Skip to main content
Erschienen in: Herz 5/2023

02.02.2023 | Original articles

Effects of hydroxychloroquine on atrial electrophysiology in in silico wild-type and PITX2+/- atrial cardiomyocytes

verfasst von: Euijun Song, MD

Erschienen in: Herz | Ausgabe 5/2023

Einloggen, um Zugang zu erhalten

Abstract

Background

Hydroxychloroquine (HCQ) is commonly used in the treatment of autoimmune diseases and increases the risk of QT interval prolongation. However, it is unclear how HCQ affects atrial electrophysiology and the risk of atrial fibrillation (AF).

Methods

We quantitatively examined the potential atrial arrhythmogenic effects of HCQ on AF using a computational model of human atrial cardiomyocytes. We measured atrial electrophysiological markers after systematically varying HCQ concentrations.

Results

The HCQ concentrations were positively correlated with the action potential duration (APD), resting membrane potential, refractory period, APD alternans threshold, and calcium transient alternans threshold (p < 0.05). By contrast, HCQ concentrations were inversely correlated with the maximum upstroke velocity and calcium transient amplitude (p < 0.05). When the therapeutic concentration (Cmax) of HCQ was applied, HCQ increased APD90 by 1.4% in normal sinus rhythm, 1.8% in wild-type AF, and 2.6% in paired-like homeodomain transcription factor 2 (PITX2)+/- AF, but did not affect the alternans thresholds. The overall in silico results suggest no significant atrial arrhythmogenic effects of HCQ at Cmax, instead implying a potential antiarrhythmic role of low-dose HCQ in AF. However, at an HCQ concentration of fourfold Cmax, a rapid pacing rate of 4 Hz induced prominent APD alternans, particularly in the PITX2+/- AF model.

