1932

Abstract

The importance of biological sex on disease etiology and outcomes has long been underinvestigated. While recent focus on characterizing sex differences in cardiac pathophysiology has led to improved inclusion of both sexes in scientific studies and clinical trials, much is still unknown about underlying differences in normal cardiac physiology. This is particularly true for the atria, where the most common arrhythmia, atrial fibrillation (AF), occurs. AF is associated with adverse structural, electrophysiological, and calcium handling remodeling that leads to patient morbidity and mortality. Differences in the onset, prevalence, presentation, and prognosis of AF are known to differ between males and females, yet the sex-specific baseline phenotypes from which AF arises are not well characterized. This review examines what is currently known about sex differences in atrial physiology, the alterations that occur in AF, potential mechanisms underlying sex divergence, and the need for sex-targeted therapeutic strategies.

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2025-02-10
2025-06-20
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Literature Cited

  1. 1.
    Nattel S, Li D, Yue L. 2000.. Basic mechanisms of atrial fibrillation—very new insights into very old ideas. . Annu. Rev. Physiol. 62::5177
    [Crossref] [Google Scholar]
  2. 2.
    Heijman J, Voigt N, Nattel S, Dobrev D. 2014.. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. . Circ. Res. 114::148399
    [Crossref] [Google Scholar]
  3. 3.
    Heijman J, Linz D, Schotten U. 2021.. Dynamics of atrial fibrillation mechanisms and comorbidities. . Annu. Rev. Physiol. 83::83106
    [Crossref] [Google Scholar]
  4. 4.
    Denham NC, Pearman CM, Caldwell JL, Madders GWP, Eisner DA, et al. 2018.. Calcium in the pathophysiology of atrial fibrillation and heart failure. . Front. Physiol. 9::1380
    [Crossref] [Google Scholar]
  5. 5.
    Nattel S, Heijman J, Zhou L, Dobrev D. 2020.. Molecular basis of atrial fibrillation pathophysiology and therapy. . Circ. Res. 127::5172
    [Crossref] [Google Scholar]
  6. 6.
    Nattel S, Burstein B, Dobrev D. 2008.. Atrial remodeling and atrial fibrillation: mechanisms and implications. . Circ. Arrhythm. Electrophysiol. 1::6273
    [Crossref] [Google Scholar]
  7. 7.
    Wakili R, Voigt N, Kääb S, Dobrev D, Nattel S. 2011.. Recent advances in the molecular pathophysiology of atrial fibrillation. . J. Clin. Investig. 121::295568
    [Crossref] [Google Scholar]
  8. 8.
    Grandi E, Maleckar MM. 2016.. Anti-arrhythmic strategies for atrial fibrillation: the role of computational modeling in discovery, development, and optimization. . Pharmacol. Ther. 168::12642
    [Crossref] [Google Scholar]
  9. 9.
    Andrade J, Khairy P, Dobrev D, Nattel S. 2014.. The clinical profile and pathophysiology of atrial fibrillation. . Circ. Res. 114::145368
    [Crossref] [Google Scholar]
  10. 10.
    Kornej J, Börschel CS, Benjamin EJ, Schnabel RB. 2020.. Epidemiology of atrial fibrillation in the 21st century. . Circ. Res. 127::420
    [Crossref] [Google Scholar]
  11. 11.
    Ko D, Rahman F, Schnabel RB, Yin X, Benjamin EJ, Christophersen IE. 2016.. Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis. . Nat. Rev. Cardiol. 13::32132
    [Crossref] [Google Scholar]
  12. 12.
    Odening KE, Deiß S, Dilling-Boer D, Didenko M, Eriksson U, et al. 2019.. Mechanisms of sex differences in atrial fibrillation: role of hormones and differences in electrophysiology, structure, function, and remodelling. . EP Europace 21::36676
    [Crossref] [Google Scholar]
  13. 13.
    Ball J, Carrington MJ, Wood KA, Stewart S. 2013.. Women versus men with chronic atrial fibrillation: insights from the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY). . PLOS ONE 8::e65795
    [Crossref] [Google Scholar]
  14. 14.
    Zhang XD, Tan HW, Gu J, Jiang WF, Zhao L, et al. 2013.. Efficacy and safety of catheter ablation for long-standing persistent atrial fibrillation in women. . Pacing Clin. Electrophysiol. 36::123644
    [Crossref] [Google Scholar]
  15. 15.
    Essebag V, Reynolds MR, Hadjis T, Lemery R, Olshansky B, et al. 2007.. Sex differences in the relationship between amiodarone use and the need for permanent pacing in patients with atrial fibrillation. . Arch. Intern. Med. 167::164853
    [Crossref] [Google Scholar]
  16. 16.
    Muzzey M, Tellor KB, Ramaswamy K, Schwarze M, Armbruster AL. 2020.. Flecainide is well-tolerated and effective in patient with atrial fibrillation at 12 months: a retrospective study. . Ther. Adv. Cardiovasc. Dis. 14::1753944720926824
    [Crossref] [Google Scholar]
  17. 17.
    US Natl. Inst. Health. 2024.. Including women and minorities in clinical research background. Off. Res. Women's Health, US Natl. Inst. Health, Bethesda, MD:. https://orwh.od.nih.gov/womens-health-research/clinical-research-trials/nih-inclusion-policies/including-women-and
    [Google Scholar]
  18. 18.
    Ravens U. 2018.. Sex differences in cardiac electrophysiology. . Can. J. Physiol. Pharmacol. 96::98590
    [Crossref] [Google Scholar]
  19. 19.
