Heart Disease

Most patients with AF have associated cardiac disease.¹ Cardiac senescence is a major predisposing factor, largely mediated by structural remodeling, which causes fibrotic alterations and microconduction slowing, as well as atrial enlargement.² Heart failure (HF), hypertensive heart disease, valvular disease, and ischemic heart disease are major contributors to AF occurrence. Less common conditions leading to AF include pericarditis, myocarditis, atrial tumors (primarily myxomas), and various cardiomyopathies.

Genetic Determinants

Knowledge of genetic determinants of AF has increased rapidly over the past 10 years.3,4 Disease-causing mutations have been established and the underlying pathophysiology studied.³ Monogenic forms have high penetrance and provide important mechanistic insights into AF mechanisms. Genome-wide association studies (GWASs) provide new insights into genetic variation–based population determinants of AF, while raising challenging pathophysiological issues.⁴

Extracardiac Contributors

A variety of extracardiac conditions can affect AF occurrence. Heavy alcohol consumption promotes AF,⁵ and hyperthyroidism is a well-recognized factor.⁶ Obesity is increasingly recognized as an AF risk factor,⁷ with obstructive sleep apnea, often associated with obesity, also noted as an important contributor. Autonomic tone may set the conditions for AF initiation and maintenance. The AF-promoting properties of vagal activation are well known, and increasing evidence suggests an important role for combined sympathovagal discharge.⁸

Focal Ectopic Activity

Several mechanisms produce abnormal impulse formation and can cause focal ectopic activity. Spontaneous automatic activity depends on the balance between inward and outward currents during phase 4 of the action potential. Increased phase 4 inward currents carried by Na⁺ or Ca²⁺, particularly time-dependent activating currents like the “funny current” I_f, and/or decreased phase 4 outward currents, produce spontaneous phase 4 depolarization. When it reaches threshold potential, the cell fires, generating automatic ectopic activity.

Focal ectopic activity may also result from afterdepolarizations, which are subdivided into early afterdepolarizations (arising before the end of phase 3) and delayed afterdepolarizations (DADs), which occur after full repolarization. Cell Ca²⁺ handling is crucial for normal contractility (Figure 45-3, A). DADs (Figure 45-3, B) are thought to be the most important cause of focal atrial ectopic firing. DADs are caused by a diastolic Ca²⁺ leak from the sarcoplasmic reticulum (SR) via SR Ca²⁺-release channels or ryanodine receptors (RyRs; RyR2 is the cardiac form). Systolic Ca²⁺ release through RyR2s causes cardiac contraction. Relaxation is mediated by diastolic Ca²⁺ removal from the cytosol into the SR by a Ca²⁺-uptake pump, the SR Ca²⁺-adenosine triphosphatase (ATPase; SERCA). RyR2s are sensitive to both cytosolic and intraluminal SR Ca²⁺ concentration; diastolic releases result when SR concentrations are excessive, or when RyR2s have an abnormally low threshold for Ca²⁺ release. Excess cytosolic Ca²⁺ is handled by the sarcolemmal Na⁺/Ca²⁺-exchanger (NCX), which moves three Na⁺ ions (charge +3) into the cell for each Ca²⁺ ion (charge +2) extruded into the extracellular space, generating net inward current (called transient inward current [I_ti]) that depolarizes the cell, producing a DAD. When DADs reach threshold, they induce premature action potential firing (dashed line in Figure 45-3, B). Repeated DADs can generate focal atrial tachycardias. RyR2 function is regulated by channel phosphorylation: Hyperphosphorylation enhances RyR Ca²⁺ sensitivity and promotes DAD formation. Calsequestrin (CSQ) is the principal Ca²⁺-storage buffer of the SR. Inadequate CSQ function/expression increases free SR Ca²⁺ concentration and promotes diastolic RyR2 Ca²⁺ release.¹³

Early afterdepolarizations (EADs) result from spontaneous depolarization during phase 2 or 3 of the action potential (AP), generally when AP duration (APD) is excessively prolonged. With very long APs, L-type Ca²⁺ currents may have enough time to recover from inactivation, carrying inward Ca²⁺ current to generate an EAD.

