Mechanism of Initiation of Atrial Fibrillation

The factors responsible for the onset of AF include triggers that induce the arrhythmia and a receptive substrate that sustains it. The triggers are diverse yet may not cause AF in the absence of other contributors. There are two different types of arrhythmias that can potentially play a role in generating AF: premature atrial complexes (PACs) that initiate AF (focal triggers) and focal tachycardia that either induces fibrillation in the atria or mimics AF by creating a pattern of rapid and irregular depolarization wavefronts in the atria for as long as the focus continues to discharge.

The mechanism of initiation of AF is not certain in most cases and likely is multifactorial. Triggers propagating into the atrial myocardium can potentially initiate multiple reentrant wavelets and AF. In some patients with paroxysmal AF, impulses initiated by ectopic focal activity propagate into the left atrium (LA) and encounter heterogeneously recovered tissue. If reentry were assumed to be the mechanism of AF, initiation would require an area of conduction block and a wavelength of activation short enough to allow the reentrant circuits to persist in the myocardium.

Once triggered, AF can be self-sustained, in which case the continued firing of the focus may not be required for maintenance of the arrhythmia, and ablation of the focus may not terminate AF, but can potentially prevent the reinitiation of AF. Conversely, initiation and maintenance of AF can depend on uninterrupted periodic activity of a few discrete reentrant or triggered sources localized to the LA (i.e., focal drivers), emanating from such sources to propagate through both atria and interact with anatomic or functional obstacles, thus leading to fragmentation and multiple wavelet formation. Factors such as wavefront curvature, sink-source relationships, and spatial and temporal organization all are relevant to the understanding of the initiation of AF by the interaction of the propagating wavefronts with such anatomic or functional obstacles. Indeed, all these factors, which differ from triggers, importantly affect the initiators of AF.

AF triggering factors include sympathetic or parasympathetic stimulation, bradycardia, PACs (which may be the most common cause; Fig. 15.2 ), atrial flutter (AFL; see Fig. 12.2 ), supraventricular tachycardias (SVTs; especially those mediated by atrioventricular [AV] bypass tracts [BTs]; Fig. 15.3 ), and acute atrial stretch. Identification of these triggers has clinical importance because treatment approaches directed at elimination of the triggers (e.g., catheter ablation of the initiating PACs or SVT) can be curative in selected patients.

Atrial Fibrillation (AF) Induction by Premature Atrial Complexes (PACs) Originating From the Right Superior Pulmonary Vein (PV) .

Two monomorphic PACs (arrows) occur at short coupling intervals and are inscribed within the T wave. The second PAC (red arrows) triggers AF.

Atrial Fibrillation (AF) Induction by Orthodromic Atrioventricular Reentrant Tachycardia (AVRT) .

CS _dist , Distal coronary sinus; CS _prox , proximal coronary sinus; HRA, high right atrium; RVA , right ventricular apex.

Mechanism of Maintenance of Atrial Fibrillation

Having been initiated, AF can be brief; however, various factors can act as perpetuators, thus ensuring the maintenance of AF. One factor is the persistence of the triggers and initiators that induced the AF, which then act as an engine driving the continuation of AF. In this setting, maintenance of AF is dependent on the continued firing of the focus (the so-called “focal driver”). Alternatively, AF can persist even in the absence of the focal drivers. Without focal drivers, persistence of AF results from a combination of electrical and structural remodeling processes characterized by atrial dilation and shortening of atrial refractoriness (see later). These factors can be present at baseline but can also be induced by the AF itself.

The mechanisms responsible human AF remain controversial. Several theories have been proposed to explain the EP mechanisms underlying AF, including the multiple wavelet theory and the localized source hypothesis.

Mapping human AF.

The complexity of AF electrograms, with varying amplitude and morphology as well as spatiotemporal CL variations, poses significant challenges to mapping human AF. Recent clinical studies have demonstrated conflicting mechanisms underlying sustained AF; one source of the discrepancies likely arises from differences in scale (global vs. regional) and spatial resolution of the mapping techniques. A second possible factor is the approach employed to analyze fibrillatory wavefront dynamics, using either phase mapping or activation time.

Conventional activation mapping techniques used in the EP lab, which assign a specific time point on the unipolar electrogram as the marker of local activation, cannot be employed during AF; fibrillation electrograms typically are fractionated and low amplitude, and are prone to artifacts. Spectral analysis and phase mapping of cardiac potentials have been used by researchers to overcome some of those challenges. Both algorithms derive originally from optical mapping experiments conducted in ex vivo hearts. Although optical mapping provides much higher spatiotemporal resolution and accuracy when tracking rotor formation and maintenance, current optical mapping strategies do not allow panoramic endocardial mapping and require the use of potentially toxic voltage-sensitive dyes that preclude their use for human in vivo studies.

The “spectrum” of a signal displays its energy distribution in the frequency domain. Frequency domain analysis can identify the frequency of the highest peak in the spectrum (i.e., “dominant frequency”), which is often used as a surrogate for the average activation rate at a specific location. Hence, spectral analysis can map the distribution of AF frequencies and localize the areas with the highest activation frequencies (i.e., the shortest CLs, dominant frequency), which usually coincide with the location of AF sources (foci or rotors) that maintain AF. Those techniques have demonstrated that AF has significant periodic elements with varying degrees of regularity, and that certain regions of the atria can have higher activation frequencies than other regions, suggesting that these areas can potentially be the drivers that maintain AF and can provide targets of ablation therapy. A limitation of spectral analysis is that frequency domain mapping produces time-averaged frequency information over space, thereby losing the ability to track temporal variations of the signal.

“Phase” is a measure of where a signal is in its cycle of oscillation at a given point in time. Phase mapping computes oscillations in the signal over its entire duration, independent of its amplitude, and characterizes a temporal signal in its instantaneous phase of the activation/recovery cycle at each time point. Computation of phase involves the transformation of the signal to the phase domain by selecting a specific CL from the temporal signal. Analysis of phase changes over space provides information on the patterns of organization (repetitive activity) and enables visualization of the spatiotemporally distributed patterns of propagation during cardiac fibrillation. Importantly, phase mapping makes it possible to detect rotational wavefronts (rotors) and determines their center of rotation (singularity point) ( eFig. 15.2 ). However, phase mapping has the propensity to introduce false rotors during complex activation patterns, such as wavefront propagation about a line of block.

Varying Activation Patterns Identified in Phase Movies From the Left Atrium of the Sheep Heart.

(A) Sequential snapshots show a rotor pivoting around a phase singularity (point where all phases converge). (B) Breakthrough activation pattern. The wave seems on the center of the field of view and propagates outward. Right, Key for the different phases of the action potential is color-coded.

(From Quintanilla JG, Pérez-Villacastín J, Pérez-Castellano N, et al. Mechanistic approaches to detect, target, and ablate the drivers of atrial fibrillation. Circ Arrhythmia Electrophysiol . 2016;9:1–12.)

In the clinical setting, recent studies employing panoramic atrial mapping during AF have used phase analysis of contact atrial endocardial electrograms from basket electrode catheters (focal impulse and rotor modulation [FIRM], Fig. 15.4 ) or reconstructed atrial electrograms from body surface recordings (electrocardiogram [ECG] imaging, eFig. 15.3 ). Those studies demonstrated the presence of atrial driver regions with a high prevalence of transient rotors, and suggested that AF is sustained by spiral waves (rotors) or focal sources, or both, which are sufficiently stable in space to be targeted by ablation. Both approaches identified phase singularity points (core of a rotor) as a target for ablation. Elimination of those rotors and focal source could acutely modify or terminate AF and substantially improve ablation outcome. Localized sources can potentially explain modulation of AF by ablation insufficient to limit critical mass and AF termination by localized intervention.

Focal Sources of Atrial Fibrillation Identified by Focal Impulse and Rotor Modulation (FIRM) Mapping.