Conclusion

Our in silico analysis suggests a potential antiarrhythmic role of low-dose HCQ in AF. Concomitant PITX2 mutations and high-dose HCQ treatments may increase the risk of AF, and this potential genotype/dose-dependent arrhythmogenic effect of HCQ should be investigated further.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Nirk EL, Reggiori F, Mauthe M (2020) Hydroxychloroquine in rheumatic autoimmune disorders and beyond. EMBO Mol Med 12:e12476PubMedPubMedCentral Nirk EL, Reggiori F, Mauthe M (2020) Hydroxychloroquine in rheumatic autoimmune disorders and beyond. EMBO Mol Med 12:e12476PubMedPubMedCentral
2.
Zurück zum Zitat Schrezenmeier E, Dorner T (2020) Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 16:155–166PubMed Schrezenmeier E, Dorner T (2020) Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 16:155–166PubMed
3.
Zurück zum Zitat Group RC, Horby P, Mafham M, Linsell L, Bell JL, Staplin N, Emberson JR, Wiselka M, Ustianowski A, Elmahi E, Prudon B, Whitehouse T, Felton T, Williams J, Faccenda J, Underwood J, Baillie JK, Chappell LC, Faust SN, Jaki T, Jeffery K, Lim WS, Montgomery A, Rowan K, Tarning J, Watson JA, White NJ, Juszczak E, Haynes R, Landray MJ (2020) Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med 383:2030–2040 Group RC, Horby P, Mafham M, Linsell L, Bell JL, Staplin N, Emberson JR, Wiselka M, Ustianowski A, Elmahi E, Prudon B, Whitehouse T, Felton T, Williams J, Faccenda J, Underwood J, Baillie JK, Chappell LC, Faust SN, Jaki T, Jeffery K, Lim WS, Montgomery A, Rowan K, Tarning J, Watson JA, White NJ, Juszczak E, Haynes R, Landray MJ (2020) Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med 383:2030–2040
4.
Zurück zum Zitat Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, Skipper CP, Nascene AA, Nicol MR, Abassi M, Engen NW, Cheng MP, LaBar D, Lother SA, MacKenzie LJ, Drobot G, Marten N, Zarychanski R, Kelly LE, Schwartz IS, McDonald EG, Rajasingham R, Lee TC, Hullsiek KH (2020) A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med 383:517–525PubMed Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, Skipper CP, Nascene AA, Nicol MR, Abassi M, Engen NW, Cheng MP, LaBar D, Lother SA, MacKenzie LJ, Drobot G, Marten N, Zarychanski R, Kelly LE, Schwartz IS, McDonald EG, Rajasingham R, Lee TC, Hullsiek KH (2020) A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med 383:517–525PubMed
5.
Zurück zum Zitat Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, Avezum A, Damiani LP, Marcadenti A, Kawano-Dourado L, Lisboa T, Junqueira DLM, de Barros ESPGM, Tramujas L, Abreu-Silva EO, Laranjeira LN, Soares AT, Echenique LS, Pereira AJ, Freitas FGR, Gebara OCE, Dantas VCS, Furtado RHM, Milan EP, Golin NA, Cardoso FF, Maia IS, Hoffmann Filho CR, Kormann APM, Amazonas RB, Bocchi de Oliveira MF, Serpa-Neto A, Falavigna M, Lopes RD, Machado FR, Berwanger O, Coalition Covid-19 Brazil I Investigators (2020) Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med 383:2041–2052PubMed Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, Avezum A, Damiani LP, Marcadenti A, Kawano-Dourado L, Lisboa T, Junqueira DLM, de Barros ESPGM, Tramujas L, Abreu-Silva EO, Laranjeira LN, Soares AT, Echenique LS, Pereira AJ, Freitas FGR, Gebara OCE, Dantas VCS, Furtado RHM, Milan EP, Golin NA, Cardoso FF, Maia IS, Hoffmann Filho CR, Kormann APM, Amazonas RB, Bocchi de Oliveira MF, Serpa-Neto A, Falavigna M, Lopes RD, Machado FR, Berwanger O, Coalition Covid-19 Brazil I Investigators (2020) Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med 383:2041–2052PubMed
6.
Zurück zum Zitat Sacre K, Criswell LA, McCune JM (2012) Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res Ther 14:R155PubMedPubMedCentral Sacre K, Criswell LA, McCune JM (2012) Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res Ther 14:R155PubMedPubMedCentral
7.
Zurück zum Zitat Wallace DJ, Linker-Israeli M, Metzger AL, Stecher VJ (1993) The relevance of antimalarial therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE. Lupus 2(1):S13–15PubMed Wallace DJ, Linker-Israeli M, Metzger AL, Stecher VJ (1993) The relevance of antimalarial therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE. Lupus 2(1):S13–15PubMed
8.
Zurück zum Zitat Banchereau R, Hong S, Cantarel B, Baldwin N, Baisch J, Edens M, Cepika AM, Acs P, Turner J, Anguiano E, Vinod P, Kahn S, Obermoser G, Blankenship D, Wakeland E, Nassi L, Gotte A, Punaro M, Liu YJ, Banchereau J, Rossello-Urgell J, Wright T, Pascual V (2016) Personalized Immunomonitoring uncovers molecular networks that stratify lupus patients. Cell 165:551–565PubMedPubMedCentral Banchereau R, Hong S, Cantarel B, Baldwin N, Baisch J, Edens M, Cepika AM, Acs P, Turner J, Anguiano E, Vinod P, Kahn S, Obermoser G, Blankenship D, Wakeland E, Nassi L, Gotte A, Punaro M, Liu YJ, Banchereau J, Rossello-Urgell J, Wright T, Pascual V (2016) Personalized Immunomonitoring uncovers molecular networks that stratify lupus patients. Cell 165:551–565PubMedPubMedCentral
9.
Zurück zum Zitat Ponticelli C, Moroni G (2017) Hydroxychloroquine in systemic lupus erythematosus (SLE). Expert Opin Drug Saf 16:411–419PubMed Ponticelli C, Moroni G (2017) Hydroxychloroquine in systemic lupus erythematosus (SLE). Expert Opin Drug Saf 16:411–419PubMed
