The antimalarial chloroquine reduces the burden of persistent atrial fibrillation
In clinical practice, reducing the burden of persistent atrial fibrillation by pharmacological means is challenging. We explored if blocking the background and the acetylcholine-activated inward rectifier potassium currents (IK1 and IKACh) could be antiarrhythmic in persistent atrial fibrillation. W...
- Autores:
- Tipo de recurso:
- Fecha de publicación:
- 2019
- Institución:
- Universidad de Medellín
- Repositorio:
- Repositorio UDEM
- Idioma:
- eng
- OAI Identifier:
- oai:repository.udem.edu.co:11407/5701
- Acceso en línea:
- http://hdl.handle.net/11407/5701
- Palabra clave:
- Chloroquine
IK1
IKACh
Persistent atrial fibrillation
Potassium inward rectifiers
antimalarial agent
apixaban
chloroquine
inwardly rectifying potassium channel subunit Kir2.1
inwardly rectifying potassium channel subunit Kir3.1
metoprolol
potassium channel
unclassified drug
action potential duration
aged
amebiasis
Article
clinical article
disease burden
drug effect
drug mechanism
drug protein binding
female
human
IC50
laboratory test
mathematical model
molecular docking
molecular model
patch clamp technique
persistent atrial fibrillation
potassium current
- Rights
- License
- http://purl.org/coar/access_right/c_16ec
| id |
REPOUDEM2_48d910fe47d48bffd691ed3d44c310f9 |
|---|---|
| oai_identifier_str |
oai:repository.udem.edu.co:11407/5701 |
| network_acronym_str |
REPOUDEM2 |
| network_name_str |
Repositorio UDEM |
| repository_id_str |
|
| dc.title.none.fl_str_mv |
The antimalarial chloroquine reduces the burden of persistent atrial fibrillation |
| title |
The antimalarial chloroquine reduces the burden of persistent atrial fibrillation |
| spellingShingle |
The antimalarial chloroquine reduces the burden of persistent atrial fibrillation Chloroquine IK1 IKACh Persistent atrial fibrillation Potassium inward rectifiers antimalarial agent apixaban chloroquine inwardly rectifying potassium channel subunit Kir2.1 inwardly rectifying potassium channel subunit Kir3.1 metoprolol potassium channel unclassified drug action potential duration aged amebiasis Article clinical article disease burden drug effect drug mechanism drug protein binding female human IC50 laboratory test mathematical model molecular docking molecular model patch clamp technique persistent atrial fibrillation potassium current |
| title_short |
The antimalarial chloroquine reduces the burden of persistent atrial fibrillation |
| title_full |
The antimalarial chloroquine reduces the burden of persistent atrial fibrillation |
| title_fullStr |
The antimalarial chloroquine reduces the burden of persistent atrial fibrillation |
| title_full_unstemmed |
The antimalarial chloroquine reduces the burden of persistent atrial fibrillation |
| title_sort |
The antimalarial chloroquine reduces the burden of persistent atrial fibrillation |
| dc.subject.none.fl_str_mv |
Chloroquine IK1 IKACh Persistent atrial fibrillation Potassium inward rectifiers antimalarial agent apixaban chloroquine inwardly rectifying potassium channel subunit Kir2.1 inwardly rectifying potassium channel subunit Kir3.1 metoprolol potassium channel unclassified drug action potential duration aged amebiasis Article clinical article disease burden drug effect drug mechanism drug protein binding female human IC50 laboratory test mathematical model molecular docking molecular model patch clamp technique persistent atrial fibrillation potassium current |
| topic |
Chloroquine IK1 IKACh Persistent atrial fibrillation Potassium inward rectifiers antimalarial agent apixaban chloroquine inwardly rectifying potassium channel subunit Kir2.1 inwardly rectifying potassium channel subunit Kir3.1 metoprolol potassium channel unclassified drug action potential duration aged amebiasis Article clinical article disease burden drug effect drug mechanism drug protein binding female human IC50 laboratory test mathematical model molecular docking molecular model patch clamp technique persistent atrial fibrillation potassium current |
| description |
In clinical practice, reducing the burden of persistent atrial fibrillation by pharmacological means is challenging. We explored if blocking the background and the acetylcholine-activated inward rectifier potassium currents (IK1 and IKACh) could be antiarrhythmic in persistent atrial fibrillation. We thus tested the hypothesis that blocking IK1 and IKACh with chloroquine decreases the burden of persistent atrial fibrillation. We used patch clamp to determine the IC50 of IK1 and IKACh block by chloroquine and molecular modeling to simulate the interaction between chloroquine and Kir2.1 and Kir3.1, the molecular correlates of IK1 and IKACh. We then tested, as a proof of concept, if oral chloroquine administration to a patient with persistent atrial fibrillation can decrease the arrhythmia burden. We also simulated the effects of chloroquine in a 3D model of human atria with persistent atrial fibrillation. In patch clamp the IC50 of IK1 block by chloroquine was similar to that of IKACh. A 14-day regimen of oral chloroquine significantly decreased the burden of persistent atrial fibrillation in a patient. Mathematical simulations of persistent atrial fibrillation in a 3D model of human atria suggested that chloroquine prolonged the action potential duration, leading to failure of reentrant excitation, and the subsequent termination of the arrhythmia. The combined block of IK1 and IKACh can be a targeted therapeutic strategy for persistent atrial fibrillation. Copyright © 2019 Tobón, Palacio, Chidipi, Slough, Tran, Tran, Reiser, Lin, Herweg, Sayad, Saiz and Noujaim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| publishDate |