(A) Fluoroscopic view (left anterior oblique) of the multielectrode basket catheter deployed in the left atrium. (B) FIRM mapping shows a left atrial rotor with counterclockwise rotation (from red to blue on the activation time scale with red representing early activation). (C) FIRM mapping shows a left atrial focal impulse originating from electrodes 2 and 3 spline C and D of the basket catheter (red represents early activation with a centrifugal pattern).

(From Sommer P, Kircher S, Rolf S, et al. Successful repeat catheter ablation of recurrent longstanding persistent atrial fibrillation with rotor elimination as the procedural endpoint: a case series. J Cardiovasc Electrophysiol . 2016;27:274–280.)

Phase Mapping of Electrocardiogram Imaging Data Showing Posterior View of Left Atrium During Paroxysmal Atrial Fibrillation.

Panel A shows serial snapshots of a single wave emerging out of the left inferior pulmonary vein (PV, white star ) and reaching right PVs in 30 milliseconds while it expands radially to the roof and inferior walls. Panel B shows serial snapshots of two successive rotations (white arrows) of a rotor located near the ostia of right PVs. The core of the rotor ( white star at the center of rainbow-colored phases of rotor) is seen meandering in a small region in this example. The blue wave indicates the depolarizing front, which makes one full rotation in 160 milliseconds. The phases of wave propagation are color coded using rainbow scale. The blue color represents depolarizing wave and the green represents the end of repolarization. The wavefront can be read by following the blue color. The time (milliseconds) at the bottom of each snapshot represents the moment in the time window when the snapshot was taken. LIPV, Left inferior PV; LSPV, left superior pulmonary vein; RIPV, right inferior PV; RSPV, right superior PV; SVC, superior vena cava.

(From Haissaguerre M, Hocini M, Shah AJ, et al. Noninvasive panoramic mapping of human atrial fibrillation mechanisms: a feasibility report. J Cardiovasc Electrophysiol . 2013;24:711–717.)

It is important to note that while both ECG imaging and FIRM mapping use phase analysis to determine rotational conduction behavior during AF, detection of rotors using those techniques provides fundamentally different results regarding the spatial behavior of rotors. FIRM mapping demonstrates spatially stable rotors in both atria; many of these rotors are detectable for many seconds up to minutes at the same location. In contrast, ECG imaging techniques show that the reentrant circuits are not spatially stable but meandered substantially throughout the atrium; nevertheless, they recurred repetitively at specific sites that can potentially provide a target for ablation. The reason for the significant discrepancy between the spatial behavior of rotors identified by these different techniques is currently unclear. In a recent study comparing resolution requirements for detection of stationary and meandering rotors found that rotor trajectories can be lost at resolutions for which stable rotors are still identifiable, which may explain differences in findings on rotor stability with basket catheters identifying stable rotors and noninvasive ECG imaging identifying transient meandering rotors.

However, despite these data, the rotor paradigm is neither confirmed nor universally accepted, with recent studies raising questions about the efficacy of rotor-targeted ablation. Sufficient spatial resolution is essential for the accurate detection of rotors and focal sources. Although stationary rotors may be identified at coarse resolutions, meandering rotors are lost. While most clinically used catheters offer sufficient spatial resolution to identify and track rotor core location for the range of wavelengths occurring in human AF, mapping catheters with localized coverage (e.g., quadripolar or ring catheters) are not capable of tracking rotors unless the catheter is fortuitously placed over a rotor that does not meander outside the margins of the catheter poles. In contrast, basket catheters provide global coverage. However, the low resolution of the basket catheters renders them prone to false detections; interpolation of phases is inherently biased toward detection of rotors as the algorithm is devised to demonstrate rotational activity, and focal activation might be displayed as rotational activity if the wavefront reaches the surrounding electrodes sequentially. This can potentially explain, in part, the large incidence of rotors using FIRM mapping, the low AF termination rate with ablation, and poor long-term success for ablating rotors detected by basket catheters. On the other hand, ECG imaging lacks the ability to discern among epicardial breakthroughs, spontaneous depolarizations, and (subcentimeter) microreentry, which are seen as focal activity.

Atrial Electrophysiological Properties

In normal atrial cardiomyocytes, phase 0 of the action potential is mediated by the rapidly activating sodium (Na ⁺ ) current (INa). These potentials are called fast response potentials ( see Chapter 1 ). As a result, the atrium has several properties that permit the development of very complex patterns of conduction and an extremely rapid atrial rate, as seen in AF. The action potential duration is relatively short, and reactivation can occur partially during phase 3 and usually completely within 10 to 50 milliseconds after return to the diastolic potential. The refractory period shortens with increasing rate, and very rapid conduction can occur.

Patients with AF and no apparent structural heart disease appear to have increased dispersion of atrial refractoriness, which correlates with enhanced inducibility of AF and spontaneous episodes. Some patients have site-specific dispersion of atrial refractoriness and intraatrial conduction delays resulting from nonuniform atrial anisotropy.

Atrial Fibrosis

Atrial fibrosis plays an important role in the pathophysiology of AF. Atrial fibrosis results from various cardiac insults that share common fibro-proliferative signaling pathways. Fibrotic myocardium exhibits slow and inhomogeneous conduction, with spatial “nonuniform anisotropic” impulse propagation, likely secondary to reduced intercellular coupling, discontinuous branching architecture, and zigzagging circuits. When combined with inhomogeneous dispersion of refractoriness within the atria, conduction block provides milieu necessary for the development of reentry. The greater the slowing of conduction velocity in fibrotic myocardium, the shorter the anatomic circuit needed to sustain a reentrant wavelet. In fact, reentrant circuits need be only a few millimeters in length in discontinuously conducting tissue. Thus atrial regions with advanced fibrosis can harbor local sources for AF. Such a hypothesis would not preclude the remainder of the atria from showing fibrillatory conduction or functional reentrant waves.

Increased atrial fibrosis is a manifestation of the normal aging process as well as various pathological conditions such as hypertension, coronary artery disease, heart failure, and sleep apnea. Increased atrial fibrosis has been demonstrated even in patients with so-called “lone” or “idiopathic” AF, suggesting that AF in these patients potentially represents an arrhythmic manifestation of “fibrotic atrial myopathy.” The strong association of sinus node dysfunction (SND) and AF (the bradycardia-tachycardia syndrome) also suggests that replacement of atrial myocytes by fibrosis likely plays an important part in the pathogenesis of AF, although in some instances the bradycardia component is a functional response to the tachycardia. Recent studies using delayed-enhancement cardiovascular magnetic resonance (CMR) imaging and electroanatomic voltage mapping demonstrated that the extent and distribution of the fibrotic atrial changes can vary widely among patients with AF. Nonetheless, a higher degree of fibrosis often is observed in patients with persistent AF versus paroxysmal AF. In addition, atrial fibrosis defined by delayed-enhancement CMR was found to be independently associated with AF recurrence in patients undergoing catheter ablation procedures.

Importantly, AF itself seems to produce various alterations of atrial architecture that further contribute to atrial remodeling, mechanical dysfunction, and perpetuation of fibrillation. Longstanding AF results in loss of myofibrils, accumulation of glycogen granules, disruption in cell-to-cell coupling at gap junctions, and organelle aggregates.

Changes in AF characteristics during evolving fibrosis also have a direct impact on why electrical or drug treatment ultimately fails to achieve conversion to NSR. In the markedly fibrotic and discontinuous atrial tissue, characterized by discontinuous anisotropy, marked degree of gap junctional uncoupling, and fiber branching, the safety factor for propagation is higher than in normal tissue. Hence, blocking of the Na ⁺ current to the same degree as is necessary for the termination of functional reentry may not terminate reentry caused by slow and fractionated conduction in fibrotic scars of remodeled atria. Conduction in discontinuous tissue is mostly structurally determined and leads to excitable gaps behind the wavefronts. If a gap is of critical size, the effectiveness of drugs that prolong atrial refractoriness will be limited. Furthermore, scar tissue is likely to exhibit multiple entry and exit points and multiple sites at which unidirectional block occurs. This can potentially lead to activity whose appearance in local extracellular electrograms changes from beat to beat, as well as beat-to-beat CL variability. Although such regions can be expected to respond to defibrillation, AF can resume after extrasystoles or normal sinus beats immediately after conversion, with unidirectional block recurring because of scar.