10.
Zurück zum Zitat Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM (2018) Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature. Drug Saf 41:919–931PubMed Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM (2018) Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature. Drug Saf 41:919–931PubMed
11.
Zurück zum Zitat Costedoat-Chalumeau N, Hulot JS, Amoura Z, Leroux G, Lechat P, Funck-Brentano C, Piette JC (2007) Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases. Rheumatology 46:808–810PubMed Costedoat-Chalumeau N, Hulot JS, Amoura Z, Leroux G, Lechat P, Funck-Brentano C, Piette JC (2007) Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases. Rheumatology 46:808–810PubMed
12.
Zurück zum Zitat Jorge A, Ung C, Young LH, Melles RB, Choi HK (2018) Hydroxychloroquine retinopathy—implications of research advances for rheumatology care. Nat Rev Rheumatol 14:693–703PubMed Jorge A, Ung C, Young LH, Melles RB, Choi HK (2018) Hydroxychloroquine retinopathy—implications of research advances for rheumatology care. Nat Rev Rheumatol 14:693–703PubMed
13.
Zurück zum Zitat O’Laughlin JP, Mehta PH, Wong BC (2016) Life threatening severe QTc prolongation in patient with systemic lupus erythematosus due to hydroxychloroquine. Case Rep Cardiol 2016:4626279PubMedPubMedCentral O’Laughlin JP, Mehta PH, Wong BC (2016) Life threatening severe QTc prolongation in patient with systemic lupus erythematosus due to hydroxychloroquine. Case Rep Cardiol 2016:4626279PubMedPubMedCentral
14.
Zurück zum Zitat Jankelson L, Karam G, Becker ML, Chinitz LA, Tsai MC (2020) QT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: a systematic review. Heart Rhythm 17:1472–1479PubMedPubMedCentral Jankelson L, Karam G, Becker ML, Chinitz LA, Tsai MC (2020) QT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: a systematic review. Heart Rhythm 17:1472–1479PubMedPubMedCentral
15.
Zurück zum Zitat Thomet U, Amuzescu B, Knott T, Mann SA, Mubagwa K, Radu BM (2021) Assessment of proarrhythmogenic risk for chloroquine and hydroxychloroquine using the CiPA concept. Eur J Pharmacol 913:174632PubMedPubMedCentral Thomet U, Amuzescu B, Knott T, Mann SA, Mubagwa K, Radu BM (2021) Assessment of proarrhythmogenic risk for chloroquine and hydroxychloroquine using the CiPA concept. Eur J Pharmacol 913:174632PubMedPubMedCentral
16.
Zurück zum Zitat Delaunois A, Abernathy M, Anderson WD, Beattie KA, Chaudhary KW, Coulot J, Gryshkova V, Hebeisen S, Holbrook M, Kramer J, Kuryshev Y, Leishman D, Lushbough I, Passini E, Redfern WS, Rodriguez B, Rossman EI, Trovato C, Wu C, Valentin JP (2021) Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off-label in the first wave of COVID-19. Clin Transl Sci 14:1133–1146PubMedPubMedCentral Delaunois A, Abernathy M, Anderson WD, Beattie KA, Chaudhary KW, Coulot J, Gryshkova V, Hebeisen S, Holbrook M, Kramer J, Kuryshev Y, Leishman D, Lushbough I, Passini E, Redfern WS, Rodriguez B, Rossman EI, Trovato C, Wu C, Valentin JP (2021) Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off-label in the first wave of COVID-19. Clin Transl Sci 14:1133–1146PubMedPubMedCentral
17.
Zurück zum Zitat Whittaker DG, Capel RA, Hendrix M, Chan XHS, Herring N, White NJ, Mirams GR, Burton RB (2021) Cardiac TdP risk stratification modelling of anti-infective compounds including chloroquine and hydroxychloroquine. R Soc open sci 8:210235PubMedPubMedCentral Whittaker DG, Capel RA, Hendrix M, Chan XHS, Herring N, White NJ, Mirams GR, Burton RB (2021) Cardiac TdP risk stratification modelling of anti-infective compounds including chloroquine and hydroxychloroquine. R Soc open sci 8:210235PubMedPubMedCentral
18.
Zurück zum Zitat Li Z, Ridder BJ, Han X, Wu WW, Sheng J, Tran PN, Wu M, Randolph A, Johnstone RH, Mirams GR, Kuryshev Y, Kramer J, Wu C, Crumb WJ Jr., Strauss DG (2019) Assessment of an in silico mechanistic model for proarrhythmia risk prediction under the CiPA initiative. Clin Pharmacol Ther 105:466–475PubMed Li Z, Ridder BJ, Han X, Wu WW, Sheng J, Tran PN, Wu M, Randolph A, Johnstone RH, Mirams GR, Kuryshev Y, Kramer J, Wu C, Crumb WJ Jr., Strauss DG (2019) Assessment of an in silico mechanistic model for proarrhythmia risk prediction under the CiPA initiative. Clin Pharmacol Ther 105:466–475PubMed
19.
Zurück zum Zitat Li Z, Dutta S, Sheng J, Tran PN, Wu W, Chang K, Mdluli T, Strauss DG, Colatsky T (2017) Improving the in silico assessment of proarrhythmia risk by combining hERG (human ether-a-go-go-related gene) channel-drug binding kinetics and multichannel pharmacology. Circ Arrhythm Electrophysiol 10:e4628PubMed Li Z, Dutta S, Sheng J, Tran PN, Wu W, Chang K, Mdluli T, Strauss DG, Colatsky T (2017) Improving the in silico assessment of proarrhythmia risk by combining hERG (human ether-a-go-go-related gene) channel-drug binding kinetics and multichannel pharmacology. Circ Arrhythm Electrophysiol 10:e4628PubMed
20.
Zurück zum Zitat Grandi E, Pandit SV, Voigt N, Workman AJ, Dobrev D, Jalife J, Bers DM (2011) Human atrial action potential and Ca2+ model: sinus rhythm and chronic atrial fibrillation. Circ Res 109:1055–1066PubMedPubMedCentral Grandi E, Pandit SV, Voigt N, Workman AJ, Dobrev D, Jalife J, Bers DM (2011) Human atrial action potential and Ca2+ model: sinus rhythm and chronic atrial fibrillation. Circ Res 109:1055–1066PubMedPubMedCentral
