltage Mapping for Atrial Fibrosis Identification Evaluated with an Electrophysiological Model. IEEE. 920-924. https://doi.org/10.23919/Eusipco47968.2020.9287670S92092