Atrial Stretch

Atrial stretch and dilation can play a role in the development and persistence of AF. Clinically, AF episodes occur more frequently in association with conditions known to cause elevated LA pressure and atrial stretch, such as acutely decompensated systolic or diastolic heart failure. In addition, the echocardiographic LA volume index and restrictive transmitral Doppler flow patterns are strong predictors of the development of AF.

The structure of the dilated atria can potentially have important EP effects related to stretch of the atrial myocardium (so-called “electromechanical feedback”). Acute atrial stretch reduces the atrial refractory period and action potential duration and depresses atrial conduction velocity, potentially through a reduction of cellular excitability by the opening of stretch-activated channels or changes in cable properties (membrane resistance, capacitance, core resistance). Regional stretch for less than 30 minutes activates the immediate early gene program, thus initiating hypertrophy and altering action potential duration in affected areas. Moreover, acutely altered stress and strain patterns augment the synthesis of angiotensin II, which induces myocyte hypertrophy. Angiotensin II can contribute to arrhythmogenic electrical dispersion by regionally increasing L-type calcium (Ca ²⁺ ) current (ICaL) and decreasing the transient outward potassium (K ⁺ ) current (Ito). Altered stretch of atrial myocytes also results in opening of stretch-activated channels, increasing G protein–coupled pathways. This leads to increased protein kinase A and C activity, and enhanced ICaL through the cell membrane, and increased release of Ca ²⁺ from the sarcoplasmic reticulum, thus promoting afterdepolarizations and triggered activity. Furthermore, acute stretch can promote an increase in dispersion of refractoriness and spatial heterogeneity by causing conduction block and potentially contributing to the development of AF. These alterations occur nonuniformly because stretch is greater in areas of thin versus thick atrial myocardium.

In addition, chronic atrial stretch, as a result of AF and several conditions associated with AF, can promote atrial fibrosis via the activation of multiple profibrotic and hypertrophic signaling pathways.

Inflammation

There is increasing evidence that implicates inflammation (and its downstream effects, including atrial fibrosis) in the pathogenesis of AF. Clinically, AF occurs frequently in the setting of inflammatory states such as cardiac surgery and acute pericarditis. In addition, the levels of inflammatory biomarkers (C-reactive protein [CRP] and interleukin-6 [IL-6]) are significantly increased in patients with AF, findings suggesting the presence of systemic inflammation in these patients. Elevation of the levels of CRP and IL-6 has been shown to predict future development, recurrence, and burden of AF. There is also evidence suggesting that inflammation is involved in electrical and structural atrial remodeling. Furthermore, inflammation appears to increase the inhomogeneity of atrial conduction directly, potentially via disruption of expression of connexin proteins, leading to impaired intercellular coupling.

It is also likely that inflammation can be a consequence of AF. CRP levels decrease following restoration of NSR. Rapid atrial activation in AF results in Ca ²⁺ overload in atrial myocytes that can potentially result in cell death, which induces a low-grade inflammatory response. The inflammation, in turn, can induce healing and reparative fibrosis that likely enhance remodeling and promote perpetuation of the arrhythmia.

Currently, the exact role of inflammation in AF is poorly defined, and it remains unclear whether inflammation is actually involved in the mechanisms underlying AF or whether it is simply an epiphenomenon. Although therapies directed at attenuating the inflammatory burden (e.g., glucocorticoids, statins, and angiotensin II inhibitors) appear promising, early clinical trials do not support a significant benefit.

Electrical Remodeling

Electrical remodeling results from the high rate of electrical activation. The EP changes typical of atrial myocytes during AF include shortening of the action potential duration and atrial refractory period, and reduction in the amplitude of the action potential plateau. Furthermore, AF results in deficiency in the ability of the repolarization time course (action potential duration) to adapt to changes in rate (“abnormal restitution”); consequently, the atrial refractory period fails to lengthen appropriately at slow rates (e.g., with return to NSR). These changes can contribute to the stability of a longer lasting form of AF because, according to the multiple wavelet theory, a short wavelength results in smaller wavelets, which increase the maximum number of wavelets, given a certain atrial mass. Tachycardia-induced changes in refractoriness are spatially heterogeneous, and there is increased variability both within and among various atrial regions, which can promote atrial vulnerability and AF maintenance and provide a substrate for reentry.

The mechanisms for electrical remodeling and shortening of the atrial refractory period are not entirely clear. Several potential explanations exist, including ion channel remodeling, angiotensin II, and atrial ischemia. The principal components of electrical remodeling include reduction in the L-type Ca ²⁺ current (ICaL), rectifier background K ⁺ current (IK1), and constitutive acetylcholine-regulated K ⁺ current (IKACh), and abnormal expression and distribution of the gap junctions.

Downregulation of ICaL seems to be responsible for shortening of the atrial action potential, whereas a decrease in Ito is considered to result in loss of physiological rate adaptation of the action potential. The fast atrial rate during AF causes accumulation of intracellular Ca ²⁺ . The reduction in ICaL can be explained by a decreased expression of the L-type Ca ²⁺ channel α1C subunit, likely as a compensatory mechanism to minimize the potential for cytosolic Ca ²⁺ overload secondary to increased Ca ²⁺ influx during the rapidly repetitive action potentials during AF. Verapamil, an L-type Ca ²⁺ channel blocker, was shown to attenuate electrical remodeling and hasten complete recovery without affecting inducibility of AF, whereas intracellular Ca ²⁺ overload, induced by hypercalcemia or digoxin, enhances electrical remodeling. Electrical remodeling can be attenuated by the sarcoplasmic reticulum’s release of the Ca ²⁺ antagonist ryanodine, a finding suggesting the importance of increased intracellular Ca ²⁺ to the maladaptation of the atrial myocardium during AF.

Angiotensin II may also be involved in electrical remodeling, and angiotensin II inhibitors may prevent the remodeling process. Angiotensin-converting enzyme inhibitors reduce the incidence of AF in patients with left ventricle (LV) dysfunction after myocardial infarction (MI) and in patients with chronic ischemic cardiomyopathy. Atrial ischemia is another possible contributor to electrical remodeling and shortening of the atrial refractory period via activation of the Na ⁺ -H ⁺ exchanger.

More recently, microRNAs (miRNAs or miRs), a group of small noncoding RNA molecules that negatively regulate gene expression, were found to have an important role in a wide range of electrical and structural atrial remodeling processes. Furthermore, experimental studies showed that the rapid rates of AF can lead to autonomic atrial remodeling, with heterogeneous increase in atrial sympathetic innervation, which can potentially promote enhanced automaticity, triggered activity, and spatially heterogeneous abbreviation of refractoriness.

Furthermore, persistent AF can result in other changes within the atria, including gap junctional remodeling, manifest as an increase in the expression and distribution of connexin 43 and heterogeneity in the distribution of connexin 40, both of which are intercellular gap junction proteins.

Contractile and Structural Remodeling

Sustained AF has also been associated with structural changes such as myocyte hypertrophy, myocyte death, tissue fibrosis, impaired atrial contractility, and atrial stretch and dilation. Atrial dilation increases electrical instability by shortening the effective refractory period and slowing atrial conduction. These structural changes, many of which probably are irreversible, appear to occur over periods of weeks to months.

Cellular remodeling is caused by the apoptotic death of myocytes with myolysis. AF results in marked changes in atrial cellular substructures, including loss of myofibrils, accumulation of glycogen, changes in mitochondrial shape and size, fragmentation of sarcoplasmic reticulum, and dispersion of nuclear chromatin.