21.
Zurück zum Zitat Courtemanche M, Ramirez RJ, Nattel S (1998) Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model. Am J Physiol 275:H301–321PubMed Courtemanche M, Ramirez RJ, Nattel S (1998) Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model. Am J Physiol 275:H301–321PubMed
22.
Zurück zum Zitat Boyle PM, Zghaib T, Zahid S, Ali RL, Deng D, Franceschi WH, Hakim JB, Murphy MJ, Prakosa A, Zimmerman SL, Ashikaga H, Marine JE, Kolandaivelu A, Nazarian S, Spragg DD, Calkins H, Trayanova NA (2019) Computationally guided personalized targeted ablation of persistent atrial fibrillation. Nat Biomed Eng 3:870–879PubMedPubMedCentral Boyle PM, Zghaib T, Zahid S, Ali RL, Deng D, Franceschi WH, Hakim JB, Murphy MJ, Prakosa A, Zimmerman SL, Ashikaga H, Marine JE, Kolandaivelu A, Nazarian S, Spragg DD, Calkins H, Trayanova NA (2019) Computationally guided personalized targeted ablation of persistent atrial fibrillation. Nat Biomed Eng 3:870–879PubMedPubMedCentral
24.
Zurück zum Zitat Moreno JD, Zhu ZI, Yang PC, Bankston JR, Jeng MT, Kang C, Wang L, Bayer JD, Christini DJ, Trayanova NA, Ripplinger CM, Kass RS, Clancy CE (2011) A computational model to predict the effects of class I anti-arrhythmic drugs on ventricular rhythms. Sci Transl Med 3:98ra83PubMedPubMedCentral Moreno JD, Zhu ZI, Yang PC, Bankston JR, Jeng MT, Kang C, Wang L, Bayer JD, Christini DJ, Trayanova NA, Ripplinger CM, Kass RS, Clancy CE (2011) A computational model to predict the effects of class I anti-arrhythmic drugs on ventricular rhythms. Sci Transl Med 3:98ra83PubMedPubMedCentral
25.
Zurück zum Zitat Dasi A, Roy A, Sachetto R, Camps J, Bueno-Orovio A, Rodriguez B (2022) In-silico drug trials for precision medicine in atrial fibrillation: from ionic mechanisms to electrocardiogram-based predictions in structurally-healthy human atria. Front Physiol 13:966046PubMedPubMedCentral Dasi A, Roy A, Sachetto R, Camps J, Bueno-Orovio A, Rodriguez B (2022) In-silico drug trials for precision medicine in atrial fibrillation: from ionic mechanisms to electrocardiogram-based predictions in structurally-healthy human atria. Front Physiol 13:966046PubMedPubMedCentral
26.
Zurück zum Zitat Gupta A, Shields KJ, Manzi S, Wasko MC, Sharma TS (2021) Association of hydroxychloroquine use with decreased incident atrial fibrillation in systemic lupus erythematosus. Arthritis Care Res (Hoboken) 73:828–832PubMed Gupta A, Shields KJ, Manzi S, Wasko MC, Sharma TS (2021) Association of hydroxychloroquine use with decreased incident atrial fibrillation in systemic lupus erythematosus. Arthritis Care Res (Hoboken) 73:828–832PubMed
27.
Zurück zum Zitat Syeda F, Holmes AP, Yu TY, Tull S, Kuhlmann SM, Pavlovic D, Betney D, Riley G, Kucera JP, Jousset F, de Groot JR, Rohr S, Brown NA, Fabritz L, Kirchhof P (2016) PITX2 modulates atrial membrane potential and the antiarrhythmic effects of sodium-channel blockers. J Am Coll Cardiol 68:1881–1894PubMedPubMedCentral Syeda F, Holmes AP, Yu TY, Tull S, Kuhlmann SM, Pavlovic D, Betney D, Riley G, Kucera JP, Jousset F, de Groot JR, Rohr S, Brown NA, Fabritz L, Kirchhof P (2016) PITX2 modulates atrial membrane potential and the antiarrhythmic effects of sodium-channel blockers. J Am Coll Cardiol 68:1881–1894PubMedPubMedCentral
28.
Zurück zum Zitat Gudbjartsson DF, Arnar DO, Helgadottir A, Gretarsdottir S, Holm H, Sigurdsson A, Jonasdottir A, Baker A, Thorleifsson G, Kristjansson K, Palsson A, Blondal T, Sulem P, Backman VM, Hardarson GA, Palsdottir E, Helgason A, Sigurjonsdottir R, Sverrisson JT, Kostulas K, Ng MC, Baum L, So WY, Wong KS, Chan JC, Furie KL, Greenberg SM, Sale M, Kelly P, MacRae CA, Smith EE, Rosand J, Hillert J, Ma RC, Ellinor PT, Thorgeirsson G, Gulcher JR, Kong A, Thorsteinsdottir U, Stefansson K (2007) Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 448:353–357PubMed Gudbjartsson DF, Arnar DO, Helgadottir A, Gretarsdottir S, Holm H, Sigurdsson A, Jonasdottir A, Baker A, Thorleifsson G, Kristjansson K, Palsson A, Blondal T, Sulem P, Backman VM, Hardarson GA, Palsdottir E, Helgason A, Sigurjonsdottir R, Sverrisson JT, Kostulas K, Ng MC, Baum L, So WY, Wong KS, Chan JC, Furie KL, Greenberg SM, Sale M, Kelly P, MacRae CA, Smith EE, Rosand J, Hillert J, Ma RC, Ellinor PT, Thorgeirsson G, Gulcher JR, Kong A, Thorsteinsdottir U, Stefansson K (2007) Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 448:353–357PubMed
29.
Zurück zum Zitat Lubitz SA, Sinner MF, Lunetta KL, Makino S, Pfeufer A, Rahman R, Veltman CE, Barnard J, Bis JC, Danik SP, Sonni A, Shea MA, Del Monte F, Perz S, Muller M, Peters A, Greenberg SM, Furie KL, van Noord C, Boerwinkle E, Stricker BH, Witteman J, Smith JD, Chung MK, Heckbert SR, Benjamin EJ, Rosand J, Arking DE, Alonso A, Kaab S, Ellinor PT (2010) Independent susceptibility markers for atrial fibrillation on chromosome 4q25. Circulation 122:976–984PubMedPubMedCentral Lubitz SA, Sinner MF, Lunetta KL, Makino S, Pfeufer A, Rahman R, Veltman CE, Barnard J, Bis JC, Danik SP, Sonni A, Shea MA, Del Monte F, Perz S, Muller M, Peters A, Greenberg SM, Furie KL, van Noord C, Boerwinkle E, Stricker BH, Witteman J, Smith JD, Chung MK, Heckbert SR, Benjamin EJ, Rosand J, Arking DE, Alonso A, Kaab S, Ellinor PT (2010) Independent susceptibility markers for atrial fibrillation on chromosome 4q25. Circulation 122:976–984PubMedPubMedCentral