    Shih HT. 1994.. Anatomy of the action potential in the heart. . Texas Heart Inst. J. 21::3041
    [Google Scholar]
  20. 20.
    Wang Z, Fermini B, Nattel S. 1994.. Rapid and slow components of delayed rectifier current in human atrial myocytes. . Cardiovasc. Res. 28::154046
    [Crossref] [Google Scholar]
  21. 21.
    Wettwer E, Hála O, Christ T, Heubach JF, Dobrev D, et al. 2004.. Role of IKur in controlling action potential shape and contractility in the human atrium: influence of chronic atrial fibrillation. . Circulation 110::2299306
    [Crossref] [Google Scholar]
  22. 22.
    Xu Y, Tuteja D, Zhang Z, Xu D, Zhang Y, et al. 2003.. Molecular identification and functional roles of a Ca2+-activated K+ channel in human and mouse hearts. . J. Biol. Chem. 278::4908594
    [Crossref] [Google Scholar]
  23. 23.
    Skibsbye L, Poulet C, Diness JG, Bentzen BH, Yuan L, et al. 2014.. Small-conductance calcium-activated potassium (SK) channels contribute to action potential repolarization in human atria. . Cardiovasc. Res. 103::15667
    [Crossref] [Google Scholar]
  24. 24.
    Limberg SH, Netter MF, Rolfes C, Rinné S, Schlichthörl G, et al. 2011.. TASK-1 channels may modulate action potential duration of human atrial cardiomyocytes. . Cell Physiol. Biochem. 28::61324
    [Crossref] [Google Scholar]
  25. 25.
    Gros D, Jarry-Guichard T, Ten Velde I, de Maziere A, van Kempen MJ, et al. 1994.. Restricted distribution of connexin40, a gap junctional protein, in mammalian heart. . Circ. Res. 74::83951
    [Crossref] [Google Scholar]
  26. 26.
    Polontchouk L, Haefliger J-A, Ebelt B, Schaefer T, Stuhlmann D, et al. 2001.. Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria. . J. Am. Coll. Cardiol. 38::88391
    [Crossref] [Google Scholar]
  27. 27.
    Caballero R, de la Fuente MG, Gómez R, Barana A, Amorós I, et al. 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. . J. Am. Coll. Cardiol. 55::234654
    [Crossref] [Google Scholar]
  28. 28.
    Voigt N, Trausch A, Knaut M, Matschke K, Varró A, et al. 2010.. Left-to-right atrial inward rectifier potassium current gradients in patients with paroxysmal versus chronic atrial fibrillation. . Circ. Arrhythm. Electrophysiol. 3::47280
    [Crossref] [Google Scholar]
  29. 29.
    Grandi E, Pandit SV, Voigt N, Workman AJ, Dobrev D, et al. 2011.. Human atrial action potential and Ca2+ model: sinus rhythm and chronic atrial fibrillation. . Circ. Res. 109::105566
    [Crossref] [Google Scholar]
  30. 30.
    Pearman CM, Madders GWP, Radcliffe EJ, Kirkwood GJ, Lawless M, et al. 2018.. Increased vulnerability to atrial fibrillation is associated with increased susceptibility to alternans in old sheep. . J. Am. Heart Assoc. 7::e009972
    [Crossref] [Google Scholar]
  31. 31.
    Aslanidi OV, Boyett MR, Dobrzynski H, Li J, Zhang H. 2009.. Mechanisms of transition from normal to reentrant electrical activity in a model of rabbit atrial tissue: interaction of tissue heterogeneity and anisotropy. . Biophys. J. 96::798817
    [Crossref] [Google Scholar]
  32. 32.
    Colman MA, Aslanidi OV, Kharche S, Boyett MR, Garratt C, et al. 2013.. Pro-arrhythmogenic effects of atrial fibrillation-induced electrical remodelling: insights from the three-dimensional virtual human atria. . J. Physiol. 591::424972
    [Crossref] [Google Scholar]
  33. 33.
    Fareh S, Villemaire C, Nattel S. 1998.. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia-induced atrial electrical remodeling. . Circulation 98::22029
    [Crossref] [Google Scholar]
  34. 34.
    Wijffels MCEF, Kirchhof CJHJ, Dorland R, Allessie MA. 1995.. Atrial fibrillation begets atrial fibrillation. . Circulation 92::195468
    [Crossref] [Google Scholar]
  35. 35.
    Krapivinsky G, Gordon EA, Wickman K, Velimirovic B, Krapivinsky L, Clapham DE. 1995.. The G-protein-gated atrial K+ channel IKAch is a heteromultimer of two inwardly rectifying K+-channel proteins. . Nature 374::13541
    [Crossref] [Google Scholar]
  36. 36.
    Amos GJ, Wettwer E, Metzger F, Li Q, Himmel HM, Ravens U. 1996.. Differences between outward currents of human atrial and subepicardial ventricular myocytes. . J. Physiol. 491:(Part 1):3150
    [Crossref] [Google Scholar]
  37. 37.
    Walden AP, Dibb KM, Trafford AW. 2009.. Differences in intracellular calcium homeostasis between atrial and ventricular myocytes. . J. Mol. Cell. Cardiol. 46::46373
    [Crossref] [Google Scholar]
  38. 38.