Reentry

Two conceptual frameworks for understanding the basis of functional reentry are shown in Figure 45-4 (top). The leading circle model (Figure 45-4, A) posits reentry around a central zone that is continuously activated by centripetal waves emanating from a reentering activation wave front. In this model, reentry establishes itself in a circuit for which the dimension equals the distance traveled during one refractory period (wavelength; refractory period times conduction velocity). When the wavelength is small because of slow conduction or brief refractoriness, multiple circuits can be accommodated in the atria and spontaneous self-termination is unlikely. In the spiral wave model (Figure 45-4, B), reentry is maintained by rotors established by tissue excitability properties (depending on both conduction and refractoriness conditions), which determine rotor rapidity, stability, and size (greater excitability generates smaller, more stable, and faster rotors). Anatomical obstacles or complexities can favor reentry by anchoring reentry circuits. Figure 45-4, C illustrates the effect of structural remodeling. Progressive atrial dilatation creates longer conduction pathways for reentry. Tissue fibrosis slows conduction and creates conduction barriers that favor the development of stable rotors and/or multiple simultaneous irregular reentry circuits that can sustain AF. In addition, fibroblast proliferation can promote arrhythmogenesis via cardiomyocyte-fibroblast interactions that alter AP properties and slow conduction.

Molecular Control of Cell Ca²⁺ Handling and DAD Generation

Normal cell Ca²⁺ handling is crucial for cellular contraction and relaxation (see Figure 45-3, A; see also Chapter 16 of this book). Abnormal SR Ca²⁺ handling is typically seen in AF patients.^14–19 Defective Ca²⁺ handling promotes spontaneous RyR2-mediated diastolic SR-Ca²⁺ releases in atrial cells from patients with chronic AF.^14,15,18,19 Figure 45-5 summarizes the detailed molecular pathobiology of DAD-inducing diastolic RyR2 Ca²⁺ release. Protein kinase A (PKA) phosphorylation of RyR2 at Ser2808¹⁷ and Ca²⁺ calmodulin–dependent kinase II (CaMKII) phosphorylation at Ser2814 are increased in dogs and goats with pacing-induced AF and in AF patients.^14,19–21 CaMKII activity is normally autoinhibited. Ca²⁺-calmodulin binding removes autoinhibition, activating CaMKII and causing autophosphorylation that activates CaMKII and makes it Ca²⁺ independent. Similar activation may result from CaMKII oxidation. Changes in RyR2 phosphorylation state at PKA and CaMKII sites may result not only from changed kinase activity, but also from alterations in dephosphorylating enzyme phosphatases.²² These posttranslational alterations increase RyR2 Ca²⁺ sensitivity, enhancing channel open probability.^14,17 Mice deficient in RyR2-inhibitory FK-505 binding protein 12.6, mice with gain-of-function mutations in RyR2, and mice with constitutively phosphorylated RyR2 channels at S2814 (S2814D mice) all exhibit increased susceptibility to pacing-induced AF in association with increased atrial cell SR Ca²⁺ leak and triggered activity.^14,20,23,24 Angiotensin effects to promote AF may be due in part to oxidative stress acting via CaMKII oxidation on diastolic RyR2 Ca²⁺ release.²⁵ RyR2 dysfunction can be induced by Ca²⁺ overload resulting from phospholamban hyperphosphorylation, which removes phospholamban inhibition of SERCA and enhances SR Ca²⁺ uptake.²² Phospholamban hyperphosphorylation can be produced by enhanced PKA or CaMKII activity, or by decreased phosphatase function. Reduced phosphatase function can be a consequence of increased activity of an inhibitory protein, I-1, typically caused by I-1 hyperphosphorylation.²²

Increases in NCX expression and/or function are also commonly noted in AF,14,19,22,26 causing I_ti resulting from any specific amount of diastolic SR Ca²⁺ leak to be larger in AF, likely contributing to the increased risk of DADs and triggered ectopic activity.^14,27 Cardiac IP₃ receptors (IP₃R2) act as Ca²⁺-transporting pathways and can facilitate SR Ca²⁺ leak to promote arrhythmogenesis. IP₃R2 expression is increased by atrial tachycardia remodeling (ATR) and is greater in atria than in ventricles.²⁸ IP₃R2-coupled amplification of atrial SR Ca²⁺-release events and related arrhythmogenesis may thus contribute to AF-related ectopic activity.