30.
Zurück zum Zitat Syeda F, Kirchhof P, Fabritz L (2017) PITX2-dependent gene regulation in atrial fibrillation and rhythm control. J Physiol 595:4019–4026PubMedPubMedCentral Syeda F, Kirchhof P, Fabritz L (2017) PITX2-dependent gene regulation in atrial fibrillation and rhythm control. J Physiol 595:4019–4026PubMedPubMedCentral
31.
Zurück zum Zitat Vagos MR, Arevalo H, de Oliveira BL, Sundnes J, Maleckar MM (2017) A computational framework for testing arrhythmia marker sensitivities to model parameters in functionally calibrated populations of atrial cells. Chaos 27:93941PubMed Vagos MR, Arevalo H, de Oliveira BL, Sundnes J, Maleckar MM (2017) A computational framework for testing arrhythmia marker sensitivities to model parameters in functionally calibrated populations of atrial cells. Chaos 27:93941PubMed
32.
Zurück zum Zitat Song E, Lee YS (2022) Interpretable machine learning of action potential duration restitution kinetics in single-cell models of atrial cardiomyocytes. J Electrocardiol 74:137–145PubMed Song E, Lee YS (2022) Interpretable machine learning of action potential duration restitution kinetics in single-cell models of atrial cardiomyocytes. J Electrocardiol 74:137–145PubMed
33.
Zurück zum Zitat Lee YS, Hwang M, Song JS, Li C, Joung B, Sobie EA, Pak HN (2016) The contribution of ionic currents to rate-dependent action potential duration and pattern of reentry in a mathematical model of human atrial fibrillation. PLoS ONE 11:e150779PubMedPubMedCentral Lee YS, Hwang M, Song JS, Li C, Joung B, Sobie EA, Pak HN (2016) The contribution of ionic currents to rate-dependent action potential duration and pattern of reentry in a mathematical model of human atrial fibrillation. PLoS ONE 11:e150779PubMedPubMedCentral
34.
Zurück zum Zitat Mirams GR, Cui Y, Sher A, Fink M, Cooper J, Heath BM, McMahon NC, Gavaghan DJ, Noble D (2011) Simulation of multiple ion channel block provides improved early prediction of compounds’ clinical torsadogenic risk. Cardiovasc Res 91:53–61PubMedPubMedCentral Mirams GR, Cui Y, Sher A, Fink M, Cooper J, Heath BM, McMahon NC, Gavaghan DJ, Noble D (2011) Simulation of multiple ion channel block provides improved early prediction of compounds’ clinical torsadogenic risk. Cardiovasc Res 91:53–61PubMedPubMedCentral
35.
Zurück zum Zitat Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S, Lu R, Li H, Tan W, Liu D (2020) In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome Coronavirus 2 (SARS-coV-2). Clin Infect Dis 71:732–739PubMed Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S, Lu R, Li H, Tan W, Liu D (2020) In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome Coronavirus 2 (SARS-coV-2). Clin Infect Dis 71:732–739PubMed
36.
Zurück zum Zitat Costedoat-Chalumeau N, Amoura Z, Hulot JS, Hammoud HA, Aymard G, Cacoub P, Frances C, Wechsler B, Huong du LT, Ghillani P, Musset L, Lechat P, Piette JC (2006) Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum 54:3284–3290PubMed Costedoat-Chalumeau N, Amoura Z, Hulot JS, Hammoud HA, Aymard G, Cacoub P, Frances C, Wechsler B, Huong du LT, Ghillani P, Musset L, Lechat P, Piette JC (2006) Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum 54:3284–3290PubMed
37.
Zurück zum Zitat Wu TJ, Kim YH, Yashima M, Athill CA, Ting CT, Karagueuzian HS, Chen PS (2001) Progressive action potential duration shortening and the conversion from atrial flutter to atrial fibrillation in the isolated canine right atrium. J Am Coll Cardiol 38:1757–1765PubMed Wu TJ, Kim YH, Yashima M, Athill CA, Ting CT, Karagueuzian HS, Chen PS (2001) Progressive action potential duration shortening and the conversion from atrial flutter to atrial fibrillation in the isolated canine right atrium. J Am Coll Cardiol 38:1757–1765PubMed
38.
Zurück zum Zitat Franz MR, Jamal SM, Narayan SM (2012) The role of action potential alternans in the initiation of atrial fibrillation in humans: a review and future directions. Europace 14(5):v58–v64PubMedPubMedCentral Franz MR, Jamal SM, Narayan SM (2012) The role of action potential alternans in the initiation of atrial fibrillation in humans: a review and future directions. Europace 14(5):v58–v64PubMedPubMedCentral
39.
Zurück zum Zitat Prodromos CC, Rumschlag T, Perchyk T (2020) Hydroxychloroquine is protective to the heart, not harmful: a systematic review. New Microbes New Infect 37:100747PubMedPubMedCentral Prodromos CC, Rumschlag T, Perchyk T (2020) Hydroxychloroquine is protective to the heart, not harmful: a systematic review. New Microbes New Infect 37:100747PubMedPubMedCentral
40.