    Richards MA, Clarke JD, Saravanan P, Voigt N, Dobrev D, et al. 2011.. Transverse tubules are a common feature in large mammalian atrial myocytes including human. . Am. J. Physiol. Heart Circ. Physiol. 301::H19962005
    [Crossref] [Google Scholar]
  39. 39.
    Gadeberg HC, Bond RC, Kong CHT, Chanoit GP, Ascione R, et al. 2016.. Heterogeneity of T-tubules in pig hearts. . PLOS ONE 11::e0156862
    [Crossref] [Google Scholar]
  40. 40.
    Brandenburg S, Kohl T, Williams GS, Gusev K, Wagner E, et al. 2016.. Axial tubule junctions control rapid calcium signaling in atria. . J. Clin. Investig. 126::39994015
    [Crossref] [Google Scholar]
  41. 41.
    Smith CER, Trafford AW, Caldwell JL, Dibb KM. 2018.. Physiology and patho-physiology of the cardiac transverse tubular system. . Curr. Opin. Physiol. 1::15360
    [Crossref] [Google Scholar]
  42. 42.
    Smith CER, Pinali C, Eisner DA, Trafford AW, Dibb KM. 2022.. Enhanced calcium release at specialised surface sites compensates for reduced t-tubule density in neonatal sheep atrial myocytes. . J. Mol. Cell. Cardiol. 173::6170
    [Crossref] [Google Scholar]
  43. 43.
    Frisk M, Koivumaki JT, Norseng PA, Maleckar MM, Sejersted OM, Louch WE. 2014.. Variable t-tubule organization and Ca2+ homeostasis across the atria. . Am. J. Physiol. Heart Circ. Physiol. 307::H60920
    [Crossref] [Google Scholar]
  44. 44.
    Zhang X, Ni H, Morotti S, Smith CER, Sato D, et al. 2023.. Mechanisms of spontaneous Ca2+ release-mediated arrhythmia in a novel 3D human atrial myocyte model: I. transverse-axial tubule variation. . J. Physiol. 601::265583
    [Crossref] [Google Scholar]
  45. 45.
    Thibault S, Long V, Fiset C. 2022.. Higher Na+-Ca2+ exchanger function and triggered activity contribute to male predisposition to atrial fibrillation. . Int. J. Mol. Sci. 23::10724
    [Crossref] [Google Scholar]
  46. 46.
    Maceira AM, Cosín-Sales J, Roughton M, Prasad SK, Pennell DJ. 2010.. Reference left atrial dimensions and volumes by steady state free precession cardiovascular magnetic resonance. . J. Cardiovasc. Magn. Reson. 12::65
    [Crossref] [Google Scholar]
  47. 47.
    Havmoller R, Carlson J, Holmqvist F, Herreros A, Meurling CJ, et al. 2007.. Age-related changes in P wave morphology in healthy subjects. . BMC Cardiovasc. Disord. 7::22
    [Crossref] [Google Scholar]
  48. 48.
    Kojodjojo P, Kanagaratnam P, Markides V, Davies DW, Peters N. 2006.. Age-related changes in human left and right atrial conduction. . J. Cardiovasc. Electrophysiol. 17::12027
    [Crossref] [Google Scholar]
  49. 49.
    Jansen HJ, Moghtadaei M, Mackasey M, Rafferty SA, Bogachev O, et al. 2017.. Atrial structure, function and arrhythmogenesis in aged and frail mice. . Sci. Rep. 7::44336
    [Crossref] [Google Scholar]
  50. 50.
    Nikitin NP, Witte KKA, Thackray SDR, Goodge LJ, Clark AL, Cleland JGF. 2003.. Effect of age and sex on left atrial morphology and function. . Eur. J. Echocardiogr. 4::3642
    [Crossref] [Google Scholar]
  51. 51.
    Thibault S, Ton AT, Huynh F, Fiset C. 2022.. Connexin lateralization contributes to male susceptibility to atrial fibrillation. . Int. J. Mol. Sci. 23::10696
    [Crossref] [Google Scholar]
  52. 52.
    Tse HF, Oral H, Pelosi F, Knight BP, Strickberger SA, Morady F. 2001.. Effect of gender on atrial electrophysiologic changes induced by rapid atrial pacing and elevation of atrial pressure. . J. Cardiovasc. Electrophysiol. 12::98689
    [Crossref] [Google Scholar]
  53. 53.
    Walters TE, Teh AW, Spence S, Morton JB, Kistler PM, Kalman JM. 2014.. Absence of gender-based differences in the atrial and pulmonary vein substrate: a detailed electroanatomic mapping study. . J. Cardiovasc. Electrophysiol. 25::106570
    [Crossref] [Google Scholar]
  54. 54.
    Tsai WC, Chen YC, Kao YH, Lu YY, Chen SA, Chen YJ. 2013.. Distinctive sodium and calcium regulation associated with sex differences in atrial electrophysiology of rabbits. . Int. J. Cardiol. 168::465866
    [Crossref] [Google Scholar]
  55. 55.
    Tsai WC, Chen YC, Lin YK, Chen SA, Chen YJ. 2011.. Sex differences in the electrophysiological characteristics of pulmonary veins and left atrium and their clinical implication in atrial fibrillation. . Circ. Arrhythm. Electrophysiol. 4::55059
    [Crossref] [Google Scholar]
  56. 56.
    Pecha S, Ismaili D, Geelhoed B, Knaut M, Reichenspurner H, et al. 2023.. Resting membrane potential is less negative in trabeculae from right atrial appendages of women, but action potential duration does not shorten with age. . J. Mol. Cell. Cardiol. 176::110
    [Crossref] [Google Scholar]
  57. 57.