2019 |
| dc.date.accessioned.none.fl_str_mv |
2020-04-29T14:53:42Z |
| dc.date.available.none.fl_str_mv |
2020-04-29T14:53:42Z |
| dc.date.none.fl_str_mv |
2019 |
| dc.type.eng.fl_str_mv |
Article |
| dc.type.coarversion.fl_str_mv |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.coar.fl_str_mv |
http://purl.org/coar/resource_type/c_6501 http://purl.org/coar/resource_type/c_2df8fbb1 |
| dc.type.driver.none.fl_str_mv |
info:eu-repo/semantics/article |
| dc.identifier.issn.none.fl_str_mv |
16639812 |
| dc.identifier.uri.none.fl_str_mv |
http://hdl.handle.net/11407/5701 |
| dc.identifier.doi.none.fl_str_mv |
10.3389/fphar.2019.01392 |
| identifier_str_mv |
16639812 10.3389/fphar.2019.01392 |
| url |
http://hdl.handle.net/11407/5701 |
| dc.language.iso.none.fl_str_mv |
eng |
| language |
eng |
| dc.relation.isversionof.none.fl_str_mv |
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85076349037&doi=10.3389%2ffphar.2019.01392&partnerID=40&md5=51edc9be3346dbe0bdcbb5d42f2a7cf2 |
| dc.relation.citationvolume.none.fl_str_mv |
10 |
| dc.relation.references.none.fl_str_mv |
Al-Bari, M.A., Chloroquine analogues in drug discovery: New directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases (2015) J. Antimicrob. Chemother., 70, pp. 1608-1621 Anisimov, S.V., Boheler, K.R., Aging-associated changes in cardiac gene expression: Large scale transcriptome analysis (2003) Advances in Gerontology = Uspekhi Gerontologii / Rossiiskaia Akademiia Nauk. Gerontol. Obshchestvo, 11, pp. 67-75 Atienza, F., Jalife, J., Reentry and atrial fibrillation (2007) Heart Rhythm.: Off. J. Heart Rhythm. Soc., 4, pp. S13-S16 Bai, J., Gladding, P.A., Stiles, M.K., Fedorov, V.V., Zhao, J., Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells (2018) Sci. Rep., 8, p. 15642 Burrell, Z.L., Jr., Martinez, A.C., Chloroquine and hydroxychloroquine in the treatment of cardiac arrhythmias (1958) New Engl. J. Med., 258, pp. 798-800 Chung, M.K., Shemanski, L., Sherman, D.G., Greene, H.L., Hogan, D.B., Kellen, J.C., Functional status in rate- Versus rhythm-control strategies for atrial fibrillation: Results of the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) functional status substudy (2005) J. Am. Coll. Cardiol., 46, pp. 1891-1899 Colman, M.A., Pinali, C., Trafford, A.W., Zhang, H., Kitmitto, A., A computational model of spatio-temporal cardiac intracellular calcium handling with realistic structure and spatial flux distribution from sarcoplasmic reticulum and t-tubule reconstructions (2017) PloS Comput. Biol., 13 Courtemanche, M., Ramirez, R.J., Nattel, S., Ionic mechanisms underlying human atrial action potential properties: Insights from a mathematical model (1998) Am. J. Physiol., 275, pp. H301-H321 DeGroot, N.M., Schalij, M.J., Fragmented,long-duration,low-amplitude electrograms characterize the origin of focal atrial tachycardia (2006) J. Cardiovasc. Electrophysiol., 17, pp. 1086-1092 Dobrev, D., Nattel, S., New insights into the molecular basis of atrial fibrillation: Mechanistic and therapeutic implications (2011) Cardiovasc. Res., 89, pp. 689-691 Duarte, M.R.A., Tobón, C., Cardona, K., Saiz, J., Chloroquine effect on human atrial action potential under normal conditions and during paroxysmal and chronic atrial fibrillation (2013) Columbia:A Simulation Study, PAHCE, pp. 71-75 Filgueiras-Rama, D., Martins, R.P., Mironov, S., Yamazaki, M., Calvo, C.J., Ennis, S.R., Chloroquine terminates stretch-induced atrial fibrillation more effectively than flecainide in the sheep heart (2012) Circ. Arrhythmia Electrophysiol., 5, pp. 561-570 Grandi, E., Pandit, S.V., Voigt, N., Workman, A.J., Dobrev, D., Jalife, J., Human atrial action potential and Ca2+ model: Sinus rhythm and chronic atrial fibrillation (2011) Circ. Res., 109, pp. 1055-1066 Greenwood, J.R., Calkins, D., Sullivan, A.P., Shelley, J.C., Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution (2010) J. Computer-Aided Mol. Design, 24, pp. 591-604 Hagens, V.E., Van Veldhuisen, D.J., Kamp, O., Rienstra, M., Bosker, H.A., Veeger, N.J., Effect of rate and rhythm control on left ventricular function and cardiac dimensions in patients with persistent atrial fibrillation: Results from the RAte Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) study (2005) Heart Rhythm.: Off. J. Heart Rhythm. Soc., 2, pp. 19-24 Harris, L., Downar, E., Shaikh, N.A., Chen, T., Antiarrhythmic potential of chloroquine: New use for an old drug (1988) Can. J. Cardiol., 4, pp. 295-300 Heidenreich, E.A., Ferrero, J.M., Doblare, M., Rodriguez, J.F., Adaptive macro finite elements for the numerical solution of monodomain equations in cardiac electrophysiology (2010) Ann. Biomed. Eng., 38, pp. 2331-2345 Humphrey, W., Dalke, A., Schulten, K., VMD: Visual molecular dynamics (1996) J. Mol. Graphics, 14 (33-8). , 27-8 Iijima, H., Dunbar, J.B., Jr., Marshall, G.R., Calibration of effective van