Zurück zum Zitat Lo CH, Wang YH, Tsai CF, Chan KC, Li LC, Lo TH, Wei JC, Su CH (2021) Association of hydroxychloroquine and cardiac arrhythmia in patients with systemic lupus erythematosus: a population-based case control study. PLoS ONE 16:e251918PubMedPubMedCentral Lo CH, Wang YH, Tsai CF, Chan KC, Li LC, Lo TH, Wei JC, Su CH (2021) Association of hydroxychloroquine and cardiac arrhythmia in patients with systemic lupus erythematosus: a population-based case control study. PLoS ONE 16:e251918PubMedPubMedCentral
41.
Zurück zum Zitat McGhie TK, Harvey P, Su J, Anderson N, Tomlinson G, Touma Z (2018) Electrocardiogram abnormalities related to anti-malarials in systemic lupus erythematosus. Clin Exp Rheumatol 36:545–551PubMed McGhie TK, Harvey P, Su J, Anderson N, Tomlinson G, Touma Z (2018) Electrocardiogram abnormalities related to anti-malarials in systemic lupus erythematosus. Clin Exp Rheumatol 36:545–551PubMed
42.
Zurück zum Zitat Lo CH, Wei JC, Wang YH, Tsai CF, Chan KC, Li LC, Lo TH, Su CH (2021) Hydroxychloroquine does not increase the risk of cardiac arrhythmia in common rheumatic diseases: a nationwide population-based cohort study. Front Immunol 12:631869PubMedPubMedCentral Lo CH, Wei JC, Wang YH, Tsai CF, Chan KC, Li LC, Lo TH, Su CH (2021) Hydroxychloroquine does not increase the risk of cardiac arrhythmia in common rheumatic diseases: a nationwide population-based cohort study. Front Immunol 12:631869PubMedPubMedCentral
43.
Zurück zum Zitat Morgan ND, Patel SV, Dvorkina O (2013) Suspected hydroxychloroquine-associated QT-interval prolongation in a patient with systemic lupus erythematosus. J Clin Rheumatol 19:286–288PubMed Morgan ND, Patel SV, Dvorkina O (2013) Suspected hydroxychloroquine-associated QT-interval prolongation in a patient with systemic lupus erythematosus. J Clin Rheumatol 19:286–288PubMed
44.
Zurück zum Zitat Park E, Giles JT, Perez-Recio T, Pina P, Depender C, Gartshteyn Y, Askanase AD, Bathon J, Geraldino-Pardilla L (2021) Hydroxychloroquine use is not associated with QTc length in a large cohort of SLE and RA patients. Arthritis Res Ther 23:271PubMedPubMedCentral Park E, Giles JT, Perez-Recio T, Pina P, Depender C, Gartshteyn Y, Askanase AD, Bathon J, Geraldino-Pardilla L (2021) Hydroxychloroquine use is not associated with QTc length in a large cohort of SLE and RA patients. Arthritis Res Ther 23:271PubMedPubMedCentral
45.
Zurück zum Zitat Tleyjeh IM, Kashour Z, AlDosary O, Riaz M, Tlayjeh H, Garbati MA, Tleyjeh R, Al-Mallah MH, Sohail MR, Gerberi D, Bin Abdulhak AA, Giudicessi JR, Ackerman MJ, Kashour T (2021) Cardiac toxicity of chloroquine or hydroxychloroquine in patients with COVID-19: a systematic review and meta-regression analysis. Mayo Clin Proc Innov Qual Outcomes 5:137–150PubMed Tleyjeh IM, Kashour Z, AlDosary O, Riaz M, Tlayjeh H, Garbati MA, Tleyjeh R, Al-Mallah MH, Sohail MR, Gerberi D, Bin Abdulhak AA, Giudicessi JR, Ackerman MJ, Kashour T (2021) Cardiac toxicity of chloroquine or hydroxychloroquine in patients with COVID-19: a systematic review and meta-regression analysis. Mayo Clin Proc Innov Qual Outcomes 5:137–150PubMed
46.
Zurück zum Zitat Saleh M, Gabriels J, Chang D, Soo Kim B, Mansoor A, Mahmood E, Makker P, Ismail H, Goldner B, Willner J, Beldner S, Mitra R, John R, Chinitz J, Skipitaris N, Mountantonakis S, Epstein LM (2020) Effect of chloroquine, hydroxychloroquine, and azithromycin on the corrected QT interval in patients with SARS-coV‑2 infection. Circ Arrhythm Electrophysiol 13:e8662PubMedPubMedCentral Saleh M, Gabriels J, Chang D, Soo Kim B, Mansoor A, Mahmood E, Makker P, Ismail H, Goldner B, Willner J, Beldner S, Mitra R, John R, Chinitz J, Skipitaris N, Mountantonakis S, Epstein LM (2020) Effect of chloroquine, hydroxychloroquine, and azithromycin on the corrected QT interval in patients with SARS-coV‑2 infection. Circ Arrhythm Electrophysiol 13:e8662PubMedPubMedCentral
47.
Zurück zum Zitat Chorin E, Wadhwani L, Magnani S, Dai M, Shulman E, Nadeau-Routhier C, Knotts R, Bar-Cohen R, Kogan E, Barbhaiya C, Aizer A, Holmes D, Bernstein S, Spinelli M, Park DS, Stefano C, Chinitz LA, Jankelson L (2020) QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin. Heart Rhythm 17:1425–1433PubMedPubMedCentral Chorin E, Wadhwani L, Magnani S, Dai M, Shulman E, Nadeau-Routhier C, Knotts R, Bar-Cohen R, Kogan E, Barbhaiya C, Aizer A, Holmes D, Bernstein S, Spinelli M, Park DS, Stefano C, Chinitz LA, Jankelson L (2020) QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin. Heart Rhythm 17:1425–1433PubMedPubMedCentral
48.
Zurück zum Zitat Mercuro NJ, Yen CF, Shim DJ, Maher TR, McCoy CM, Zimetbaum PJ, Gold HS (2020) Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for Coronavirus disease 2019 (COVID-19). JAMA Cardiol 5:1036–1041PubMed Mercuro NJ, Yen CF, Shim DJ, Maher TR, McCoy CM, Zimetbaum PJ, Gold HS (2020) Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for Coronavirus disease 2019 (COVID-19). JAMA Cardiol 5:1036–1041PubMed
49.
Zurück zum Zitat Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, Weinberg P, Kirkwood J, Muse A, DeHovitz J, Blog DS, Hutton B, Holtgrave DR, Zucker HA (2020) Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state. JAMA 323:2493–2502PubMedPubMedCentral Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, Weinberg P, Kirkwood J, Muse A, DeHovitz J, Blog DS, Hutton B, Holtgrave DR, Zucker HA (2020) Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state. JAMA 323:2493–2502PubMedPubMedCentral