    Parks RJ, Howlett SE. 2013.. Sex differences in mechanisms of cardiac excitation-contraction coupling. . Pflügers Arch. 465::74763
    [Crossref] [Google Scholar]
  58. 58.
    Collins HE. 2023.. Female cardiovascular biology and resilience in the setting of physiological and pathological stress. . Redox Biol. 63::102747
    [Crossref] [Google Scholar]
  59. 59.
    Ambrosi CM, Yamada KA, Nerbonne JM, Efimov IR. 2013.. Gender differences in electrophysiological gene expression in failing and non-failing human hearts. . PLOS ONE 8::e54635
    [Crossref] [Google Scholar]
  60. 60.
    Yue X, Zhang R, Kim B, Ma A, Philipson KD, Goldhaber JI. 2017.. Heterogeneity of transverse-axial tubule system in mouse atria: remodeling in atrial-specific Na+-Ca2+ exchanger knockout mice. . J. Mol. Cell. Cardiol. 108::5060
    [Crossref] [Google Scholar]
  61. 61.
    Winters J, Isaacs A, Zeemering S, Kawczynski M, Maesen B, et al. 2023.. Heart failure, female sex, and atrial fibrillation are the main drivers of human atrial cardiomyopathy: results from the CATCH ME Consortium. . J. Am. Heart Assoc. 12::e031220
    [Crossref] [Google Scholar]
  62. 62.
    Herraiz-Martínez A, Tarifa C, Jiménez-Sábado V, Llach A, Godoy-Marín H, et al. 2021.. Influence of sex on intracellular calcium homeostasis in patients with atrial fibrillation. . Cardiovasc. Res. 118::103345
    [Crossref] [Google Scholar]
  63. 63.
    Schwertz DW, Vizgirda V, Solaro RJ, Piano MR, Ryjewski C. 1999.. Sexual dimorphism in rat left atrial function and response to adrenergic stimulation. . Mol. Cell. Biochem. 200::14353
    [Crossref] [Google Scholar]
  64. 64.
    Pecha S, Geelhoed B, Kempe R, Berk E, Engel A, et al. 2021.. No impact of sex and age on beta-adrenoceptor-mediated inotropy in human right atrial trabeculae. . Acta Physiol. 231::e13564
    [Crossref] [Google Scholar]
  65. 65.
    Machuki JO, Zhang H-Y, Geng J, Fu L, Adzika GK, et al. 2019.. Estrogen regulation of cardiac cAMP-L-type Ca2+ channel pathway modulates sex differences in basal contraction and responses to β2AR-mediated stress in left ventricular apical myocytes. . Cell Commun. Signal. 17::34
    [Crossref] [Google Scholar]
  66. 66.
    Ueoka A, Sung YL, Liu X, Rosenberg C, Chen Z, et al. 2022.. Testosterone does not shorten action potential duration in Langendorff-perfused rabbit ventricles. . Heart Rhythm 19::186471
    [Crossref] [Google Scholar]
  67. 67.
    Papp R, Bett GCL, Lis A, Rasmusson RL, Baczkó I, et al. 2017.. Genomic upregulation of cardiac Cav1.2α and NCX1 by estrogen in women. . Biol. Sex Differ. 8::26
    [Crossref] [Google Scholar]
  68. 68.
    Tsuneda T, Yamashita T, Kato T, Sekiguchi A, Sagara K, et al. 2009.. Deficiency of testosterone associates with the substrate of atrial fibrillation in the rat model. . J. Cardiovasc. Electrophysiol. 20::105560
    [Crossref] [Google Scholar]
  69. 69.
    Velasco L, Sánchez M, Rubín JM, Hidalgo A, Bordallo C, Cantabrana B. 2002.. Intracellular cAMP increases during the positive inotropism induced by androgens in isolated left atrium of rat. . Eur. J. Pharmacol. 438::4552
    [Crossref] [Google Scholar]
  70. 70.
    Regitz-Zagrosek V. 2020.. Sex and gender differences in heart failure. . Int. J. Heart Fail. 2::15781
    [Crossref] [Google Scholar]
  71. 71.
    Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, et al. 2004.. Lifetime risk for development of atrial fibrillation. . Circulation 110::104246
    [Crossref] [Google Scholar]
  72. 72.
    Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. 2014.. Epidemiology of atrial fibrillation: European perspective. . Clin. Epidemiol. 6::21320
    [Crossref] [Google Scholar]
  73. 73.
    Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, et al. 2021.. Heart disease and stroke statistics—2021 update. . Circulation 143::e254743
    [Crossref] [Google Scholar]
  74. 74.
    de Vos CB, Pisters R, Nieuwlaat R, Prins MH, Tieleman RG, et al. 2010.. Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis. . J. Am. Coll. Cardiol. 55::72531
    [Crossref] [Google Scholar]
  75. 75.
    Padfield GJ, Steinberg C, Swampillai J, Qian H, Connolly SJ, et al. 2017.. Progression of paroxysmal to persistent atrial fibrillation: 10-year follow-up in the Canadian Registry of Atrial Fibrillation. . Heart Rhythm 14::8017
    [Crossref] [Google Scholar]
  76. 76.
    Lévy S, Maarek M, Coumel P, Guize L, Lekieffre J, et al. 1999.. Characterization of different subsets of atrial fibrillation in general practice in France: the ALFA study. . Circulation 99::302835
    [Crossref] [Google Scholar]
  77. 77.