Congestive heart failure (CHF) is a very important cause of AF. Focal drivers and triggered activity play a role in CHF-related AF.²⁹ In experimental dilated cardiomyopathy, CHF increases SR Ca²⁺ load and reduces calsequestrin expression, thereby promoting spontaneous SR Ca²⁺ release.³⁰ Coronary artery disease (CAD) is also an important risk factor for AF. Atrial ischemia promotes AF maintenance.³¹ In a dog model of chronic occlusive coronary artery disease affecting the atrium, frequent spontaneous atrial ectopy is associated with an increased incidence of atrial cardiomyocyte-triggered activity.³¹ Triggered activity is likely due to spontaneous SR Ca²⁺-release events and increased NCX function in cardiomyocytes from the ischemic border zone.³¹

Two AF-promoting genetic variants have been linked to DAD mechanisms: (1) a mutation of the gene encoding the adapter protein ankyrin-B (long QT syndrome-4 [LQTS4]), which causes multiple proteins to be poorly addressed to their membrane targets, altering Ca²⁺ handling and leading to DADs/triggered activity32,33; and (2) a predicted loss-of-function single-nucleotide polymorphism (SNP) of the SLN gene encoding the Ca²⁺-binding protein sarcolipin, which could increase SR Ca²⁺ load, thereby affecting DAD susceptibility.³⁴

Beta-adrenoceptor activation phosphorylates RyR2, promoting diastolic SR Ca²⁺-release events.³⁴ Conditions that directly cause DAD-promoting abnormalities in Ca²⁺ handling may require adrenergic stimulation to induce Ca²⁺ sparks and triggered activity.³¹ Spontaneous AF paroxysms occur in dog models of autonomic hyperinnervation,³⁶ with sympathovagal discharge preceding AF paroxysms.³⁷ Vagal activation promotes arrhythmogenesis by reducing APD, allowing afterdepolarizations induced by adrenergic stimulation to induce ectopic firing in pulmonary veins.^38–40

Molecular Control of L-Type Ca²⁺ Current and Pathophysiology in AF

AF⁴¹ and indeed all very rapid atrial tachyarrhythmias⁴² remodel atrial electrical properties to promote AF initiation and maintenance (ATR). A major AF-promoting component of ATR is refractory period reduction due to APD abbreviation (see Figure 45-4, B). Reduced depolarizing L-type Ca²⁺ current (I_Ca,L) and increased repolarizing inward-rectifier K⁺ currents underlie ATR-induced APD shortening.^43–50 The molecular complex basis of I_Ca,L reduction seen in AF is illustrated in Figure 45-6, A. Rapid atrial activation induces Ca²⁺ loading, activating Ca²⁺-calmodulin/calcineurin/nuclear factor of activated T-lymphocyte (NFAT) signaling that causes downregulation of Cav1.2 α-subunit mRNA.^51–53 Other contributors to I_Ca,L downregulation may include decreased expression of accessory β₁-, β_2a-, β_2b-, β₃-, and α₂δ₂-subunits^45,54,55; Cav1.2 dephosphorylation via type 1 (PP1) and/or type 2A (PP2A) protein phosphatases^22,45,56; and increased Cav1.2 α-subunit s-nitrosylation.⁵⁷ MicroRNAs (miRNAs) are short RNA sequences that regulate cardiac gene expression by translational suppression and/or mRNA destabilization.⁵⁸ They are centrally involved in cardiac remodeling and appear to play a major role in AF.⁵⁸ Recent work implicates increased miRNA-328 in AF promotion due to I_Ca,L-downregulation mediated by inhibition of translation and mRNA destabilization.⁵⁹ Finally, impaired Cav1.2 and Cav1.3 protein trafficking induced by a zinc-binding protein (Znt-1) and ankyrin B reduction, respectively, may contribute to I_Ca,L reduction in AF.^33,60

Figure 45-6 Mechanisms of Ionic Current Remodeling in AF
A, L-type Ca²⁺-current (I_Ca,L) downregulation. High atrial rates in AF enhance intracellular Ca²⁺ load and activating calcineurin via Ca²⁺/calmodulin (CaM) binding. Calcineurin dephosphorylates nuclear factor of activated T-lymphocytes (NFAT), allowing it to translocate into the nucleus and reduce mRNA levels of the I_Ca,L alpha subunit, Cav1.2. Breakdown of Cav1.2 protein by calpains might also contribute to reduced Cav1.2 protein expression. The protein zinc transporter 1 (ZnT-1) impairs Cav1.2 membrane trafficking and is upregulated in AF. Increased protein phosphatase (PP) activity dephosphorylates Cav1.2 phosphorylation and may decrease I_Ca,L. B, Inward-rectifier K⁺-current upregulation. Increased Kir2.1 subunit expression is caused by decreases in inhibitory microRNAs like miR-101, miR-26, and miR-1. Acetylcholine-regulated K⁺ current (I_K,AChc) is increased because of increased membrane abundance of the stimulatory protein kinase C (PKC) isoform PKCε and decreased cellular expression of the inhibitory isoform PKCα. PP,

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