50.
Zurück zum Zitat Kirchhof P, Eckardt L, Franz MR, Monnig G, Loh P, Wedekind H, Schulze-Bahr E, Breithardt G, Haverkamp W (2003) Prolonged atrial action potential durations and polymorphic atrial tachyarrhythmias in patients with long QT syndrome. J Cardiovasc Electrophysiol 14:1027–1033PubMed Kirchhof P, Eckardt L, Franz MR, Monnig G, Loh P, Wedekind H, Schulze-Bahr E, Breithardt G, Haverkamp W (2003) Prolonged atrial action potential durations and polymorphic atrial tachyarrhythmias in patients with long QT syndrome. J Cardiovasc Electrophysiol 14:1027–1033PubMed
51.
Zurück zum Zitat Shenthar J, Rachaiah JM, Pillai V, Chakali SS, Balasubramanian V, Chollenhalli Nanjappa M (2017) Incidence of drug-induced torsades de pointes with intravenous amiodarone. Indian Heart J 69:707–713PubMedPubMedCentral Shenthar J, Rachaiah JM, Pillai V, Chakali SS, Balasubramanian V, Chollenhalli Nanjappa M (2017) Incidence of drug-induced torsades de pointes with intravenous amiodarone. Indian Heart J 69:707–713PubMedPubMedCentral
52.
Zurück zum Zitat Lim HE, Pak HN, Ahn JC, Song WH, Kim YH (2006) Torsade de pointes induced by short-term oral amiodarone therapy. Europace 8:1051–1053PubMed Lim HE, Pak HN, Ahn JC, Song WH, Kim YH (2006) Torsade de pointes induced by short-term oral amiodarone therapy. Europace 8:1051–1053PubMed
53.
Zurück zum Zitat Yuan Y, Zhao J, Gong Y, Wang D, Wang X, Yun F, Liu Z, Zhang S, Li W, Zhao X, Sun L, Sheng L, Pan Z, Li Y (2018) Autophagy exacerbates electrical remodeling in atrial fibrillation by ubiquitin-dependent degradation of L‑type calcium channel. Cell Death Dis 9:873PubMedPubMedCentral Yuan Y, Zhao J, Gong Y, Wang D, Wang X, Yun F, Liu Z, Zhang S, Li W, Zhao X, Sun L, Sheng L, Pan Z, Li Y (2018) Autophagy exacerbates electrical remodeling in atrial fibrillation by ubiquitin-dependent degradation of L‑type calcium channel. Cell Death Dis 9:873PubMedPubMedCentral
54.
Zurück zum Zitat Fedai H, Altiparmak IH, Tascanov MB, Tanriverdi Z, Bicer A, Gungoren F, Demirbag R, Koyuncu I (2022) The relationship between oxidative stress and autophagy and apoptosis in patients with paroxysmal atrial fibrillation. Scand J Clin Lab Invest 82:391–397PubMed Fedai H, Altiparmak IH, Tascanov MB, Tanriverdi Z, Bicer A, Gungoren F, Demirbag R, Koyuncu I (2022) The relationship between oxidative stress and autophagy and apoptosis in patients with paroxysmal atrial fibrillation. Scand J Clin Lab Invest 82:391–397PubMed
55.
Zurück zum Zitat Bai J, Lo A, Gladding PA, Stiles MK, Fedorov VV, Zhao J (2020) In silico investigation of the mechanisms underlying atrial fibrillation due to impaired Pitx2. PLoS Comput Biol 16:e1007678PubMedPubMedCentral Bai J, Lo A, Gladding PA, Stiles MK, Fedorov VV, Zhao J (2020) In silico investigation of the mechanisms underlying atrial fibrillation due to impaired Pitx2. PLoS Comput Biol 16:e1007678PubMedPubMedCentral
56.
Zurück zum Zitat Cherry EM, Hastings HM, Evans SJ (2008) Dynamics of human atrial cell models: restitution, memory, and intracellular calcium dynamics in single cells. Prog Biophys Mol Biol 98:24–37PubMedPubMedCentral Cherry EM, Hastings HM, Evans SJ (2008) Dynamics of human atrial cell models: restitution, memory, and intracellular calcium dynamics in single cells. Prog Biophys Mol Biol 98:24–37PubMedPubMedCentral
57.
Zurück zum Zitat Azzolin L, Schuler S, Dossel O, Loewe A (2021) A reproducible protocol to assess arrhythmia vulnerability in silico: pacing at the end of the effective refractory period. Front Physiol 12:656411PubMedPubMedCentral Azzolin L, Schuler S, Dossel O, Loewe A (2021) A reproducible protocol to assess arrhythmia vulnerability in silico: pacing at the end of the effective refractory period. Front Physiol 12:656411PubMedPubMedCentral
58.
Zurück zum Zitat Song E, Wang RS, Leopold JA, Loscalzo J (2020) Network determinants of cardiovascular calcification and repositioned drug treatments. Faseb J 34:11087–11100PubMed Song E, Wang RS, Leopold JA, Loscalzo J (2020) Network determinants of cardiovascular calcification and repositioned drug treatments. Faseb J 34:11087–11100PubMed
59.
Zurück zum Zitat Lal JC, Mao C, Zhou Y, Gore-Panter SR, Rennison JH, Lovano BS, Castel L, Shin J, Gillinov AM, Smith JD, Barnard J, Van Wagoner DR, Luo Y, Cheng F, Chung MK (2022) Transcriptomics-based network medicine approach identifies metformin as a repurposable drug for atrial fibrillation. Cell Rep Med 3:100749PubMedPubMedCentral Lal JC, Mao C, Zhou Y, Gore-Panter SR, Rennison JH, Lovano BS, Castel L, Shin J, Gillinov AM, Smith JD, Barnard J, Van Wagoner DR, Luo Y, Cheng F, Chung MK (2022) Transcriptomics-based network medicine approach identifies metformin as a repurposable drug for atrial fibrillation. Cell Rep Med 3:100749PubMedPubMedCentral
Metadaten
Titel
Effects of hydroxychloroquine on atrial electrophysiology in in silico wild-type and PITX2+/- atrial cardiomyocytes
verfasst von
Euijun Song, MD
Publikationsdatum
02.02.2023
Verlag
Springer Medizin
Erschienen in
Herz / Ausgabe 5/2023
Print ISSN: 0340-9937
Elektronische ISSN: 1615-6692
DOI
https://doi.org/10.1007/s00059-023-05162-w