Contractile remodeling is likely caused by downregulation of ICaL (resulting in reduced release of Ca ²⁺ during systole), as well as myolysis (loss of sarcomeres). Contractile remodeling can potentially cause thrombus formation and atrial dilation. Contractile remodeling starts early after onset of AF, and its recovery generally takes longer than reversal of electrical remodeling, likely because of the time it takes for the atria to replace lost sarcomeres.

In addition to remodeling of the atria, the sinus node can undergo remodeling, resulting in SND and bradyarrhythmias caused by reduced sinus node automaticity or prolonged sinoatrial conduction. The phenomenon of sinus node remodeling likely contributes to the episodes of bradycardia seen in the tachycardia-bradycardia syndrome and may reduce sinus rhythm stability and increase the stability of AF. As mentioned earlier, elements of the sinus bradycardia appear to be functionally reversible if the tachycardia is prevented.

Studies suggest that the PVs are more susceptible to electrical alterations resulting from AF than the atria. Although the PVs display significantly longer refractory periods at baseline than the atria, they exhibit more prominent shortening of refractoriness after a brief episode of pacing-induced AF. Moreover, the short-term presence of AF does influence PV EP properties by slowing the conduction velocity without affecting the conduction times of the atria. Structural changes in the atria after remodeling, such as stretch, can also lead to increased PV activity. Atrial stretch can lead to increased intraatrial pressure, causing a rise in the rate and spatiotemporal organization of electrical waves originating in the PVs. These changes imply that electrical and structural remodeling increases the likelihood of ectopic PV automaticity and AF maintenance.

Tachycardia-induced atrial remodeling can potentially underlie various clinically important phenomena, such as the tendency of patients with other forms of supraventricular arrhythmias to develop AF, the tendency of AF to recur early after electrical cardioversion, the resistance of longer duration AF to antiarrhythmic medications, and the tendency of paroxysmal AF to become persistent.

If NSR is restored within a reasonable time period, EP changes and atrial electrical remodeling appear to normalize gradually, atrial size decreases, and atrial mechanical function is restored. These observations lend support to the idea that the negative downhill spiral in which AF begets AF can be arrested with NSR that perpetuates NSR, and restoration of NSR may forestall progressive remodeling and the increase in duration and frequency of arrhythmic episodes by reverse remodeling.

Pulmonary Vein Anatomy

PVs can have variable anatomy. Most hearts examined are found to have four PVs with distinct ostia. The PV ostia are ellipsoid with a longer superoinferior dimension, and funnel-shaped ostia are frequently noted in patients with AF. The right superior PV lies just behind the SVC or RA, and the right inferior PV projects horizontally. The left superior PV lies between the LA appendage (LAA) and the descending aorta, and the left inferior PV courses near the descending aorta ( Fig. 15.5 ). The superior PVs project forward and upward, whereas the inferior PVs project backward and downward. PVs are larger in patients with AF than in normal subjects, in men than in women, and in persistent versus paroxysmal AF.

Segmented Cardiac Computed Tomography Images Demonstrating Anatomic Relationship of the Left Atrium (LA) and Pulmonary Veins (PVs).

Images are viewed from multiple projections: right lateral (RL) , right anterior oblique (RAO) , anteroposterior (AP) , left anterior oblique (LAO) , left lateral (LL) , and posteroanterior view (PA) . AO, Aorta; IVC, inferior vena cava; LAA, LA appendage, LI, left inferior PV; LPA, left pulmonary artery; LS, left superior PV; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RI, right inferior PV; RPA, right pulmonary artery; RV, right ventricle; RS, right superior PV; SVC, superior vena cava.

Significant variability of PV morphologies can be observed in 40% of patients undergoing AF ablation, including: (1) common ostium (in approximately 25% of patients; Fig. 15.6 ) of left-sided or, less frequently, right-sided PV; (2) supernumerary right PVs (right middle PV is observed in 8% to 29% of patients; see Fig. 15.6 ); (3) anomalous PVs arising from the LA roof; and (4) multiple ramification and early branching (especially of the right inferior PV).

Cardiac Computed Tomography Angiogram (Posteroanterior and Cardioscopic Views) of the Left Atrium and Pulmonary Veins (PVs).

(A and B) The left-sided PVs share a common ostium. (C and D) Three PVs are observed on the right side. LAA, Left atrial appendage; LCPV, left common PV; LSPV, left superior PV; RIPV, right inferior PV; RMPV, right middle PV; RSPV, right superior pulmonary vein.

The PVs are covered by myocardial sleeves formed by one or more layers of myocardial fibers oriented in a circular, longitudinal, oblique, or spiral direction. These sleeves, continuing from the LA into the PV, vary from 2 to 25 mm in length (mean, 13 mm). The length of the myocardial sleeves usually has a distinctive distribution; superior PVs have longer and better developed myocardial sleeves than inferior PVs, which can potentially explain why arrhythmogenic foci are found more often in the superior PVs than in the inferior PVs. It should be noted that all PVs in all individuals have such myocardial sleeves, regardless of the presence or absence of AF.

The walls of the PVs are composed of a thin endothelium, a media of smooth muscle, and a thick outer fibrous adventitia. The transition from atrial to venous walls is gradual because the myocardial sleeves from the LA overlap with the smooth muscle of the venous wall. The myocardial sleeves are thickest at the venoatrial junction (mean, 1.1 mm) and then gradually taper distally. Furthermore, the thickness of the sleeves is not uniform, with the inferior walls of the superior veins and the superior walls of the inferior veins having the thicker sleeves. Throughout the PV, and even at the venoatrial junction, there are gaps in the myocardial sleeves mainly composed of fibrous tissue. The arrangement of the myocyte bundles within the sleeves is rather complex. There appears to be a mesh-like arrangement of muscle fascicles made up of circularly oriented bundles (spiraling around the long axis of the vein) that interconnect with bundles that run in a longitudinal orientation (along the long axis of the vein). Such an arrangement, together with the patchy areas of fibrosis seen, can be relevant to the role of the PVs in the initiation of AF.

Electrophysiology of Pulmonary Vein Musculature

As noted, the PVs play a crucial role in the initiation and, in some cases, maintenance of AF. However, it is not clear what makes this region so susceptible to the arrhythmia. There are, at present, limited data available on the ionic mechanisms that underlie the arrhythmogenicity of PVs. Detailed mapping studies have suggested that reentry within the PVs is most likely responsible for their arrhythmogenicity, although abnormal automaticity and triggered activity have also been observed. However, the rarity with which AF continues within the PV after electrical isolation (see later) calls into question whether the PVs are adequate in themselves to maintain AF.

The EP features of the PV, with its distinct area of slow conduction, decremental conduction, nonuniform anisotropy, and heterogeneous repolarization, create potential substrates for reentry. The heterogeneous fiber orientation in the transition from the LA to the PV sleeve results in unique conduction properties in this area. It is possible that the complex arrangement of muscle fibers within the myocardial sleeves and the uneven distribution of interspersed connective and adipose tissue account for the greater degree of decremental conduction observed in the myocardial sleeves than in the LA and for the heterogeneity in conduction properties and refractory periods among the fascicles in the myocardial sleeves. Therefore the fractionation of PV potentials commonly observed during premature stimulation (which usually indicates local slowing of conduction) is consistent with anisotropic properties that can be attributable to the complex arrangement of muscle fascicles within the myocardial sleeves.

Several studies suggested that abnormal automaticity or triggered activity, either alone or in combination with the reentrant mechanisms described previously, can play a role in the initiation of AF. These studies suggested that the propensity of PVs to exhibit abnormal automaticity or triggered activity is enhanced by pathological conditions. Further work also implicated LA posterior wall in the genesis of AF. Studies suggested that the PVs, together with the posterior LA, have an important role in the persistent form of AF. However, the nature of the relationship between this arrhythmogenic region and the pathological conditions that provide a substrate for AF has not been elucidated. Whether the critical region is the posterior LA, the PVs, or both, has been the source of ongoing debate.