der Waals atomic contact radii for proteins and peptides (1987) Proteins, 2, pp. 330-339 Kalifa, J., Tanaka, K., Zaitsev, A.V., Warren, M., Vaidyanathan, R., Auerbach, D., Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation (2006) Circulation, 113, pp. 626-633 Karunajeewa, H.A., Salman, S., Mueller, I., Baiwog, F., Gomorrai, S., Law, I., Pharmacokinetics of chloroquine and monodesethylchloroquine in pregnancy (2010) Antimicrob. Agents Chemother., 54, pp. 1186-1192 Kneller, J., Zou, R., Vigmond, E.J., Wang, Z., Leon, L.J., Nattel, S., Cholinergic atrial fibrillation in a computer model of a two-dimensional sheet of canine atrial cells with realistic ionic properties (2002) Circ. Res., 90, pp. E73-E87 Koura, T., Hara, M., Takeuchi, S., Ota, K., Okada, Y., Miyoshi, S., Anisotropic conduction properties in canine atria analyzed by high-resolution optical mapping: Preferential direction of conduction block changes from longitudinal to transverse with increasing age (2002) Circulation, 105, pp. 2092-2098 Kumar, S., Teh, A.W., Medi, C., Kistler, P.M., Morton, J.B., Kalman, J.M., Atrial remodeling in varying clinical substrates within beating human hearts: Relevance to atrial fibrillation (2012) Prog. In Biophys. Mol. Biol., 110, pp. 278-294 Liao, J.N., Chao, T.F., Liu, C.J., Wang, K.L., Chen, S.J., Tuan, T.C., Risk and prediction of dementia in patients with atrial fibrillation a nationwide population-based cohort study (2015) Int. J. Cardiol., 199, pp. 25-30 Mahler, J., Persson, I., A study of the hydration of the alkali metal ions in aqueous solution (2012) Inorg. Chem., 51, pp. 425-438 Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., Autodock4 and AutoDockTools4: Automated docking with selective receptor flexibility (2009) J. Comput. Chem., 30, pp. 2785-2791 Moslehi, J., DePinho, R.A., Sahin, E., Telomeres and mitochondria in the aging heart (2012) Circ. Res., 110, pp. 1226-1237 Narayan, S.M., Krummen, D.E., Targeting stable rotors to treat atrial fibrillation (2012) Arrhythm Electrophysiol. Rev., 1, pp. 34-38 Narayan, S.M., Krummen, D.E., Enyeart, M.W., Rappel, W.J., Computational mapping identifies localized mechanisms for ablation of atrial fibrillation (2012) PloS One, 7 Narayan, S.M., Krummen, D.E., Rappel, W.J., Clinical mapping approach to diagnose electrical rotors and focal impulse sources for human atrial fibrillation (2012) J. Cardiovasc. Electrophysiol., 23, pp. 447-454 Narayan, S.M., Krummen, D.E., Shivkumar, K., Clopton, P., Rappel, W.J., Miller, J.M., Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation with or without Focal Impulse and Rotor Modulation) trial (2012) J. Am. Coll. Cardiol., 60, pp. 628-636 Narayan, S.M., Patel, J., Mulpuru, S., Krummen, D.E., Focal impulse and rotor modulation ablation of sustaining rotors abruptly terminates persistent atrial fibrillation to sinus rhythm with elimination on follow-up: A video case study (2012) Heart Rhythm.: Off. J. Heart Rhythm. Soc., 9, pp. 1436-1439 Noujaim, S.F., Pandit, S.V., Berenfeld, O., Vikstrom, K., Cerrone, M., Mironov, S., Up-regulation of the inward rectifier K+ current (I K1) in the mouse heart accelerates and stabilizes rotors (2007) J. Physiol., 578, pp. 315-326 Noujaim, S.F., Stuckey, J.A., Ponce-Balbuena, D., Ferrer-Villada, T., Lopez-Izquierdo, A., Pandit, S., Specific residues of the cytoplasmic domains of cardiac inward rectifier potassium channels are effective antifibrillatory targets (2010) FASEB J.: Off. Publ. Fed. Am. Soc. Exp. Biol., 24, pp. 4302-4312 Noujaim, S.F., Stuckey, J.A., Ponce-Balbuena, D., Ferrer-Villada, T., Lopez-Izquierdo, A., Pandit, S.V., Structural bases for the different anti-fibrillatory effects of chloroquine and quinidine (2011) Cardiovasc. Res., 89, pp. 862-869 Olshansky, B., Combining ablation of atrial fibrillation with ablation of atrial flutter: Are we there yet? (2004) J. Am. Coll. Cardiol., 43, pp. 2063-2065 Pegan, S., Arrabit, C., Zhou, W., Kwiatkowski, W., Collins, A., Slesinger, P.A., Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification (2005) Nat. Neurosci., 8, pp. 279-287 Podd, S.J., Freemantle, N., Furniss, S.S., Sulke, N., First clinical trial of specific IKACh blocker shows no reduction in atrial fibrillation burden in patients with paroxysmal atrial fibrillation: Pacemaker assessment of BMS 914392 in patients with paroxysmal atrial fibrillation (2016) Eur.: Eur. Pacing Arrhythmias Cardiac Electrophysiol.: J. Working Groups Cardiac Pacing Arrhythmias Cardiac Cell. Electrophysiol. Eur. Soc. Cardiol., 18, pp. 340-346 Pond, A.L., Scheve, B.K., Benedict, A.T., Petrecca, K., Van Wagoner, D.R., Shrier, A., Expression of distinct ERG proteins in rat, mouse, and human heart (2000) Relat. Funct. I(Kr) Channels J. Biol. Chem., 275, pp. 5997-6006 Rienstra, M., Van Veldhuisen, D.J., Hagens, V.E., Ranchor, A.V., Veeger, N.J., Crijns, H.J., Gender-related differences in rhythm control treatment in persistent atrial fibrillation: Data of the Rate Control Versus Electrical Cardioversion (RACE) study (2005) J. Am. Coll. Cardiol., 46, pp. 1298-1306 Rietbrock, S., Heeley, E., Plumb, J., Van Staa, T., Chronic atrial fibrillation: Incidence, prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme (2008) Am. Heart J., 156, pp. 57-64 Riou, B., Barriot, P., Rimailho, A., Baud, F.J., Treatment