Weitere Artikel der Ausgabe 5/2023

Herz 5/2023 Zur Ausgabe

Herzstillstand nach Energy-Drinks

18.06.2024 Plötzlicher Herztod Nachrichten

Energy-Drinks können sich in Kombination mit anderen Risikofaktoren offenbar zu einem „perfekten Sturm“ zusammenbrauen, der schlimmstenfalls in einen plötzlichen Herzstillstand mündet. Sieben solcher Fälle schildert ein auf Rhythmusstörungen spezialisiertes US-Team.

Schleifendiuretikum ohne Herzinsuffizienz? Verordnung hinterfragen!

18.06.2024 Diuretika Nachrichten

Werden Schleifendiuretika häufig ohne sorgfältige Diagnostik verschrieben? Eine Kohortenstudie aus Schottland scheint darauf hinzudeuten.

Was eine zu kleine Klappe für die Langzeitprognose bedeutet

18.06.2024 Aortenklappenersatz Nachrichten

Stellt sich nach der Implantation eines biologischen Aortenklappenersatzes die Prothese als zu klein für den Patienten heraus, hat das offenbar nur geringe Auswirkungen auf Langzeitüberleben und Reoperationsrisiko; zumindest solange die effektive Öffnungsfläche über 0,65 cm2/m2 liegt.

Vorteile für Blutdruckselbstmanagement

18.06.2024 Hypertonie Nachrichten

Kontrollieren Hypertoniker ihren Blutdruck regelmäßig selbst, und passen sie entsprechend eigenständig ihre Antihypertensivadosis an, wird der Blutdruck um etwa 3 mmHg stärker gesenkt als unter dem üblichen ärztlichen Therapieplan.

Update Kardiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.