Pulmonary Vein Tachycardia Versus Pulmonary Vein Fibrillation

In patients with paroxysmal AF originating from the PVs, a wide spectrum of atrial arrhythmias can coexist. Extensive monitoring frequently documents coexisting paroxysms of AT and AF. Furthermore, patients with paroxysmal AF usually have multiple foci in multiple PVs, and many of these foci originate distally in those veins.

In patients whose only clinical arrhythmia is PV AT, the clinical course is more comparable to that in patients with AT from other anatomic locations than to patients with PV AF. Those patients demonstrate a largely focal process, without evidence of a more progressive and diffuse disease as observed in the population with paroxysmal AF, and they have no tendency to develop further atrial arrhythmias during long-term follow-up. Notably, when patients with PV AT present with recurrence, in almost all cases this is from the original focus. In contrast, patients with paroxysmal AF have recurrences from foci in other PVs and from within the body of the LA. Importantly, in most patients with PV AT, the focus is located at the ostium of the vein (or within 1 cm of the ostium), rather than from further distally (2 to 4 cm). These observations suggest that patients with focal PV AT can potentially represent a different population from those with PV AF: PV AT patients having a discrete and focally curable process, in contrast to the more diffuse process involving multiple PVs and the LA seen in AF.

The spontaneous onset of focal AT from the PVs and its lack of inducibility with programmed stimulation suggest that this arrhythmia is more likely to be caused by abnormal automaticity or triggered activity rather than reentry. However, attempts to classify the arrhythmia mechanism of focal AT definitively in the EP laboratory are limited because of the significant overlap in the arrhythmia characteristics (initiation, response to drugs).

Unmodifiable Risk Factors

Modifiable Risk Factors

Epidemiology

Postoperative AF complicates cardiac surgery in 15% to 63% of patients. The risk of AF is highest among patients undergoing combined coronary artery bypass grafting and mitral valve replacement (63%) and the lowest among patients undergoing isolated coronary revascularization surgery (15% to 40%) and cardiac transplantation (11% to 24%). Postoperative AF has also been known to complicate noncardiac surgery (incidence, 0.3% to 13.7%), especially thoracic and large colorectal surgeries.

Clinical risk factors for the development of postoperative AF include advanced age (greater than 65 years), male gender, Caucasian race, hypertension, prior AF, mitral valve disease, heart failure, LV hypertrophy, diastolic dysfunction, increased LA size, history of MI, withdrawal of beta-blocker therapy, obesity, low BMI, chronic obstructive pulmonary disease, anemia, prolonged PR interval, diabetes, renal dysfunction, tobacco use, and high baseline CRP levels. The CHADS2 and CHA2DS2-VASc scores were also found to be predictive of AF after cardiac surgery.

Several factors related to the surgical procedure also potentially contribute to the development of AF. These include operative trauma from surgical dissection and manipulation, pericardial lesions, atrial dilation (caused by LV dysfunction and intraoperative volume overload), perioperative use of catecholamines, parasympathetic activation, and electrolyte imbalances.

The onset of postoperative AF peaks at 24 to 72 hours after surgery, and declines to 2% at discharge. Among patients with no prior history of AF, postoperative is usually self-limited, terminating within 24 hours in the majority of patients, with a mean duration of about 11 to 12 hours. However, despite its usually transient nature, the arrhythmia is not limited to the early postoperative phase, and can recur between day 6 and day 30 after the operation in about 25% of patients.

Prognosis

The occurrence of postoperative AF is associated with a twofold increase in cardiovascular mortality and morbidity. Postoperative AF is associated with a two- to fourfold increase in stroke risk at 30 days, and is an important predictor of in-hospital and long-term mortality. Numerous postoperative complications have been correlated with postoperative AF, including congestive heart failure, stroke, bleeding complications (from anticoagulation), renal insufficiency, infection, ventricular arrhythmias, prolonged ventilation, reintubation, readmission to the intensive care unit, and prolongation of hospital stay (by about 4 to 5 days). However, it is important to note that a causal relationship between postoperative AF and its associated adverse outcomes is still not well defined.

Mechanism

Although the exact pathophysiology of postoperative AF remains incompletely understood, both acute perioperative and chronic factors appear to play an important role in the initiation and maintenance of the arrhythmia. Acute perioperative factors that have been implicated in the creation of atrial susceptibility to AF include pericardial inflammation, heightened sympathetic tone, use of inotropes, acute atrial injury, ischemia, and oxidative stress, as well as acute atrial dilation secondary to pressure or volume overload. Also, it is likely that a preexisting atrial electrical and structural arrhythmogenic substrate increases the vulnerability to the development of AF when subjected to the acute perioperative stress. In fact, the majority of patients with postoperative AF have underlying atrial disease. Further, the presence of preexistent atrial substrate likely explains the increased risk for developing future AF among patients with new-onset postoperative AF, suggesting that the development of postoperative AF can be a surrogate for an underlying cardiac substrate.

Accuracy of Device-Detected Atrial Fibrillation

Atrial high-rate episodes have been used as a surrogate for AF, and several studies have documented positive correlation between device-identified atrial high-rate episodes and ECG-documented episodes of AF or AFL with a high degree of sensitivity and specificity. However, different trials used different definitions of an atrial high-rate event (i.e., different programmed detection parameters of atrial rate and duration), and a clear consensus definition is still lacking. Nonetheless, employing an atrial rate cut-off of at least 220 beats/min (or greater than 250 beats/min for better specificity) sustained for durations exceeding 5 minutes provides good sensitivity and specificity for clinically confirmed AF (approaching 98% sensitivity and 100% specificity). Shorter cutoffs can lead to over-detection, commonly due to far-field R- and T-wave oversensing.

It is important to interpret device-stored data with caution. False-positive AF detection can result from oversensing (e.g., far-field R- and T-wave oversensing by the atrial lead, electrical interference, myopotentials, or repetitive nonreentrant ventriculoatrial synchrony) (see eFig. 15.4 ). On the other hand, under-detection of atrial activity is not uncommon due to the small amplitude of atrial electrograms during AF. In addition, atrial high-rate episodes are not specific for AF and can be triggered by AT and AFL. Inspection of device-stored electrograms (and not only marker channels) is important to verify the accuracy of the device diagnostics. However, because of the limited memory allocated for intracardiac electrograms, pacing devices may store only limited electrogram data to corroborate that the events labeled as atrial high-rate episodes or automatic mode switch events are indeed AF or AFL.

False-positive AF detection is also frequently encountered with implantable loop recorders with AF detection algorithms. False-positive detections are often caused by noise oversensing, frequent atrial or ventricular premature beats, T-wave oversensing, or sinus arrhythmia. In one report, the accuracy of implantable loop recorders to detect true AF on a per patient basis was 96%; however, when the same analysis was performed on a per episode basis, then the overall accuracy of AF detection was only 48%.

Clinical Implications of Device-Detected Atrial Fibrillation

Several studies have clearly demonstrated that device-detected silent AFs are associated with increased risk of ischemic stroke and systemic embolism. The risk of thromboembolism appears to be related to the duration of AF episodes (or atrial high-rate episodes) as well as the patients’ risk factor profile (CHA2DS2-VASc score).

The critical burden of atrial high-rate episodes beyond which thromboembolic risk is increased and that warrants therapeutic intervention remains to be defined. Several studies attempted to assess the burden of AF that is associated with adverse clinical outcomes, and AF burden thresholds ranging from 5 minutes to 24 hours were found in different reports to have clinical relevance. However, data are sparse on whether treatment with anticoagulation for subclinical device-detected atrial high-rate episodes reduces the risk of stroke to a similar degree as it does in clinical AF. In addition, current clinical practice guidelines for the treatment of device-detected atrial high-rate episodes are lacking. Based on current evidence, it seems appropriate to consider long-term oral anticoagulation for stroke prevention in high-risk patients with atrial high-rate episodes lasting longer than 5 to 6 minutes, when false-positive AF detections are excluded.

