Cardiolipotoxicity, Inflammation, and Arrhythmias: Role for Interleukin-6 Molecular Mechanisms

Fatty acid infiltration of the myocardium, acquired in metabolic disorders (obesity, type-2 diabetes, insulin resistance, and hyperglycemia) is critically associated with the development of lipotoxic cardiomyopathy. According to a recent Presidential Advisory from the American Heart Association published in 2017, the current average dietary intake of saturated free-fatty acid (SFFA) in the US is 11–12%, which is significantly above the recommended <10%. Increased levels of circulating SFFAs (or lipotoxicity) may represent an unappreciated link that underlies increased vulnerability to cardiac dysfunction. Thus, an important objective is to identify novel targets that will inform pharmacological and genetic interventions for cardiomyopathies acquired through excessive consumption of diets rich in SFFAs. However, the molecular mechanisms involved are poorly understood. The increasing epidemic of metabolic disorders strongly implies an undeniable and critical need to further investigate SFFA mechanisms. A rapidly emerging and promising target for modulation by lipotoxicity is cytokine secretion and activation of pro-inflammatory signaling pathways. This objective can be advanced through fundamental mechanisms of cardiac electrical remodeling. In this review, we discuss cardiac ion channel modulation by SFFAs. We further highlight the contribution of downstream signaling pathways involving toll-like receptors and pathological increases in pro-inflammatory cytokines. Our expectation is that if we understand pathological remodeling of major cardiac ion channels from a perspective of lipotoxicity and inflammation, we may be able to develop safer and more effective therapies that will be beneficial to patients

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

Neurological Disorders and Risk of Arrhythmia

Neurological disorders including depression, anxiety, post-traumatic stress disorder (PTSD), schizophrenia, autism and epilepsy are associated with an increased incidence of cardiovascular disorders and susceptibility to heart failure. The underlying molecular mechanisms that link neurological disorders and adverse cardiac function are poorly understood. Further, a lack of progress is likely due to a paucity of studies that investigate the relationship between neurological disorders and cardiac electrical activity in health and disease. Therefore, there is an important need to understand the spatiotemporal behavior of neurocardiac mechanisms. This can be advanced through the identification and validation of neurological and cardiac signaling pathways that may be adversely regulated. In this review we highlight how dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis, autonomic nervous system (ANS) activity and inflammation, predispose to psychiatric disorders and cardiac dysfunction. Moreover, antipsychotic and antidepressant medications increase the risk for adverse cardiac events, mostly through the block of the human ether-a-go-go-related gene (hERG), which plays a critical role in cardiac repolarization. Therefore, understanding how neurological disorders lead to adverse cardiac ion channel remodeling is likely to have significant implications for the development of effective therapeutic interventions and helps improve the rational development of targeted therapeutics with significant clinical implications