of severe chloroquine poisoning (1988) New Engl. J. Med., 318, pp. 1-6 Rodriguez-Menchaca, A.A., Navarro-Polanco, R.A., Ferrer-Villada, T., Rupp, J., Sachse, F.B., Tristani-Firouzi, M., The molecular basis of chloroquine block of the inward rectifier Kir2.1 channel (2008) Proc. Natl. Acad. Sci. U. States America, 105, pp. 1364-1368 Ryu, K., Sahadevan, J., Khrestian, C.M., Stambler, B.S., Waldo, A.L., Use of fast fourier transform analysis of atrial electrograms for rapid characterization of atrial activation-implications for delineating possible mechanisms of atrial tachyarrhythmias (2006) J. Cardiovasc. Electrophysiol., 17, pp. 198-206 Sanchez-Chapula, J.A., Salinas-Stefanon, E., Torres-Jacome, J., Benavides-Haro, D.E., Navarro-Polanco, R.A., Blockade of currents by the antimalarial drug chloroquine in feline ventricular myocytes (2001) J. Pharmacol. Exp. Ther., 297, pp. 437-445 Sanchez-Chapula, J.A., Navarro-Polanco, R.A., Culberson, C., Chen, J., Sanguinetti, M.C., Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block (2002) J. Biol. Chem., 277, pp. 23587-23595 Sastry, G.M., Adzhigirey, M., Day, T., Annabhimoju, R., Sherman, W., Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments (2013) J. Computer-Aided Mol. Design, 27, pp. 221-234 Schotten, U., Greiser, M., Benke, D., Buerkel, K., Ehrenteidt, B., Stellbrink, C., Atrial fibrillation-induced atrial contractile dysfunction: A tachycardiomyopathy of a different sort (2002) Cardiovasc. Res., 53, pp. 192-201 Shelley, J.C., Cholleti, A., Frye, L.L., Greenwood, J.R., Timlin, M.R., Uchimaya, M., EPIK: A software program for pK(a) prediction and protonation state generation for drug-like molecules (2007) J. Computer-Aided Mol. Design, 21, pp. 681-691 Shivakumar, D., Williams, J., Wu, Y., Damm, W., Shelley, J., Sherman, W., Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field (2010) J. Chem. Theory Comput., 6, pp. 1509-1519 Shukla, A., Curtis, A.B., Avoiding permanent atrial fibrillation: Treatment approaches to prevent disease progression (2014) Vasc. Health Risk Manage., 10, pp. 1-12 Singh-Manoux, A., Fayosse, A., Sabia, S., Canonico, M., Bobak, M., Elbaz, A., Atrial fibrillation as a risk factor for cognitive decline and dementia (2017) Eur. Heart J., 38, pp. 2612-2618 Skibsbye, L., Jespersen, T., Christ, T., Maleckar, M.M., Van Den Brink, J., Tavi, P., Refractoriness in human atria: Time and voltage dependence of sodium channel availability (2016) J. Mol. Cell. Cardiol., 101, pp. 26-34 Stas, P., Faes, D., Noyens, P., Conduction disorder and QT prolongation secondary to long-term treatment with chloroquine (2008) Int. J. Cardiol., 127, pp. e80-e82 Takemoto, Y., Slough, D.P., Meinke, G., Katnik, C., Graziano, Z.A., Chidipi, B., Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule (2018) FASEB J.: Off. Publ. Fed. Am. Soc. Exp. Biol., 32, pp. 1778-1793 Teixeira, R.A., Borba, E.F., Pedrosa, A., Nishioka, S., Viana, V.S., Ramires, J.A., Evidence for cardiac safety and antiarrhythmic potential of chloroquine in systemic lupus erythematosus (2014) Eur.: Eur. Pacing Arrhythmias Cardiac Electrophysiol.: J. Working Groups Cardiac Pacing Arrhythmias Cardiac Cell. Electrophysiol. Eur. Soc. Cardiol., 16, pp. 887-892 Tobon, C., Ruiz-Villa, C.A., Heidenreich, E., Romero, L., Hornero, F., Saiz, J., A three-dimensional human atrial model with fiber orientation. Electrograms arrhythmic activation patterns relat (2013) PloS One, 8 Traebert, M., Dumotier, B., Meister, L., Hoffmann, P., Dominguez-Estevez, M., Suter, W., Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells (2004) Eur. J. Pharmacol., 484, pp. 41-48 Van Wagoner, D.R., Electrophysiological remodeling in human atrial fibrillation (2003) Pacing Clin. Electrophysiol.: PACE, 26, pp. 1572-1575 Vest, J.A., Wehrens, X.H., Reiken, S.R., Lehnart, S.E., Dobrev, D., Chandra, P., Defective cardiac ryanodine receptor regulation during atrial fibrillation (2005) Circulation, 111, pp. 2025-2032 Voigt, N., Friedrich, A., Bock, M., Wettwer, E., Christ, T., Knaut, M., Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated IK,ACh channels in patients with chronic atrial fibrillation (2007) Cardiovasc. Res., 74, pp. 426-437 Voigt, N., Trausch, A., Knaut, M., Matschke, K., Varro, A., Van Wagoner, D.R., Left-to-right atrial inward rectifier potassium current gradients in patients with paroxysmal versus chronic atrial fibrillation (2010) Circ. Arrhythmia Electrophysiol., 3, pp. 472-480 Volkova, M., Garg, R., Dick, S., Boheler, K.R., Aging-associated changes in cardiac gene expression (2005) Cardiovasc. Res., 66, pp. 194-204 Walfridsson, H., Anfinsen, O.G., Berggren, A., Frison, L., Jensen, S., Linhardt, G., Is the acetylcholine-regulated inwardly rectifying potassium current a viable antiarrhythmic target? Translational discrepancies of AZD2927 and A7071 in dogs and humans (2015) Eur.: Eur. Pacing Arrhythmias Cardiac Electrophysiol.: J. Working Groups Cardiac Pacing Arrhythmias Cardiac Cell. Electrophysiol. Eur. Soc. Cardiol., 17, pp. 473-482 White, N.J., Cardiotoxicity of antimalarial drugs (2007) Lancet Infect. Dis., 7, pp. 549-558 Wishart, D.S., Knox, C., Guo, A.C., Cheng, D., Shrivastava, S., Tzur, D., Drugbank: A knowledgebase for drugs, drug actions and drug targets (2008) Nucleic Acids Res, 