    Flaker GC, Belew K, Beckman K, Vidaillet H, Kron J, et al. 2005.. Asymptomatic atrial fibrillation: demographic features and prognostic information from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. . Am. Heart J. 149::65763
    [Crossref] [Google Scholar]
  78. 78.
    Boriani G, Laroche C, Diemberger I, Fantecchi E, Popescu MI, et al. 2015.. Asymptomatic atrial fibrillation: clinical correlates, management, and outcomes in the EORP-AF Pilot General Registry. . Am. J. Med. 128::50918.e2
    [Crossref] [Google Scholar]
  79. 79.
    Dagres N, Nieuwlaat R, Vardas PE, Andresen D, Lévy S, et al. 2007.. Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Heart Survey on Atrial Fibrillation. . J. Am. Coll. Cardiol. 49::57277
    [Crossref] [Google Scholar]
  80. 80.
    Rienstra M, Lubitz SA, Mahida S, Magnani JW, Fontes JD, et al. 2012.. Symptoms and functional status of patients with atrial fibrillation: state of the art and future research opportunities. . Circulation 125::293343
    [Crossref] [Google Scholar]
  81. 81.
    Uhm JS, Mun HS, Wi J, Shim J, Joung B, et al. 2013.. Prolonged atrial effective refractory periods in atrial fibrillation patients associated with structural heart disease or sinus node dysfunction compared with lone atrial fibrillation. . Pacing Clin. Electrophysiol. 36::16371
    [Crossref] [Google Scholar]
  82. 82.
    Zheng Y, Xia Y, Carlson J, Kongstad O, Yuan S. 2017.. Atrial average conduction velocity in patients with and without paroxysmal atrial fibrillation. . Clin. Physiol. Funct. Imaging 37::596601
    [Crossref] [Google Scholar]
  83. 83.
    Wong GR, Nalliah CJ, Lee G, Voskoboinik A, Chieng D, et al. 2022.. Sex-related differences in atrial remodeling in patients with atrial fibrillation: relationship to ablation outcomes. . Circ. Arrhythm. Electrophysiol. 15::e009925
    [Crossref] [Google Scholar]
  84. 84.
    Yu W-C, Chen S-A, Lee S-H, Tai C-T, Feng A-N, et al. 1998.. Tachycardia-induced change of atrial refractory period in humans. . Circulation 97::233137
    [Crossref] [Google Scholar]
  85. 85.
    Daoud EG, Bogun F, Goyal R, Harvey M, Man KC, et al. 1996.. Effect of atrial fibrillation on atrial refractoriness in humans. . Circulation 94::16006
    [Crossref] [Google Scholar]
  86. 86.
    Heida A, van Schie MS, van der Does WFB, Taverne Y, Bogers A, de Groot NMS. 2021.. Reduction of conduction velocity in patients with atrial fibrillation. . J. Clin. Med. 10::2614
    [Crossref] [Google Scholar]
  87. 87.
    Kim B-S, Kim Y-H, Hwang G-S, Pak H-N, Lee SC, et al. 2002.. Action potential duration restitution kinetics in human atrial fibrillation. . J. Am. Coll. Cardiol. 39::132936
    [Crossref] [Google Scholar]
  88. 88.
    Akoum N, Mahnkopf C, Kholmovski EG, Brachmann J, Marrouche NF. 2018.. Age and sex differences in atrial fibrosis among patients with atrial fibrillation. . EP Europace 20::108692
    [Crossref] [Google Scholar]
  89. 89.
    Platonov PG, Mitrofanova LB, Orshanskaya V, Ho SY. 2011.. Structural abnormalities in atrial walls are associated with presence and persistency of atrial fibrillation but not with age. . J. Am. Coll. Cardiol. 58::222532
    [Crossref] [Google Scholar]
  90. 90.
    Bao L, Cheng L, Gao X, Yan F, Fan H, et al. 2022.. Left atrial morpho-functional remodeling in atrial fibrillation assessed by three dimensional speckle tracking echocardiography and its value in atrial fibrillation screening. . Cardiovasc. Ultrasound 20::13
    [Crossref] [Google Scholar]
  91. 91.
    Bettoni M, Zimmermann M. 2002.. Autonomic tone variations before the onset of paroxysmal atrial fibrillation. . Circulation 105::275359
    [Crossref] [Google Scholar]
  92. 92.
    Brooks AG, Rangnekar G, Ganesan AN, Salna I, Middeldorp ME, et al. 2012.. Characteristics of ectopic triggers associated with paroxysmal and persistent atrial fibrillation: evidence for a changing role. . Heart Rhythm 9::136774
    [Crossref] [Google Scholar]
  93. 93.
    Lee SH, Chen SA, Yu WC, Cheng JJ, Kaun P, et al. 1999.. Change of atrial refractory period after short duration of rapid atrial pacing: regional differences and possible mechanisms. . Pacing Clin. Electrophysiol. 22::92734
    [Crossref] [Google Scholar]
  94. 94.
    Frontera A, Pagani S, Limite LR, Peirone A, Fioravanti F, et al. 2022.. Slow conduction corridors and pivot sites characterize the electrical remodeling in atrial fibrillation. . JACC Clin. Electrophysiol. 8::56177
    [Crossref] [Google Scholar]
  95. 95.
    Conte G, Luca A, Yazdani S, Caputo ML, Regoli F, et al. 2017.. Usefulness of P-wave duration and morphologic variability to identify patients prone to paroxysmal atrial fibrillation. . Am. J. Cardiol. 119::27579
    [Crossref] [Google Scholar]
  96. 96.