Of note, while device-detected silent AF is known to increase stroke risk, there does not seem to be a proximate temporal relationship between device-detected atrial high-rate episodes and the occurrence of strokes. In fact, in the majority of patients of a study population, no AF was detected on device recordings in the 30 days preceding the thromboembolic events. Although these data imply that the mechanism of stroke may not be related solely to the AF episodes, the association between the observation of atrial high-rate episodes and increased risk of stroke has been consistent, and silent AF is viewed as the culprit in cryptogenic stroke in these patients. However, the value of continuous device-detected atrial arrhythmia information to guide therapeutic intervention for stroke prevention remains to be determined. A recent study suggested that a strategy of urgent initiation of anticoagulation based on device-detected AF did not improve outcomes, likely because of temporal dissociation between AF and stroke. Furthermore, withdrawal of anticoagulation in AF patients after arrhythmia-free periods on device interrogation was associated with worse outcome, implying that the decision on long-term anticoagulation in patients with AF should be based on more comprehensive, individualized assessment of risk and benefit rather than temporal incidence of arrhythmias detected by cardiac devices.

Antithrombotic Drug Therapy

Nonpharmacological Interventions

The LAA has been implicated as the source of emboli in approximately 90% of patients with nonvalvular AF. Therefore several approaches have targeted exclusion of the LAA from the systemic circulation to prevent systemic thromboembolism and obviate the need for long-term oral anticoagulation therapy in patients with nonvalvular AF. These approaches can be of value in many AF patients, given the fact that up to 44% of patients with AF have one or more absolute or relative contraindications for chronic oral anticoagulation therapy, most commonly related to increased risk of bleeding. Furthermore, the safety and efficacy of chronic anticoagulation therapy can be limited by medication compliance, costs, and interactions with food and other medications.

Three main techniques are being utilized to accomplish LAA exclusion: percutaneous endocardial, percutaneous epicardial, and surgical approaches. Device-based endocardial LAA exclusion, such as Watchman (Boston Scientific, Natick, MA, United States) and Amplatzer Cardiac Plug (St. Jude Medical, Minneapolis, MN, United States), result in mechanical occlusion of the LAA. LAA exclusion with the endo-epicardial system (Lariat, SentreHEART, Redwood City, CA, United States) and surgical epicardial ligation result in both mechanical and electrical isolation of the LAA as a result of LAA infarction. Currently, these techniques are in different stages of evaluation and clinical development.

The ESC recommends percutaneous LAA closure device (Watchman and Amplatzer) use in nonvalvular AF patients with high stroke risk and contraindications to long-term oral anticoagulation. The 2014 AHA/ACC/HRS currently only recommends surgical excision of the LAA in patients undergoing cardiac surgery.

Potential candidates for percutaneous LAA closure include AF patients at high stroke risk with high risk of bleeding under oral anticoagulation, those with ischemic stroke despite well-controlled oral anticoagulation therapy, high probability of therapeutic noncompliance to oral anticoagulation, and intolerance to oral anticoagulation therapy due to severe hepatic or renal dysfunction or drug interactions ( Box 15.1 ). The procedure is contraindicated in patients at low stroke risk, those with valvular AF (e.g., mitral stenosis, mechanical cardiac valves), in the presence of other indications for long-term or lifelong oral anticoagulation therapy (e.g., venous thromboembolism, intracardiac clots), LAA thrombus, and contraindications for transseptal catheterization ( Box 15.2 ).

It is important to note that, although LAA exclusion procedures have been increasingly used for patients with nonvalvular AF, these procedures should not be considered universally as a substitute for oral anticoagulation therapy. Many of the disadvantages of warfarin therapy can be addressed by using NOACs rather than LAA exclusion, especially given the paucity of data supporting such procedures as compared to the large, prospective, randomized studies indicating the efficacy and safety of NOACs.

Recommendations for Long-Term Stroke Prevention

The cornerstone of management of patients with AF is adequate thromboprophylaxis. Essential to this is appropriate risk stratification and the need to balance the benefit of stroke prevention and the risk of bleeding with anticoagulant therapies (see above). Decision making for thromboprophylaxis by antithrombotic therapy must balance the risk of stroke against the risk of major bleeding, especially intracranial hemorrhage, which is associated with a high risk of death and disability.

Patients with valvular AF (those with mitral stenosis or valvular prosthesis) should be managed with oral anticoagulation. For nonvalvular AF, the CHA2DS2-VASc scoring system (see Tables 15.6 and 15.7 ) is currently the best validated and most clinically useful for risk stratification and is advocated by both European and United States guidelines. The initial decision step is to identify patients who are truly at low risk for ischemic stroke, in whom no antithrombotic therapy is recommended. These include patients without clinical stroke risk factors (i.e., CHA2DS2-VASc score of 0 in men or 1 in women); female gender does not appear to increase stroke risk in the absence of other stroke risk factors. On the other hand, oral anticoagulation therapy is recommended for patients of both sexes with CHA2DS2-VASc stroke risk score greater than or equal to 2. Those recommendations apply to all patients with AF irrespective of the type of AF (paroxysmal or nonparoxysmal).

There is uncertainty regarding the optimal antithrombotic therapy in low thromboembolic risk patients (i.e., CHA2DS2-VASc score of 1 in men or 2 in women). According to the 2014 AHA/ACC/HRS guidelines, no antithrombotic therapy or treatment with an oral anticoagulant or aspirin can be considered in these patients. On the other hand, recent studies, as well as ESC guidelines, support a positive advantage for stroke prevention with oral anticoagulation compared with no therapy or with aspirin in these patients. Furthermore, the use of NOACs may lower the threshold for initiating anticoagulation for AF patients, given the positive net clinical benefit of NOACs, even in patients with a CHA2DS2-VASc score of 1.

Importantly, treatment decisions should be individualized. Careful assessment of the risk of bleeding and patient preference is crucial. The expected clinical benefit of anticoagulation therapy should be balanced against the bleeding risk and should be thoroughly discussed with the informed patient. For equivocal cases, considering other possible risk predictors and risk models beyond the CHA2DS2-VASc scheme (e.g., renal function, biomarkers, findings on TEE) can potentially provide additional prognostic information and help identify those patients at a truly low thromboembolic risk.

The choice of anticoagulation therapy (warfarin vs. NOACs) is usually influenced by patient’s preference, comorbidities, renal function, cost, and drug interactions. The use of SAMe-TT2R2 score ( Table 15.13 ) can potentially identify those patients in whom warfarin therapy is more likely to be associated with labile INRs and, consequently, serious bleeding and thromboembolism (SAMe-TT2R2 score greater than 2). In those patients, NOACs are expected to offer a particular advantage.

In high-risk patients who cannot be treated with oral anticoagulation because of poor tolerance or noncompliance issues or because of strong patient preference, dual antiplatelet therapy (aspirin plus clopidogrel) can be considered. However, dual antiplatelet therapy is not an alternative to oral anticoagulation in patients at high bleeding risk because the risk of major bleeding associated with dual antiplatelet therapy is generally similar to that with oral anticoagulation. In the latter group, aspirin monotherapy is associated with lesser bleeding risk, although at the expense of less protection from systemic thromboembolism. Percutaneous LAA exclusion procedures have become an important therapeutic alternative to long-term antithrombotic therapy in these patients.

Anticoagulation in the Pericardioversion Period

Patients without a contraindication to oral anticoagulation who have been in AF for more than 48 hours should receive 3 to 4 weeks of oral anticoagulation with warfarin or NOACs (with documented therapeutic INRs for those on warfarin) prior to and after cardioversion. This approach is also recommended for patients with AF who have valvular disease, evidence of LV dysfunction, recent thromboembolism, or AF of unknown duration.