36, pp. D901-D906 Wolf, P.A., Abbott, R.D., Kannel, W.B., Atrial fibrillation as an independent risk factor for stroke: The Framingham Study (1991) Stroke J. Cereb. Circ., 22, pp. 983-988 Workman, A.J., Kane, K.A., Rankin, A.C., The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation (2001) Cardiovasc. Res., 52, pp. 226-235 Wozniacka, A., Cygankiewicz, I., Chudzik, M., Sysa-Jedrzejowska, A., Wranicz, J.K., The cardiac safety of chloroquine phosphate treatment in patients with systemic lupus erythematosus: The influence on arrhythmia, heart rate variability and repolarization parameters (2006) Lupus, 15, pp. 521-525 Zimetbaum, P., Antiarrhythmic drug therapy for atrial fibrillation (2012) Circulation, 125, pp. 381-389 Zlochiver, S., Yamazaki, M., Kalifa, J., Berenfeld, O., Rotor meandering contributes to irregularity in electrograms during atrial fibrillation (2008) Heart Rhythm.: Off. J. Heart Rhythm. Soc., 5, pp. 846-854 |
| dc.rights.coar.fl_str_mv |
http://purl.org/coar/access_right/c_16ec |
| rights_invalid_str_mv |
http://purl.org/coar/access_right/c_16ec |
| dc.publisher.none.fl_str_mv |
Frontiers Media S.A. |
| dc.publisher.program.none.fl_str_mv |
Facultad de Ciencias Básicas |
| dc.publisher.faculty.none.fl_str_mv |
Facultad de Ciencias Básicas |
| publisher.none.fl_str_mv |
Frontiers Media S.A. |
| dc.source.none.fl_str_mv |
Frontiers in Pharmacology |
| institution |
Universidad de Medellín |
| repository.name.fl_str_mv |
Repositorio Institucional Universidad de Medellin |
| repository.mail.fl_str_mv |
repositorio@udem.edu.co |
| _version_ |
1814159163655192576 |
| spelling |
20192020-04-29T14:53:42Z2020-04-29T14:53:42Z16639812http://hdl.handle.net/11407/570110.3389/fphar.2019.01392In clinical practice, reducing the burden of persistent atrial fibrillation by pharmacological means is challenging. We explored if blocking the background and the acetylcholine-activated inward rectifier potassium currents (IK1 and IKACh) could be antiarrhythmic in persistent atrial fibrillation. We thus tested the hypothesis that blocking IK1 and IKACh with chloroquine decreases the burden of persistent atrial fibrillation. We used patch clamp to determine the IC50 of IK1 and IKACh block by chloroquine and molecular modeling to simulate the interaction between chloroquine and Kir2.1 and Kir3.1, the molecular correlates of IK1 and IKACh. We then tested, as a proof of concept, if oral chloroquine administration to a patient with persistent atrial fibrillation can decrease the arrhythmia burden. We also simulated the effects of chloroquine in a 3D model of human atria with persistent atrial fibrillation. In patch clamp the IC50 of IK1 block by chloroquine was similar to that of IKACh. A 14-day regimen of oral chloroquine significantly decreased the burden of persistent atrial fibrillation in a patient. Mathematical simulations of persistent atrial fibrillation in a 3D model of human atria suggested that chloroquine prolonged the action potential duration, leading to failure of reentrant excitation, and the subsequent termination of the arrhythmia. The combined block of IK1 and IKACh can be a targeted therapeutic strategy for persistent atrial fibrillation. Copyright © 2019 Tobón, Palacio, Chidipi, Slough, Tran, Tran, Reiser, Lin, Herweg, Sayad, Saiz and Noujaim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.engFrontiers Media S.A.Facultad de Ciencias BásicasFacultad de Ciencias Básicashttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85076349037&doi=10.3389%2ffphar.2019.01392&partnerID=40&md5=51edc9be3346dbe0bdcbb5d42f2a7cf210Al-Bari, M.A., Chloroquine analogues in drug discovery: New directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases (2015) J. Antimicrob. Chemother., 70, pp. 1608-1621Anisimov, S.V., Boheler, K.R., Aging-associated changes in cardiac gene expression: Large scale transcriptome analysis (2003) Advances in Gerontology = Uspekhi Gerontologii / Rossiiskaia Akademiia Nauk. Gerontol. Obshchestvo, 11, pp. 67-75Atienza, F., Jalife, J., Reentry and atrial fibrillation (2007) Heart Rhythm.: Off. J. Heart Rhythm. Soc., 4, pp. S13-S16Bai, J., Gladding, P.A., Stiles, M.K., Fedorov, V.V., Zhao, J., Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells (2018) Sci. Rep., 8, p. 15642Burrell, Z.L., Jr., Martinez, A.C., Chloroquine and hydroxychloroquine in the treatment of cardiac arrhythmias (1958) New Engl. J. Med., 258, pp. 798-800Chung, M.K., Shemanski, L., Sherman, D.G., Greene, H.L., Hogan, D.B., Kellen, J.C., Functional status in rate- Versus rhythm-control strategies for atrial fibrillation: Results of the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) functional status substudy (2005) J. Am. Coll. Cardiol., 46, pp. 1891-1899Colman, M.A., Pinali, C., Trafford, A.W., Zhang, H., Kitmitto, A., A computational model of spatio-temporal cardiac intracellular calcium handling with realistic structure and spatial flux distribution from sarcoplasmic reticulum and t-tubule reconstructions (2017) PloS Comput. Biol., 13Courtemanche, M., Ramirez, R.J., Nattel, S., Ionic mechanisms underlying human atrial action potential properties: Insights from a mathematical model (1998) Am. J. Physiol., 275, pp. H301-H321DeGroot, N.M., Schalij, M.J., Fragmented,long-duration,low-amplitude electrograms