Atrial fibrillation is the most prevalent cardiac arrhythmia. Paroxysmal atrial fibrillation (pAF) may occur in episodes lasting from minutes to days. Recent studies suggest that some pAF episodes present a left-to-right dominant frequency gradient caused by ionic current gradients. However, how each ionic current gradient affects the left-to-right dominant frequency gradient during pAF has not been studied. In this work, we use a 3D model of human atria to study how the ionic current gradients affect the dominant frequency gradient during pAF induced by continuous ectopic activity. The role of the specific gradients of acetylcholine-activated potassium current (IKACh) and inward-rectifier potassium current (IK1) on determining the left-to-right dominant frequency gradient was assessed. The main outcome of this study is that either or both of the IKACh or IK1 gradients are necessary to induce a left-to-right dominant frequency gradient during pAF. However, both gradients are necessary to the left atrium maintaining, by itself, the pAF episode. These findings have potentially important implications for the development of atrial-selective therapeutic approaches.
KirchhofPBenussiSKotechaD, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. EP Europace2016; 18(11): 1609–1678.
2.
NattelSBursteinBDobrevD.Atrial remodeling and atrial fibrillation: Mechanisms and implications. Circ Arrhythm Electrophysiol2008; 1(1): 62–73.
3.
NiwanoSWakisakaYKojimaJ, et al. Monitoring the progression of the atrial electrical remodeling in patients with paroxysmal atrial fibrillation. Circ J2003; 67(2): 133–138.
4.
HaissaguerreMJaisPShahDC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med1998; 339(10): 659–666.
5.
ChenSAHsiehMHTaiCT, et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: Electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation1999; 100(18): 1879–1886.
6.
ArentzTHaegeliLSandersP, et al. High-density mapping of spontaneous pulmonary vein activity initiating atrial fibrillation in humans. J Cardiovasc Electrophysiol2007; 18(1): 31–38.
7.
PattersonEJackmanWMBeckmanKJ, et al. Spontaneous pulmonary vein firing in man: Relationship to tachycardia-pause early afterdepolarizations and triggered arrhythmia in canine pulmonary veins in vitro. J Cardiovasc Electrophysiol2007; 18(10): 1067–1075.
8.
TraykovVBPapRGinglZ, et al. Role of triggering pulmonary veins in the maintenance of sustained paroxysmal atrial fibrillation. Pacing Clin Electrophysiol2013; 36(7): 845–854.
9.
JaïsPHaïssaguerreMShahDC, et al. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation1997; 95(3): 572–576.
10.
KumagaiKGondoNMatsumotoN, et al. New technique for simultaneous catheter mapping of pulmonary veins for catheter ablation in focal atrial fibrillation. Cardiology2000; 94(4): 233–238.
11.
PisonLTilzRJalifeJ, et al. Pulmonary vein triggers, focal sources, rotors and atrial cardiomyopathy: Implications for the choice of the most effective ablation therapy. J Intern Med2016; 279(5): 449–456.
12.
MandapatiRSkanesAChenJ, et al. Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart. Circulation2000; 101(2): 194–199.
13.
JalifeJBerenfeldOMansourM.Mother rotors and fibrillatory conduction: A mechanism of atrial fibrillation. Cardiovasc Res2002; 54(2): 204–216.
14.
BelhassenBGlickAViskinS.Reentry in a pulmonary vein as a possible mechanism of focal atrial fibrillation. J Cardiovasc Electrophysiol2004; 15(7): 824–828.
15.
SandersPBerenfeldOHociniM, et al. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation2005; 112(6): 789–797.
16.
YamazakiMFilgueiras-RamaDBerenfeldO, et al. Ectopic and reentrant activation patterns in the posterior left atrium during stretch-related atrial fibrillation. Prog Biophys Mol Biol2012; 110(2–3): 269–277.
17.
BingenBOEngelsMCSchalijMJ, et al. Light-induced termination of spiral wave arrhythmias by optogenetic engineering of atrial cardiomyocytes. Cardiovasc Res2014; 104(1): 194–205.
18.