    Maesen B, Verheule S, Zeemering S, La Meir M, Nijs J, et al. 2022.. Endomysial fibrosis, rather than overall connective tissue content, is the main determinant of conduction disturbances in human atrial fibrillation. . EP Europace 24::101524
    [Crossref] [Google Scholar]
  97. 97.
    Gould PA, Yii M, McLean C, Finch S, Marshall T, et al. 2006.. Evidence for increased atrial sympathetic innervation in persistent human atrial fibrillation. . Pacing Clin. Electrophysiol. 29::82129
    [Crossref] [Google Scholar]
  98. 98.
    Liu L, Nattel S. 1997.. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. . Am. J. Physiol. 273::H80516
    [Google Scholar]
  99. 99.
    Arora R, Ng J, Ulphani J, Mylonas I, Subacius H, et al. 2007.. Unique autonomic profile of the pulmonary veins and posterior left atrium. . J. Am. Coll. Cardiol. 49::134048
    [Crossref] [Google Scholar]
  100. 100.
    Van Wagoner DR, Pond AL, McCarthy PM, Trimmer JS, Nerbonne JM. 1997.. Outward K+ current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation. . Circ. Res. 80::77281
    [Crossref] [Google Scholar]
  101. 101.
    Dobrev D, Friedrich A, Voigt N, Jost N, Wettwer E, et al. 2005.. The G protein–gated potassium current IK,ACh is constitutively active in patients with chronic atrial fibrillation. . Circulation 112::3697706
    [Crossref] [Google Scholar]
  102. 102.
    Heijman J, Zhou X, Morotti S, Molina CE, Abu-Taha IH, et al. 2023.. Enhanced Ca2+-dependent SK-channel gating and membrane trafficking in human atrial fibrillation. . Circ. Res. 132::e11633
    [Crossref] [Google Scholar]
  103. 103.
    Dobrev D, Graf E, Wettwer E, Himmel HM, Hála O, et al. 2001.. Molecular basis of downregulation of G-protein–coupled inward rectifying K+ current (IK,ACh) in chronic human atrial fibrillation. . Circulation 104::255157
    [Crossref] [Google Scholar]
  104. 104.
    Voigt N, Heijman J, Wang Q, Chiang DY, Li N, et al. 2014.. Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation. . Circulation 129::14556
    [Crossref] [Google Scholar]
  105. 105.
    Sossalla S, Kallmeyer B, Wagner S, Mazur M, Maurer U, et al. 2010.. Altered Na+ currents in atrial fibrillation: effects of ranolazine on arrhythmias and contractility in human atrial myocardium. . J. Am. Coll. Cardiol. 55::233042
    [Crossref] [Google Scholar]
  106. 106.
    Christ T, Boknik P, Wöhrl S, Wettwer E, Graf EM, et al. 2004.. L-type Ca2+ current downregulation in chronic human atrial fibrillation is associated with increased activity of protein phosphatases. . Circulation 110::265157
    [Crossref] [Google Scholar]
  107. 107.
    Neef S, Dybkova N, Sossalla S, Ort KR, Fluschnik N, et al. 2010.. CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation. . Circ. Res. 106::113444
    [Crossref] [Google Scholar]
  108. 108.
    Schmidt C, Wiedmann F, Voigt N, Zhou X-B, Heijman J, et al. 2015.. Upregulation of K2P3.1 K+ current causes action potential shortening in patients with chronic atrial fibrillation. . Circulation 132::8292
    [Crossref] [Google Scholar]
  109. 109.
    Voigt N, Li N, Wang Q, Wang W, Trafford AW, et al. 2012.. Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+-Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation. . Circulation 125::205970
    [Crossref] [Google Scholar]
  110. 110.
    Narayan SM, Franz MR, Clopton P, Pruvot EJ, Krummen DE. 2011.. Repolarization alternans reveals vulnerability to human atrial fibrillation. . Circulation 123::292230
    [Crossref] [Google Scholar]
  111. 111.
    Narayan SM, Bayer JD, Lalani G, Trayanova NA. 2008.. Action potential dynamics explain arrhythmic vulnerability in human heart failure: a clinical and modeling study implicating abnormal calcium handling. . J. Am. Coll. Cardiol. 52::178292
    [Crossref] [Google Scholar]
  112. 112.
    Avula UMR, Abrams J, Katchman A, Zakharov S, Mironov S, et al. 2019.. Heterogeneity of the action potential duration is required for sustained atrial fibrillation. . JCI Insight 4::e128765
    [Crossref] [Google Scholar]
  113. 113.
    Chaldoupi S-M, Loh P, Hauer RNW, de Bakker JMT, van Rijen HVM. 2009.. The role of connexin40 in atrial fibrillation. . Cardiovasc. Res. 84::1523
    [Crossref] [Google Scholar]
  114. 114.
    Gemel J, Levy AE, Simon AR, Bennett KB, Ai X, et al. 2014.. Connexin40 abnormalities and atrial fibrillation in the human heart. . J. Mol. Cell. Cardiol. 76::15968
    [Crossref] [Google Scholar]
  115. 115.
    Macquaide N, Tuan HT, Hotta J, Sempels W, Lenaerts I, et al. 2015.. Ryanodine receptor cluster fragmentation and redistribution in persistent atrial fibrillation enhance calcium release. . Cardiovasc. Res. 108::38798
    [Crossref] [Google Scholar]
  116. 116.