characterize the origin of focal atrial tachycardia (2006) J. Cardiovasc. Electrophysiol., 17, pp. 1086-1092Dobrev, D., Nattel, S., New insights into the molecular basis of atrial fibrillation: Mechanistic and therapeutic implications (2011) Cardiovasc. Res., 89, pp. 689-691Duarte, M.R.A., Tobón, C., Cardona, K., Saiz, J., Chloroquine effect on human atrial action potential under normal conditions and during paroxysmal and chronic atrial fibrillation (2013) Columbia:A Simulation Study, PAHCE, pp. 71-75Filgueiras-Rama, D., Martins, R.P., Mironov, S., Yamazaki, M., Calvo, C.J., Ennis, S.R., Chloroquine terminates stretch-induced atrial fibrillation more effectively than flecainide in the sheep heart (2012) Circ. Arrhythmia Electrophysiol., 5, pp. 561-570Grandi, E., Pandit, S.V., Voigt, N., Workman, A.J., Dobrev, D., Jalife, J., Human atrial action potential and Ca2+ model: Sinus rhythm and chronic atrial fibrillation (2011) Circ. Res., 109, pp. 1055-1066Greenwood, J.R., Calkins, D., Sullivan, A.P., Shelley, J.C., Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution (2010) J. Computer-Aided Mol. Design, 24, pp. 591-604Hagens, V.E., Van Veldhuisen, D.J., Kamp, O., Rienstra, M., Bosker, H.A., Veeger, N.J., Effect of rate and rhythm control on left ventricular function and cardiac dimensions in patients with persistent atrial fibrillation: Results from the RAte Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) study (2005) Heart Rhythm.: Off. J. Heart Rhythm. Soc., 2, pp. 19-24Harris, L., Downar, E., Shaikh, N.A., Chen, T., Antiarrhythmic potential of chloroquine: New use for an old drug (1988) Can. J. Cardiol., 4, pp. 295-300Heidenreich, E.A., Ferrero, J.M., Doblare, M., Rodriguez, J.F., Adaptive macro finite elements for the numerical solution of monodomain equations in cardiac electrophysiology (2010) Ann. Biomed. Eng., 38, pp. 2331-2345Humphrey, W., Dalke, A., Schulten, K., VMD: Visual molecular dynamics (1996) J. Mol. Graphics, 14 (33-8). , 27-8Iijima, H., Dunbar, J.B., Jr., Marshall, G.R., Calibration of effective van der Waals atomic contact radii for proteins and peptides (1987) Proteins, 2, pp. 330-339Kalifa, J., Tanaka, K., Zaitsev, A.V., Warren, M., Vaidyanathan, R., Auerbach, D., Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation (2006) Circulation, 113, pp. 626-633Karunajeewa, H.A., Salman, S., Mueller, I., Baiwog, F., Gomorrai, S., Law, I., Pharmacokinetics of chloroquine and monodesethylchloroquine in pregnancy (2010) Antimicrob. Agents Chemother., 54, pp. 1186-1192Kneller, J., Zou, R., Vigmond, E.J., Wang, Z., Leon, L.J., Nattel, S., Cholinergic atrial fibrillation in a computer model of a two-dimensional sheet of canine atrial cells with realistic ionic properties (2002) Circ. Res., 90, pp. E73-E87Koura, T., Hara, M., Takeuchi, S., Ota, K., Okada, Y., Miyoshi, S., Anisotropic conduction properties in canine atria analyzed by high-resolution optical mapping: Preferential direction of conduction block changes from longitudinal to transverse with increasing age (2002) Circulation, 105, pp. 2092-2098Kumar, S., Teh, A.W., Medi, C., Kistler, P.M., Morton, J.B., Kalman, J.M., Atrial remodeling in varying clinical substrates within beating human hearts: Relevance to atrial fibrillation (2012) Prog. In Biophys. Mol. Biol., 110, pp. 278-294Liao, J.N., Chao, T.F., Liu, C.J., Wang, K.L., Chen, S.J., Tuan, T.C., Risk and prediction of dementia in patients with atrial fibrillation a nationwide population-based cohort study (2015) Int. J. Cardiol., 199, pp. 25-30Mahler, J., Persson, I., A study of the hydration of the alkali metal ions in aqueous solution (2012) Inorg. Chem., 51, pp. 425-438Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., Autodock4 and AutoDockTools4: Automated docking with selective receptor flexibility (2009) J. Comput. Chem., 30, pp. 2785-2791Moslehi, J., DePinho, R.A., Sahin, E., Telomeres and mitochondria in the aging heart (2012) Circ. Res., 110, pp. 1226-1237Narayan, S.M., Krummen, D.E., Targeting stable rotors to treat atrial fibrillation (2012) Arrhythm Electrophysiol. Rev., 1, pp. 34-38Narayan, S.M., Krummen, D.E., Enyeart, M.W., Rappel, W.J., Computational mapping identifies localized mechanisms for ablation of atrial fibrillation (2012) PloS One, 7Narayan, S.M., Krummen, D.E., Rappel, W.J., Clinical mapping approach to diagnose electrical rotors and focal impulse sources for human atrial fibrillation (2012) J. Cardiovasc. Electrophysiol., 23, pp. 447-454Narayan, S.M., Krummen, D.E., Shivkumar, K., Clopton, P., Rappel, W.J., Miller, J.M., Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation with or without Focal Impulse and Rotor Modulation) trial (2012) J. Am. Coll. Cardiol., 60, pp. 628-636Narayan, S.M., Patel, J., Mulpuru, S., Krummen, D.E., Focal impulse and rotor modulation ablation of sustaining rotors abruptly terminates persistent atrial fibrillation to sinus rhythm with elimination on follow-up: A video case study (2012) Heart Rhythm.: Off. J. Heart Rhythm. Soc., 9, pp. 1436-1439Noujaim, S.F., Pandit, S.V., Berenfeld, O., Vikstrom, K., Cerrone, M., Mironov, S., Up-regulation of the inward rectifier K+ current (I K1) in the mouse heart accelerates and stabilizes rotors (2007) J. Physiol., 578, pp. 