ClimentAMGuillemMSFuentesL, et al. Role of atrial tissue remodeling on rotor dynamics: An in vitro study. Am J Physiol Circ Physiol2015; 309(11): H1964–H1973.
19.
VarelaMColmanMAHancoxJC, et al. Atrial heterogeneity generates re-entrant substrate during atrial fibrillation and anti-arrhythmic drug action: Mechanistic insights from canine atrial models. PLoS Comput Biol2016; 12(12): e1005245.
20.
LimHSHociniMDuboisR, et al. Complexity and distribution of drivers in relation to duration of persistent atrial fibrillation. J Am Coll Cardiol2017; 69(10): 1257–1269.
21.
MillerJMKalraVDasMK, et al. Clinical benefit of ablating localized sources for human atrial fibrillation: The Indiana University FIRM registry. J Am Coll Cardiol2017; 69(10): 1247–1256.
22.
HasebeHYoshidaKIidaM, et al. Right-to-left frequency gradient during atrial fibrillation initiated by right atrial ectopies and its augmentation by adenosine triphosphate: Implications of right atrial fibrillation. Heart Rhythm2016; 13(2): 354–363.
23.
AtienzaFAlmendralJJalifeJ, et al. Real-time dominant frequency mapping and ablation of dominant frequency sites in atrial fibrillation with left-to-right frequency gradients predicts long-term maintenance of sinus rhythm. Heart Rhythm2009; 6(1): 33–40.
24.
ZhouZJinQChenLY, et al. Noninvasive imaging of high-frequency drivers and reconstruction of global dominant frequency maps in patients with paroxysmal and persistent atrial fibrillation. IEEE Trans Biomed Eng2016; 63(6): 1333–1340.
25.
CervigónRCastellsFGómez-PulidoJ, et al. Granger causality and Jensen–Shannon divergence to determine dominant atrial area in atrial fibrillation. Entropy2018; 20(1): 57.
26.
CsepeTAHansenBJFedorovVV.Atrial fibrillation driver mechanisms: Insight from the isolated human heart. Trends Cardiovasc Med2017; 27(1): 1–11.
27.
VoigtNTrauschAKnautM, et al. Left-to-right atrial inward rectifier potassium current gradients in patients with paroxysmal versus chronic atrial fibrillation. Circ Arrhythm Electrophysiol2010; 3(5): 472–480.
28.
SamieFHBerenfeldOAnumonwoJ, et al. Rectification of the background potassium current: A determinant of rotor dynamics in ventricular fibrillation. Circ Res2001; 89(12): 1216–1223.
29.
SekarRBKizanaEChoHC, et al. IK1 heterogeneity affects genesis and stability of spiral waves in cardiac myocyte monolayers. Circ Res2009; 104(3): 355–364.
30.
BerenfeldO.The major role of IK1 in mechanisms of rotor drift in the atria: A computational study. Clin Med Insights Cardiol. 2016; 10(1): 71–79.
31.
BerenfeldOJalifeJ.Mechanisms of atrial fibrillation: Rotors, ionic determinants, and excitation frequency. Cardiol Clin2014; 32(4): 495–506.
32.
EhrlichJR.Inward rectifier potassium currents as a target for atrial fibrillation therapy. J Cardiovasc Pharmacol2008; 52(2): 129–135.
33.
SarmastFKolliAZaitsevA, et al. Cholinergic atrial fibrillation: IK,ACh gradients determine unequal left/right atrial frequencies and rotor dynamics. Cardiovasc Res2003; 59(4): 863–873.
34.
MansourMMandapatiRBerenfeldO, et al. Left-to-right gradient of atrial frequencies during acute atrial fibrillation in the isolated sheep heart. Circulation2001; 103(21): 2631–2636.
35.
TobónCRuiz-VillaCAHeidenreichE, et al. A three-dimensional human atrial model with fiber orientation. Electrograms and arrhythmic activation patterns relationship. PLoS One2013; 8(2): e50883.
36.
SaizJTobónC. Supraventricular arrhythmias in a realistic 3D model of the human atria. In: ZipesDPJalifeJ (eds.) Cardiac electrophysiology: From cell to bedside. 6th ed.Philadelphia, PA, USA: Elsevier Saunders, 2013, pp. 351–359.