    Lenaerts I, Bito V, Heinzel FR, Driesen RB, Holemans P, et al. 2009.. Ultrastructural and functional remodeling of the coupling between Ca2+ influx and sarcoplasmic reticulum Ca2+ release in right atrial myocytes from experimental persistent atrial fibrillation. . Circ. Res. 105::87685
    [Crossref] [Google Scholar]
  117. 117.
    El-Armouche A, Boknik P, Eschenhagen T, Carrier L, Knaut M, et al. 2006.. Molecular determinants of altered Ca2+ handling in human chronic atrial fibrillation. . Circulation 114::67080
    [Crossref] [Google Scholar]
  118. 118.
    Schotten U, Greiser M, Benke D, Buerkel K, Ehrenteidt B, et al. 2002.. Atrial fibrillation-induced atrial contractile dysfunction: a tachycardiomyopathy of a different sort. . Cardiovasc. Res. 53::192201
    [Crossref] [Google Scholar]
  119. 119.
    Shanmugam M, Molina CE, Gao S, Severac-Bastide R, Fischmeister R, Babu GJ. 2011.. Decreased sarcolipin protein expression and enhanced sarco(endo)plasmic reticulum Ca2+ uptake in human atrial fibrillation. . Biochem. Biophys. Res. Commun. 410::97101
    [Crossref] [Google Scholar]
  120. 120.
    Hove-Madsen L, Llach A, Bayes-Genís A, Roura S, Rodriguez Font E, et al. 2004.. Atrial fibrillation is associated with increased spontaneous calcium release from the sarcoplasmic reticulum in human atrial myocytes. . Circulation 110::135863
    [Crossref] [Google Scholar]
  121. 121.
    Vest JA, Wehrens XH, Reiken SR, Lehnart SE, Dobrev D, et al. 2005.. Defective cardiac ryanodine receptor regulation during atrial fibrillation. . Circulation 111::202532
    [Crossref] [Google Scholar]
  122. 122.
    Schotten U, Ausma J, Stellbrink C, Sabatschus I, Vogel M, et al. 2001.. Cellular mechanisms of depressed atrial contractility in patients with chronic atrial fibrillation. . Circulation 103::69198
    [Crossref] [Google Scholar]
  123. 123.
    Reinhardt F, Beneke K, Pavlidou NG, Conradi L, Reichenspurner H, et al. 2021.. Abnormal calcium handling in atrial fibrillation is linked to changes in cyclic AMP dependent signaling. . Cells 10::3042
    [Crossref] [Google Scholar]
  124. 124.
    Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, et al. 2012.. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. . Circulation 125::e2220
    [Crossref] [Google Scholar]
  125. 125.
    Kaiser DW, Fan J, Schmitt S, Than CT, Ullal AJ, et al. 2016.. Gender differences in clinical outcomes after catheter ablation of atrial fibrillation. . JACC. Clin. Electrophysiol. 2::70310
    [Crossref] [Google Scholar]
  126. 126.
    Rienstra M, Van Veldhuisen DJ, Hagens VE, Ranchor AV, Veeger NJGM, et al. 2005.. Gender-related differences in rhythm control treatment in persistent atrial fibrillation: data of the Rate Control Versus Electrical Cardioversion (RACE) study. . J. Am. Coll. Cardiol. 46::1298306
    [Crossref] [Google Scholar]
  127. 127.
    Washam JB, Stevens SR, Lokhnygina Y, Halperin JL, Breithardt G, et al. 2015.. Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). . Lancet 385::236370
    [Crossref] [Google Scholar]
  128. 128.
    Masuda M, Matsuda Y, Uematsu H, Sugino A, Ooka H, et al. 2023.. Gender differences in atrial fibrosis and cardiomyopathy assessed by left atrial low-voltage areas during catheter ablation of atrial fibrillation. . Am. J. Cardiol. 203::3744
    [Crossref] [Google Scholar]
  129. 129.
    Laureanti R, Conte G, Corino VDA, Osswald S, Conen D, et al. 2020.. Sex-related electrocardiographic differences in patients with different types of atrial fibrillation: results from the SWISS-AF study. . Int. J. Cardiol. 307::6370
    [Crossref] [Google Scholar]
  130. 130.
    Frye J, Patel N, Horn E, Ip JE, Thomas G, et al. 2021.. B-PO05-082 sex-related differences in atrial substrate in patients undergoing pulmonary vein isolation: an age and atrial fibrillation-type matched analysis. . Heart Rhythm 18::S4045
    [Crossref] [Google Scholar]
  131. 131.
    Li Z, Wang Z, Yin Z, Zhang Y, Xue X, et al. 2017.. Gender differences in fibrosis remodeling in patients with long-standing persistent atrial fibrillation. . Oncotarget 8::5371429
    [Crossref] [Google Scholar]
  132. 132.
    Andrade JG, Deyell MW, Lee AYK, Macle L. 2018.. Sex differences in atrial fibrillation. . Can. J. Cardiol. 34::42936
    [Crossref] [Google Scholar]
  133. 133.
    Pfannmüller B, Boldt A, Reutemann A, Duerrschmidt N, Krabbes-Graube S, et al. 2013.. Gender-specific remodeling in atrial fibrillation?. Thorac. Cardiovasc. Surg. 61::6673
    [Crossref] [Google Scholar]
  134. 134.