315-326Noujaim, S.F., Stuckey, J.A., Ponce-Balbuena, D., Ferrer-Villada, T., Lopez-Izquierdo, A., Pandit, S., Specific residues of the cytoplasmic domains of cardiac inward rectifier potassium channels are effective antifibrillatory targets (2010) FASEB J.: Off. Publ. Fed. Am. Soc. Exp. Biol., 24, pp. 4302-4312Noujaim, S.F., Stuckey, J.A., Ponce-Balbuena, D., Ferrer-Villada, T., Lopez-Izquierdo, A., Pandit, S.V., Structural bases for the different anti-fibrillatory effects of chloroquine and quinidine (2011) Cardiovasc. Res., 89, pp. 862-869Olshansky, B., Combining ablation of atrial fibrillation with ablation of atrial flutter: Are we there yet? (2004) J. Am. Coll. Cardiol., 43, pp. 2063-2065Pegan, S., Arrabit, C., Zhou, W., Kwiatkowski, W., Collins, A., Slesinger, P.A., Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification (2005) Nat. Neurosci., 8, pp. 279-287Podd, S.J., Freemantle, N., Furniss, S.S., Sulke, N., First clinical trial of specific IKACh blocker shows no reduction in atrial fibrillation burden in patients with paroxysmal atrial fibrillation: Pacemaker assessment of BMS 914392 in patients with paroxysmal atrial fibrillation (2016) Eur.: Eur. Pacing Arrhythmias Cardiac Electrophysiol.: J. Working Groups Cardiac Pacing Arrhythmias Cardiac Cell. Electrophysiol. Eur. Soc. Cardiol., 18, pp. 340-346Pond, A.L., Scheve, B.K., Benedict, A.T., Petrecca, K., Van Wagoner, D.R., Shrier, A., Expression of distinct ERG proteins in rat, mouse, and human heart (2000) Relat. Funct. I(Kr) Channels J. Biol. Chem., 275, pp. 5997-6006Rienstra, M., Van Veldhuisen, D.J., Hagens, V.E., Ranchor, A.V., Veeger, N.J., Crijns, H.J., Gender-related differences in rhythm control treatment in persistent atrial fibrillation: Data of the Rate Control Versus Electrical Cardioversion (RACE) study (2005) J. Am. Coll. Cardiol., 46, pp. 1298-1306Rietbrock, S., Heeley, E., Plumb, J., Van Staa, T., Chronic atrial fibrillation: Incidence, prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme (2008) Am. Heart J., 156, pp. 57-64Riou, B., Barriot, P., Rimailho, A., Baud, F.J., Treatment of severe chloroquine poisoning (1988) New Engl. J. Med., 318, pp. 1-6Rodriguez-Menchaca, A.A., Navarro-Polanco, R.A., Ferrer-Villada, T., Rupp, J., Sachse, F.B., Tristani-Firouzi, M., The molecular basis of chloroquine block of the inward rectifier Kir2.1 channel (2008) Proc. Natl. Acad. Sci. U. States America, 105, pp. 1364-1368Ryu, K., Sahadevan, J., Khrestian, C.M., Stambler, B.S., Waldo, A.L., Use of fast fourier transform analysis of atrial electrograms for rapid characterization of atrial activation-implications for delineating possible mechanisms of atrial tachyarrhythmias (2006) J. Cardiovasc. Electrophysiol., 17, pp. 198-206Sanchez-Chapula, J.A., Salinas-Stefanon, E., Torres-Jacome, J., Benavides-Haro, D.E., Navarro-Polanco, R.A., Blockade of currents by the antimalarial drug chloroquine in feline ventricular myocytes (2001) J. Pharmacol. Exp. Ther., 297, pp. 437-445Sanchez-Chapula, J.A., Navarro-Polanco, R.A., Culberson, C., Chen, J., Sanguinetti, M.C., Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block (2002) J. Biol. Chem., 277, pp. 23587-23595Sastry, G.M., Adzhigirey, M., Day, T., Annabhimoju, R., Sherman, W., Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments (2013) J. Computer-Aided Mol. Design, 27, pp. 221-234Schotten, U., Greiser, M., Benke, D., Buerkel, K., Ehrenteidt, B., Stellbrink, C., Atrial fibrillation-induced atrial contractile dysfunction: A tachycardiomyopathy of a different sort (2002) Cardiovasc. Res., 53, pp. 192-201Shelley, J.C., Cholleti, A., Frye, L.L., Greenwood, J.R., Timlin, M.R., Uchimaya, M., EPIK: A software program for pK(a) prediction and protonation state generation for drug-like molecules (2007) J. Computer-Aided Mol. Design, 21, pp. 681-691Shivakumar, D., Williams, J., Wu, Y., Damm, W., Shelley, J., Sherman, W., Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field (2010) J. Chem. Theory Comput., 6, pp. 1509-1519Shukla, A., Curtis, A.B., Avoiding permanent atrial fibrillation: Treatment approaches to prevent disease progression (2014) Vasc. Health Risk Manage., 10, pp. 1-12Singh-Manoux, A., Fayosse, A., Sabia, S., Canonico, M., Bobak, M., Elbaz, A., Atrial fibrillation as a risk factor for cognitive decline and dementia (2017) Eur. Heart J., 38, pp. 2612-2618Skibsbye, L., Jespersen, T., Christ, T., Maleckar, M.M., Van Den Brink, J., Tavi, P., Refractoriness in human atria: Time and voltage dependence of sodium channel availability (2016) J. Mol. Cell. Cardiol., 101, pp. 26-34Stas, P., Faes, D., Noyens, P., Conduction disorder and QT prolongation secondary to long-term treatment with chloroquine (2008) Int. J. Cardiol., 127, pp. e80-e82Takemoto, Y., Slough, D.P., Meinke, G., Katnik, C., Graziano, Z.A., Chidipi, B., Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule (2018) FASEB J.: Off. Publ. Fed. Am. Soc. Exp. Biol., 32, pp. 1778-1793Teixeira, R.A., Borba, E.F., Pedrosa, A., Nishioka, S., Viana, V.S., Ramires, J.A., Evidence for cardiac safety and antiarrhythmic potential of chloroquine in systemic lupus erythematosus (2014) Eur.: Eur. Pacing Arrhythmias Cardiac Electrophysiol.: J. Working Groups Cardiac Pacing Arrhythmias Cardiac Cell. Electrophysiol. Eur. Soc. Cardiol., 16, pp. 887-892Tobon, C., Ruiz-Villa, C.A., Heidenreich, E., Romero, L., Hornero, F., Saiz, J., A