37.
Sanchez-QuintanaDAndersonRCabreraJ, et al. The terminal crest: Morphological features relevant to electrophysiology. Heart2002; 88(4): 406–411.
38.
CabreraJAHoSYClimentV, et al. The architecture of the left lateral atrial wall: A particular anatomic region with implications for ablation of atrial fibrillation. Eur Heart J2008; 29(3): 356–362.
39.
HoSYSánchez-QuintanaD.The importance of atrial structure and fibers. Clin Anat2009; 22(1): 52–63.
40.
CourtemancheMRamirezRJNattelS. Ionic mechanisms underlying human atrial action potential properties: Insights from a mathematical model. Am J Physiol1998; 275(1Pt 2): H301–H321.
41.
KnellerJZouRVigmondEJ, et al. Cholinergic atrial fibrillation in a computer model of a two-dimensional sheet of canine atrial cells with realistic ionic properties. Circ Res2002; 90(9): E73–E87.
42.
FengJYueLWangZ, et al. Ionic mechanisms of regional action potential heterogeneity in the canine right atrium. Circ Res1998; 83(5): 541–551.
43.
ChaTJEhrlichJRZhangL, et al. Atrial tachycardia remodeling of pulmonary vein cardiomyocytes: Comparison with left atrium and potential relation to arrhythmogenesis. Circulation2005; 111(6): 728–735.
44.
LiDZhangLKnellerJ, et al. Potential ionic mechanism for repolarization differences between canine right and left atrium. Circ Res2001; 88(11): 1168–1175.
45.
HeidenreichEAFerreroJMDoblaréM, et al. Adaptive macro finite elements for the numerical solution of monodomain equations in cardiac electrophysiology. Ann Biomed Eng2010; 38(7): 2331–2345.
46.
BoineauJPCanavanTESchuesslerRB, et al. Demonstration of a widely distributed atrial pacemaker complex in the human heart. Circulation1988; 77(6): 1221–1237.
47.
ShahDCHaissaguerreMJaisP, et al. High-resolution mapping of tachycardia originating from the superior vena cava: Evidence of electrical heterogeneity, slow conduction, and possible circus movement reentry. J Cardiovasc Electrophysiol2002; 13(4): 388–392.
48.
UgarteJPOrozco-DuqueATobónC, et al. Dynamic approximate entropy electroanatomic maps detect rotors in a simulated atrial fibrillation model. PLoS One2014; 9(12): e114577.
49.
SchuesslerRBGraysonTMBrombergBI, et al. Cholinergically mediated tachyarrhythmias induced by a single extrastimulus in the isolated canine right atrium. Circ Res1992; 71(5): 1254–1267.
TsaiCFTaiCTHsiehMH, et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava: Electrophysiological characteristics and results of radiofrequency ablation. Circulation2000; 102: 67–74.
52.
BerenfeldOZaitsevAVMironovSF, et al. Frequency-dependent breakdown of wave propagation into fibrillatory conduction across the pectinate muscle network in the isolated sheep right atrium. Circ Res2002; 90(11): 1173–1180.
53.
BerenfeldO.Ionic and substrate mechanism of atrial fibrillation: Rotors and the exitation frequency approach. Arch Cardiol Mex2010; 80(4): 301–314.
54.
AtienzaFAlmendralJMorenoJ, et al. Activation of inward rectifier potassium channels accelerates atrial fibrillation in humans: Evidence for a reentrant mechanism. Circulation2006; 114(23): 2434–2442.
55.
LazarSDixitSMarchlinskiFE, et al. Presence of left-to-right atrial frequency gradient in paroxysmal but not persistent atrial fibrillation in humans. Circulation2004; 110(20): 3181–3186.
56.
EhrlichJRBiliczkiPHohnloserSH, et al. Atrial-selective approaches for the treatment of atrial fibrillation. J Am Coll Cardiol2008; 51(8): 787–792.
57.
NadimiAEEbrahimipourSYAfsharEG, et al. Nano-scale drug delivery systems for antiarrhythmic agents. Eur J Med Chem2018; 157: 1153–1163.