    Zhang X, Wu Y, Smith C, Louch WE, Morotti S, et al. 2024.. Enhanced Ca2+-driven arrhythmogenic events in female patients with atrial fibrillation: insights from computational modeling. . JACC Clin. Electrophysiol. 10::237191
    [Crossref] [Google Scholar]
  135. 135.
    Llach A, Molina CE, Prat-Vidal C, Fernandes J, Casadó V, et al. 2010.. Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A2A receptors. . Eur. Heart J. 32::72129
    [Crossref] [Google Scholar]
  136. 136.
    Kim K, Blackwell DJ, Yuen SL, Thorpe MP, Johnston JN, et al. 2023.. The selective RyR2 inhibitor ent-verticilide suppresses atrial fibrillation susceptibility caused by Pitx2 deficiency. . J. Mol. Cell Cardiol. 180::19
    [Crossref] [Google Scholar]
  137. 137.
    Hartley A, Shalhoub J, Ng FS, Krahn AD, Laksman Z, et al. 2021.. Size matters in atrial fibrillation: the underestimated importance of reduction of contiguous electrical mass underlying the effectiveness of catheter ablation. . EP Europace 23::1698707
    [Crossref] [Google Scholar]
  138. 138.
    Siddiqi HK, Vinayagamoorthy M, Gencer B, Ng C, Pester J, et al. 2022.. Sex differences in atrial fibrillation risk: the VITAL Rhythm Study. . JAMA Cardiol. 7::102735
    [Crossref] [Google Scholar]
  139. 139.
    Dart AM, Du X-J, Kingwell BA. 2002.. Gender, sex hormones and autonomic nervous control of the cardiovascular system. . Cardiovasc. Res. 53::67887
    [Crossref] [Google Scholar]
  140. 140.
    Kuo TBJ, Lin T, Yang CCH, Li C-L, Chen C-F, Chou P. 1999.. Effect of aging on gender differences in neural control of heart rate. . Am. J. Physiol. Heart Circ. Physiol. 277::H223339
    [Crossref] [Google Scholar]
  141. 141.
    Yamasaki Y, Kodama M, Matsuhisa M, Kishimoto M, Ozaki H, et al. 1996.. Diurnal heart rate variability in healthy subjects: effects of aging and sex difference. . Am. J. Physiol. 271::H30310
    [Google Scholar]
  142. 142.
    Lee J, Kim Y, Park H, Kim C, Cho S, Kim J. 2021.. Clinical impact of hormone replacement therapy on atrial fibrillation in postmenopausal women: a nationwide cohort study. . J. Clin. Med. 10::5497
    [Crossref] [Google Scholar]
  143. 143.
    Zeller T, Schnabel RB, Appelbaum S, Ojeda F, Berisha F, et al. 2018.. Low testosterone levels are predictive for incident atrial fibrillation and ischaemic stroke in men, but protective in women - results from the FINRISK study. . Eur. J. Prev. Cardiol. 25::113339
    [Crossref] [Google Scholar]
  144. 144.
    Sharma R, Oni OA, Gupta K, Sharma M, Sharma R, et al. 2017.. Normalization of testosterone levels after testosterone replacement therapy is associated with decreased incidence of atrial fibrillation. . J. Am. Heart Assoc. 6::e004880
    [Crossref] [Google Scholar]
  145. 145.
    Rosano GM, Leonardo F, Sarrel PM, Beale CM, De Luca F, Collins P. 1996.. Cyclical variation in paroxysmal supraventricular tachycardia in women. . Lancet 347::78688
    [Crossref] [Google Scholar]
  146. 146.
    Zhang X, Smith CER, Morotti S, Edwards AG, Sato D, et al. 2023.. Mechanisms of spontaneous Ca2+ release-mediated arrhythmia in a novel 3D human atrial myocyte model: II Ca2+-handling protein variation. . J. Physiol. 601::2685710
    [Crossref] [Google Scholar]
  147. 147.
    Ni H, Morotti S, Zhang X, Dobrev D, Grandi E. 2023.. Integrative human atrial modelling unravels interactive protein kinase A and Ca2+/calmodulin-dependent protein kinase II signalling as key determinants of atrial arrhythmogenesis. . Cardiovasc. Res. 119::2294311
    [Crossref] [Google Scholar]
  148. 148.
    Yang PC, Kurokawa J, Furukawa T, Clancy CE. 2010.. Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: a simulation study. . PLOS Comput. Biol. 6::e1000658
    [Crossref] [Google Scholar]
  149. 149.
    Fogli Iseppe A, Ni H, Zhu S, Zhang X, Coppini R, et al. 2021.. Sex-specific classification of drug-induced torsade de pointes susceptibility using cardiac simulations and machine learning. . Clin. Pharmacol. Ther. 110::38091
    [Crossref] [Google Scholar]
  150. 150.
    Hellgren KT, Ni H, Morotti S, Grandi E. 2023.. Predictive male-to-female translation of cardiac electrophysiological response to drugs. . JACC Clin. Electrophysiol. 9::264248
    [Crossref] [Google Scholar]
  151. 151.
    Ho I, Wong C-K, Wong Y-K, Lam T-H, Leung IS-H, et al. Aromatase inhibitor therapy increases the risk of new-onset atrial fibrillation in patients with breast cancer. . JACC Asia 4::15060
    [Crossref] [Google Scholar]
  152. 152.
    Antwi-Amoabeng D, Doshi R, Adalja D, Kumar A, Desai R, et al. 2020.. Burden of arrythmias in transgender patients hospitalized for gender-affirming surgeries. . J. Arrhythm. 36::797800
    [Crossref] [Google Scholar]
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