The rationale for anticoagulation prior to cardioversion is based on observational studies showing that more than 85% of LA thrombi resolve after 4 weeks of anticoagulation therapy. Cardioversion-related clinical thromboembolic events have been reported in 5% to 7% of patients who did not receive anticoagulation before cardioversion (this risk appears to be much lower [less than 1%] for AF of less than 48-hour duration).

An alternative approach that eliminates the need for prolonged anticoagulation prior to cardioversion, particularly in low-risk patients who would benefit from earlier cardioversion, is the use of TEE-guided cardioversion. Cardioversion is performed if TEE excludes the presence of intracardiac clots. Anticoagulation after cardioversion, however, is still necessary.

After cardioversion, it is recommended to continue oral anticoagulation therapy for at least 4 weeks. This recommendation deals only with protection from embolic events related to the cardioversion period. Subsequently, the long-term recommendations for patients who have been cardioverted to NSR but are at high risk for thromboembolism are similar to those for patients with chronic AF, even though the patients are in NSR.

A different approach with respect to anticoagulation can be used in low-risk patients (with no mitral valve disease, severe LV dysfunction, or history of recent thromboembolism) in whom there is reasonable certainty that AF has been present for less than 48 hours. Such patients have a low risk of clinical thromboembolism (0.8% in one study) if converted early, even without surveillance TEE. The ACC/AHA guidelines do not recommend long-term anticoagulation prior to cardioversion in such patients, but they do recommend heparin use at presentation and during the pericardioversion period. The optimal therapy after cardioversion in this group is uncertain. A common practice is to administer aspirin for a first episode of AF that converts spontaneously and anticoagulation for at least 4 weeks in all other patients. Aspirin should not be considered for patients with AF of less than 48 hours’ duration if there is associated rheumatic mitral valve disease, severe LV dysfunction, or recent thromboembolism. Such patients should be treated the same as patients with AF of longer duration: 3 to 4 weeks of oral anticoagulation or shorter term anticoagulation with screening TEE prior to elective electrical or pharmacological cardioversion, followed by prolonged anticoagulation therapy after cardioversion.

Pharmacologic Therapy

Ventricular rate control during AF is important to prevent hemodynamic instability, improve symptoms and functional capacity, improve quality of life, and, over the long-term, prevent tachycardia-mediated cardiomyopathy. Oral or intravenous (IV) atrioventricular node (AVN) blockers are used for rate control, depending on the severity of symptoms and the degree of hemodynamic compromise caused by the tachycardia. In addition, correction of secondary causes of fast ventricular rates during AF (e.g., infection, hyperthyroidism, anemia, pain, and pulmonary embolism) is essential to achieve adequate rate control.

Beta-blockers or nondihydropyridine calcium channel blockers (verapamil and diltiazem) are the drugs of choice for rate control, and appear to have equivalent efficacy. Care should be used in administering those medications in patients with acutely decompensated heart failure. Beta-blockers are preferred in patients with cardiomyopathy, ischemic heart disease, and following surgical procedures. Verapamil and diltiazem are preferred in patients with reactive airway disease.

Digoxin is less effective and requires a longer time to achieve rate control, but may be considered if beta-blockers and calcium channel blockers have failed or have intolerable side effects. While digoxin reduces the resting heart rate, it is seldom effective in ambulatory patients because its effects are mediated by enhancement of vagal tone, which is offset during exertion. Thus digoxin has traditionally been used as a second-line agent, usually in sedentary patients or those with heart failure or hypotension. Recently, however, several systematic reviews and meta-analyses found that digoxin use was independently associated with a greater risk for mortality in patients with AF, regardless of concomitant heart failure. Some studies have suggested that AF nullifies the effect of digoxin in reducing hospitalizations for heart failure patients. Hence, the long-term use of digoxin is discouraged.

Amiodarone can be considered for rate control when other AVN blockers are unsuccessful or not tolerated. IV amiodarone is useful for acute control of the ventricular rate, and can be of particular value in acutely ill patients or those with acutely decompensated heart failure or severe hemodynamic compromise. Because of the probability of termination of AF by amiodarone, though very small, pericardioversion anticoagulation strategies should be considered, depending on the individual patient’s risk/benefit profile. Oral amiodarone can be useful for ventricular rate control when other measures are unsuccessful or contraindicated; however, long-term potential toxicity should be carefully considered.

In patients with AF and ventricular preexcitation causing rapid ventricular response, prompt direct-current cardioversion is recommended, especially when hemodynamic compromise is present. IV procainamide or ibutilide to restore NSR or slow the ventricular rate can be considered in hemodynamically stable patients. Importantly, drugs that preferentially slow AVN conduction without prolonging BT refractoriness (such as verapamil, diltiazem, adenosine, oral or IV digoxin, and IV amiodarone) can accelerate the ventricular rate and potentially precipitate hemodynamic collapse and VF in high-risk patients. Unlike the IV route of administration, chronic oral amiodarone therapy can slow or block BT conduction. Limited data exist regarding the use of beta-blockers; nonetheless, these drugs theoretically pose a similar potential risk and they should be used with caution.

Adequacy of rate control should be assessed at rest and with exertion. However, parameters for optimal rate control in AF remain controversial. It appears reasonable to target a resting heart rate of 60 to 80 beats/min and 90 to 115 beats/min during moderate exercise. Ambulatory monitoring can help assess adequacy of rate control; goals of therapy include a 24-hour average heart rate lower than 100 beats/min and no heart rate higher than 100% of the maximum age-adjusted predicted exercise heart rate. Also, a maximum heart rate of 110 beats/min during a 6-minute walk test is a commonly used target. Nonetheless, one study found that a more lenient rate control (resting heart rate less than 110 beats/min) is not inferior to strict rate control (heart rate less than 80 beats/min at rest and less than 110 beats/min during moderate exercise). Such an approach can be more convenient in clinical practice and can be considered especially in asymptomatic patients with permanent AF and no significant structural heart disease, but periodic monitoring of LV function is necessary to evaluate for the potential risk of tachycardia-mediated cardiomyopathy. Of note, lenient rate control does not seem to increase the risk of adverse atrial or ventricular remodeling.

In some patients with SND or tachycardia-bradycardia syndrome, pacemaker implantation can be required to protect from severe bradycardia while allowing the use of AVN blockers for adequate control of fast ventricular rates during AF or the use of antiarrhythmic drug therapy for maintenance of NSR ( see Fig. 8.6 ). In one report, nearly 20% of patients with AF required pacemaker placement for symptomatic bradycardia, most within 5 years of their AF diagnosis, which was especially common in those with a history of heart failure. In patients with SND, atrial or dual-chamber pacing significantly decreases the incidence of subsequent AF compared with ventricular pacing.

Atrioventricular Junction Ablation

Ablation of the AV junction combined with permanent pacemaker implantation (the “ablate and pace” approach), provides robust control of ventricular rate as well as regularization of the R-R interval. However, because it is permanent and mandates lifelong pacing, AV junction ablation usually is considered as a last resort approach in AF patients when rhythm control strategies fail and pharmacological rate control therapy is poorly tolerated or unsuccessful. AV junction ablation is especially useful when excessive ventricular rates induce a tachycardia-mediated decline in LV systolic function, despite appropriate medical therapy.