three-dimensional human atrial model with fiber orientation. Electrograms arrhythmic activation patterns relat (2013) PloS One, 8Traebert, M., Dumotier, B., Meister, L., Hoffmann, P., Dominguez-Estevez, M., Suter, W., Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells (2004) Eur. J. Pharmacol., 484, pp. 41-48Van Wagoner, D.R., Electrophysiological remodeling in human atrial fibrillation (2003) Pacing Clin. Electrophysiol.: PACE, 26, pp. 1572-1575Vest, J.A., Wehrens, X.H., Reiken, S.R., Lehnart, S.E., Dobrev, D., Chandra, P., Defective cardiac ryanodine receptor regulation during atrial fibrillation (2005) Circulation, 111, pp. 2025-2032Voigt, N., Friedrich, A., Bock, M., Wettwer, E., Christ, T., Knaut, M., Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated IK,ACh channels in patients with chronic atrial fibrillation (2007) Cardiovasc. Res., 74, pp. 426-437Voigt, N., Trausch, A., Knaut, M., Matschke, K., Varro, A., Van Wagoner, D.R., Left-to-right atrial inward rectifier potassium current gradients in patients with paroxysmal versus chronic atrial fibrillation (2010) Circ. Arrhythmia Electrophysiol., 3, pp. 472-480Volkova, M., Garg, R., Dick, S., Boheler, K.R., Aging-associated changes in cardiac gene expression (2005) Cardiovasc. Res., 66, pp. 194-204Walfridsson, H., Anfinsen, O.G., Berggren, A., Frison, L., Jensen, S., Linhardt, G., Is the acetylcholine-regulated inwardly rectifying potassium current a viable antiarrhythmic target? Translational discrepancies of AZD2927 and A7071 in dogs and humans (2015) Eur.: Eur. Pacing Arrhythmias Cardiac Electrophysiol.: J. Working Groups Cardiac Pacing Arrhythmias Cardiac Cell. Electrophysiol. Eur. Soc. Cardiol., 17, pp. 473-482White, N.J., Cardiotoxicity of antimalarial drugs (2007) Lancet Infect. Dis., 7, pp. 549-558Wishart, D.S., Knox, C., Guo, A.C., Cheng, D., Shrivastava, S., Tzur, D., Drugbank: A knowledgebase for drugs, drug actions and drug targets (2008) Nucleic Acids Res, 36, pp. D901-D906Wolf, P.A., Abbott, R.D., Kannel, W.B., Atrial fibrillation as an independent risk factor for stroke: The Framingham Study (1991) StrokeJ. Cereb. Circ., 22, pp. 983-988Workman, A.J., Kane, K.A., Rankin, A.C., The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation (2001) Cardiovasc. Res., 52, pp. 226-235Wozniacka, A., Cygankiewicz, I., Chudzik, M., Sysa-Jedrzejowska, A., Wranicz, J.K., The cardiac safety of chloroquine phosphate treatment in patients with systemic lupus erythematosus: The influence on arrhythmia, heart rate variability and repolarization parameters (2006) Lupus, 15, pp. 521-525Zimetbaum, P., Antiarrhythmic drug therapy for atrial fibrillation (2012) Circulation, 125, pp. 381-389Zlochiver, S., Yamazaki, M., Kalifa, J., Berenfeld, O., Rotor meandering contributes to irregularity in electrograms during atrial fibrillation (2008) Heart Rhythm.: Off. J. Heart Rhythm. Soc., 5, pp. 846-854Frontiers in PharmacologyChloroquineIK1IKAChPersistent atrial fibrillationPotassium inward rectifiersantimalarial agentapixabanchloroquineinwardly rectifying potassium channel subunit Kir2.1inwardly rectifying potassium channel subunit Kir3.1metoprololpotassium channelunclassified drugaction potential durationagedamebiasisArticleclinical articledisease burdendrug effectdrug mechanismdrug protein bindingfemalehumanIC50laboratory testmathematical modelmolecular dockingmolecular modelpatch clamp techniquepersistent atrial fibrillationpotassium currentThe antimalarial chloroquine reduces the burden of persistent atrial fibrillationArticleinfo:eu-repo/semantics/articlehttp://purl.org/coar/version/c_970fb48d4fbd8a85http://purl.org/coar/resource_type/c_6501http://purl.org/coar/resource_type/c_2df8fbb1Tobón, C., MATBIOM, Universidad de Medellín, Medellín, Colombia; Palacio, L.C., MATBIOM, Universidad de Medellín, Medellín, Colombia; Chidipi, B., Molecular Pharmacology and Physiology Department, University of South Florida Morsani College of Medicine, Tampa, FL, United States; Slough, D.P., Department of Chemistry, Tufts University, Medford, MA, United States; Tran, T., Cardiology Department, University of South Florida Morsani College of Medicine, Tampa, FL, United States; Tran, N., Cardiology Department, University of South Florida Morsani College of Medicine, Tampa, FL, United States; Reiser, M., Molecular Pharmacology and Physiology Department, University of South Florida Morsani College of Medicine, Tampa, FL, United States; Lin, Y.-S., Department of Chemistry, Tufts University, Medford, MA, United States; Herweg, B., Cardiology Department, University of South Florida Morsani College of Medicine, Tampa, FL, United States; Sayad, D., Cardiology Department, University of South Florida Morsani College of Medicine, Tampa, FL, United States; Saiz, J., Ci2 B, Universitat Politècnica de València, Valencia, Spain; Noujaim, S., Molecular Pharmacology and Physiology Department, University of South Florida Morsani College of Medicine, Tampa, FL, United Stateshttp://purl.org/coar/access_right/c_16ecTobón C.Palacio L.C.Chidipi B.Slough D.P.Tran T.Tran N.Reiser M.Lin Y.-S.Herweg B.Sayad D.Saiz J.Noujaim S.11407/5701oai:repository.udem.edu.co:11407/57012020-05-27 16:37:54.527Repositorio Institucional Universidad de Medellinrepositorio@udem.edu.co |