A, Mechanisms underlying early afterdepolarizations. Reduced repolarizing K+ currents (slow delayed-rectifier K+ current [IKs], rapid delayed-rectifier K+ current [IKr], ultrarapid delayed-rectifier K+ current [IKur]) or increased depolarizing currents (persistent/late Na+ current [INa,late], L-type Ca2+ current [ICa,L]) prolong action potential duration (APD), allowing recovery from inactivation of ICa,L, augmenting inward currents, and causing membrane depolarization during AP phase 2 or 3. B, Mechanisms underlying delayed afterdepolarizations. Dysfunction of cardiac ryanodine receptor channel type 2 (RyR2) because of enhanced Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation or reduced stabilizing subunits (FKBP12.6, junctophilin-2 [JPH-2]), and increased sarcoplasmic reticulum (SR) Ca2+ load via increased SR Ca2+ uptake because of phospholamban (PLB) hyperphosphorylation promotes spontaneous SR Ca2+ release events (SCaEs), activating the Na+/Ca2+ exchanger (NCX) and producing a depolarizing transient-inward current (Iti), which causes delayed afterdepolarization. Inward-rectifier K+ currents offset the resulting membrane depolarization. CSQ indicates calsequestrin; IM, membrane current; SERCA2a, SR Ca2+-ATPase type 2a; and SLN, sarcolipin
Molecular determinants of delayed afterdepolarization (DAD) generation, showing the changes identified to lead to DADs/triggered activity in patients with paroxysmal atrial fibrillation (pAF).50 Green upward arrows, grey left-right arrows, and red downward arrows indicate properties that are increased, unchanged, or decreased in patients with pAF, respectively. Phospholamban (PLB) hyperphosphorylation increases sarcoplasmic reticulum (SR) Ca2+ uptake and SR Ca2+ load, despite decreased SR Ca2+-ATPase type 2a (SERCA2a) expression. Ryanodine receptor channel type 2 (RyR2) dysregulation includes increased expression and single-channel open probability. Protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII), protein phophatases type 1 and type 2A (PP1, PP2A), calsequestrin (CSQ) expression, and L-type Ca2+ current (ICa,L), basal inward-rectifier K+ current (IK1), and Na+/Ca2+ exchanger current (INCX) are unchanged, whereas agonist-activated acetylcholine-dependent inward-rectifier K+ current (IK,ACh) is reduced. IKr indicates rapid delayed-rectifier K+ current; IKs, slow delayed-rectifier K+ current; IKur, ultrarapid delayed-rectifier K+ current; INa, Na+ current; Ito, transient-outward K+ current; JPH-2, junctophilin-2; PMCA, plasmalemmal Ca2+-ATPase; SCaEs, spontaneous SR Ca2+ release event; and SLN, sarcolipin.
Arrhythmogenic changes in atrial fibroblasts. Disease- and atrial fibrillation (AF)–related remodeling promotes fibroblast differentiation into myofibroblasts, involving altered expression of several ion channel proteins and microRNAs (miRs). Myofibroblasts facilitate AF maintenance by promoting re-entry through fibrosis/collagen deposition, as well as paracrine and direct electrotonic interactions with cardiomyocytes. Ado indicates aldosterone; Ang-II, angiotensin II; TGFβ1, transforming growth factor β1; TNFα, tumor necrosis factor α; TRPC3, transient receptor potential (TRP) canonical-3; and TRPM, TRP melastatin–related 7.
Mechanisms responsible for atrial fibrillation (AF)–dependent electric remodeling promoting AF maintenance and progression. Atrial tachycardia–related Ca2+ loading causes intracellular signaling events that increase K+ currents and reduce L-type Ca2+ current (ICa,L). APD indicates action potential duration; CaM, calmodulin; IK1, basal inward-rectifier K+ current; IK,ACh, acetylcholine-dependent inward-rectifier K+ current; IKr, rapid delayed-rectifier K+ current; IKs, slow delayed-rectifier K+ current; IK,ATP, ATP-dependent K+ current; INa, Na+ current; INaK, Na+-K+-ATPase current; INa,late, persistent/late Na+ current; INCX, Na+/Ca2+ exchanger current; ISK, small-conductance Ca2+-activated K+ current; Ito, transient-outward K+ current; miR, microRNA; NFAT, nuclear factor of activated T cells; PKC, protein kinase C; PP1, protein phosphatase type 1; PP2A, protein phosphatase type 2A; and RMP, resting membrane potential
Ca2+-handling abnormalities and alterations in ion currents in patients with long-standing persistent (chronic) atrial fibrillation (cAF) and their potential arrhythmogenic consequences. Green upward arrows, grey left-right arrows, and red downward arrows indicate properties that are increased, unchanged, or decreased in patients with cAF, respectively. Reduced L-type Ca2+ current (ICa,L) and increased basal inward-rectifier K+ current (IK1) and constitutively active acetylcholine-dependent inward-rectifier K+ current (IK,ACh) contribute to action potential duration (APD) shortening. Ca2+/calmodulin-dependent protein kinase II (CaMKII)–dependent ryanodine receptor channel type 2 (RyR2) hyperphosphorylation increases sarcoplasmic reticulum (SR) Ca2+ leak. Phosphodiesterase type 4 (PDE4) is reduced, increasing cyclic-AMP (cAMP) and promoting protein kinase A (PKA)–dependent phosphorylation of phospholamban (PLB) and inhibitor-1 (I-1), which together with reduced expression of sarcolipin (SLN) contributes to the unaltered SR Ca2+ load despite increased SR Ca2+ leak. CCh-act. indicates carbachol activated; Const., constitutively active; CSQ, calsequestrin; Expr., expression; IKr, rapid delayed-rectifier K+ current; IKs, slow delayed-rectifier K+ current; IKur, ultrarapid delayed-rectifier K+ current; INa, Na+ current; INaK, Na+-K+-ATPase current; INCX, Na+/Ca2+ exchanger current; ISK, small-conductance Ca2+-activated K+ current; Ito, transient-outward K+ current; JPH-2, junctophilin-2; PMCA, plasmalemmal Ca2+-ATPase; Po, open probability; PP1, protein phosphatase type 1; PP2A, protein phosphatase type 2A; SERCA2a, SR Ca2+-ATPase type 2a; and T35-P, Thr35-phosphorylated.
Conceptual framework of atrial fibrillation (AF) initiation, maintenance, and progression. A, In patients with a sufficiently large genetic predisposition, AF onset may occur at a relatively young age. AF-induced remodeling helps to maintain the arrhythmia, as well as promoting AF progression. B, In most patients, the genetic substrate alone does not provide sufficient susceptibility for AF. Additional disease-related remodeling may increase vulnerability and allow the initiation of paroxysmal AF episodes. Over time, some patients with paroxysmal AF may progress to longer-lasting persistent AF forms. C, Because of the composition of substrate and trigger, some patients have a first AF episode lasting >7 d and may progress to permanent AF due either to progression of underlying disease or to a medical decision to leave the patient in AF. (Note that for convenience the time scale for AF episodes, in gray, is expanded compared with the lower axis providing a sense of lifetime time course.)
Major arrhythmogenic mechanisms include focal ectopic/triggered activity and re-entry. Focal ectopic/triggered activity is mediated by early and delayed afterdeplarizations, which are promoted by prolonged repolarization and Ca2+-handling abnormalities, respectively. Conceptual interpretations of functional re-entry include leading circle and spiral wave. For detailed discussion of the differences between leading circle and spiral wave concepts, see Comtois et al.17 ERP indicates effective refractory period.
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