Furthermore, among patients with LV systolic dysfunction and AF, AV junction ablation has emerged as an important adjunctive therapy for cardiac resynchronization recipients. It has been estimated that 20% to 25% of those eligible for cardiac resynchronization have AF, and the cumulative incidence of new-onset AF/ATs ranges between 20% and 40% according to device interrogations. In patients with permanent AF or frequent persistent or paroxysmal arrhythmia episodes despite attempts to maintain NSR, intrinsic ventricular rate during AF (even though within the normal range) can override the biventricular pacing rate and reduce the percentage of effectively biventricular paced QRS complexes, thus precluding optimal ventricular resynchronization. Ablation of the AV junction in this setting has been associated with a reduction in all-cause mortality, a reduction in cardiovascular mortality, and an improvement in LVEF compared with those patients who were managed medically. It is important to note that the percentage of biventricular pacing determined by device counters often is artificially high because of invalid counting of fusion (hybrid between paced and intrinsic QRS morphologies) and pseudo–fusion complexes (pacing artifacts delivered but intrinsic QRS morphology not altered). In these patients, exercise ECG testing can help detect loss of effective ventricular synchronization and determine the percentage of pure biventricular pacing. AV junction ablation can also be required in ICD patients experiencing inappropriate therapies triggered by fast ventricular rates during AF.

Reversion to Normal Sinus Rhythm

When rhythm control strategy is chosen, both electrical and pharmacological cardioversion methods are appropriate options. The timing of attempted cardioversion is influenced by the duration of AF, severity of patient’s symptoms, adequacy of rate control, and risk of thromboembolism. Prompt cardioversion is recommended for patients with rapid ventricular rates and hemodynamic compromise attributed to AF (hypotension, acute heart failure, myocardial ischemia) or ventricular preexcitation, when rate-control drug therapy is unsuccessful or not tolerated. Cardioversion is also considered to restore NSR in stable but symptomatic patients with persistent AF, especially when ventricular rate control remains suboptimal.

Maintenance of Normal Sinus Rhythm

Only 20% to 30% of patients who are successfully cardioverted maintain NSR for more than 1 year without chronic antiarrhythmic therapy. This is more likely to occur in patients with AF for less than 1 year, no enlargement of the LA (less than 4.0 cm), and a reversible cause of AF (such as hyperthyroidism, pericarditis, pulmonary embolism, or cardiac surgery). It has been thought that the drugs most likely to maintain NSR suppress triggering ectopic beats and arrhythmias and affect atrial EP properties to diminish the likelihood of AF. There is therefore a strong rationale for antiarrhythmic drug therapy in patients who have a moderate to high risk of recurrence, provided that the therapy is effective and that toxic and proarrhythmic effects are low. Prophylactic drug treatment is seldom indicated in patients with a first-detected episode of AF and can also be avoided in patients with infrequent and well-tolerated paroxysmal AF.

Amiodarone has been directly compared to dronedarone, sotalol, and propafenone and found to be substantially more effective, with a 1-year rate of maintaining NSR of 65%. Dofetilide offers 50% to 65% efficacy in maintaining NSR at 1 year. Other antiarrhythmic agents have only modest efficacy (30% to 50% at 1 year). Drug selection is largely driven by the safety profile, the presence and extent of concomitant cardiovascular disease, hepatic and renal dysfunction, and drug-drug interactions. A safer, although possibly less efficacious, drug is usually recommended before resorting to more effective but less safe therapies ( Fig. 15.8 ; Table 15.14 ).

Strategies for Rhythm Control in Patients With Paroxysmal and Persistent Atrial Fibrillation.

Drugs are listed alphabetically. ^a Catheter ablation is only recommended as first-line therapy for patients with paroxysmal AF (class IIa recommendation), depending on patient preference when performed in experienced centers. ^b Not recommended with severe LVH (wall thickness greater than 1.5 cm). ^c Should be used with caution in patients at risk for torsades de pointes ventricular tachycardia. ^d Should be combined with AV nodal blocking agents. AF, Atrial fibrillation; AV, atrioventricular; CAD, coronary artery disease; HF, heart failure; LVH, left ventricular hypertrophy.

(From January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol . 2014;64:e1–e76.)

In patients with AF and minimal or no heart disease, flecainide, propafenone, sotalol, and dronedarone are preferred; amiodarone should be chosen later in the sequence of drug therapy because of its potential toxicity. In patients with adrenergically mediated AF, beta-blockers represent first-line treatment, followed by sotalol. The anticholinergic activity of long-acting disopyramide makes it a relatively attractive choice for patients with vagally mediated AF. In contrast, propafenone is not recommended in vagally mediated AF because its (weak) intrinsic beta-blocking activity may aggravate this type of paroxysmal AF.

In patients with substantial LV hypertrophy (LV wall thickness greater than 1.4 cm), it is recommended to avoid sotalol, flecainide, and propafenone because of concern of increased proarrhythmic risk. Dronedarone, although not specifically tested in this population, is likely to be safe. Amiodarone is usually considered when symptomatic AF recurrences continue to affect the quality of life in these patients.

In patients with coronary artery disease, sotalol, dofetilide, or dronedarone are recommended as first-line therapy, while flecainide and propafenone are contraindicated. Amiodarone is considered the drug of last resort in this population because of its potential toxicity.

Dofetilide and amiodarone are the only agents available for patients with AF with concomitant heart failure; other antiarrhythmic agents can be associated with substantial toxicity and proarrhythmia.

Quinidine is associated with increased mortality, likely the result of ventricular proarrhythmia secondary to QT interval prolongation. Hence, this drug has largely been abandoned for AF therapy.

Given the suboptimal efficacy of antiarrhythmic drug therapy, expectations and treatment goals have to be pragmatic. Reduction of the burden of AF and its impact on quality of life can be a reasonable outcome. Occasional AF recurrences may not require a change in antiarrhythmic drug therapy. When treatment with a single drug fails, combinations of antiarrhythmic drugs can be tried. Useful combinations include sotalol or amiodarone in addition to a class IC agent. However, when drug therapy is deemed unsuccessful and a rhythm control strategy is abandoned, antiarrhythmic drug should not be continued.

Rhythm Control Versus Rate Control

In the past, many physicians preferred rhythm control to rate control. Reversion of AF and maintenance of NSR restores normal hemodynamics and had been thought to reduce the frequency of embolism. However, two major randomized clinical trials—AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) and RACE (RAte Control versus Electrical Cardioversion for Persistent Atrial Fibrillation)—compared rhythm and rate control in a select population at moderate stroke risk and found that embolic events occurred with equal frequency, regardless of whether a rate control or rhythm control strategy was pursued, and this occurred most often after warfarin had been stopped or when the INR was subtherapeutic. Both studies also showed an almost significant trend toward a lower incidence of the primary endpoint with rate control strategy. There was no difference in the functional status or quality of life. Hence, those trials provided evidence that both rhythm control and rate control are reasonable approaches (both strategies requiring long-term anticoagulation for stroke prevention), and suggested that rate control is an acceptable approach in most patients. The AF-Congestive Heart Failure (AF-CHF) study demonstrated similar results among patients with AF with concomitant heart failure. The results of those randomized controlled comparisons of rhythm and rate control therapies were confirmed by more recent observation studies, registries, and meta-analyses.

However, it would be incorrect to extrapolate that NSR offers no benefit over AF and that effective treatments to maintain NSR need not be pursued. First, these trials were not comparisons of NSR and AF; they compared a rate control strategy to a rhythm control strategy that attempted to maintain NSR but fell short, and crossover between treatment arms occurred at a high rate. The failure of AFFIRM and RACE trials in showing any difference between rate and rhythm control is not so much a positive statement for rate control but rather a testimony to the ineffectiveness of antiarrhythmic drug therapy in maintaining NSR over the long term. When the data from these trials were analyzed according to the patient’s actual rhythm (as opposed to his or her treatment strategy), the benefit of NSR over AF became apparent: the presence of NSR was found to be one of the most powerful independent predictors of survival, along with the use of warfarin, even after adjustment for all other relevant clinical variables. Patients in NSR are almost half as likely to die compared with those with AF. This benefit, however, is offset by the use of antiarrhythmic drug therapy, which increases the risk of death.

Therefore achieving and maintaining NSR remain viable and important treatment goals. However, because currently available antiarrhythmic agents commonly fail to suppress AF completely and have safety profiles that are less than ideal, it is reasonable to reserve it to the populations of patients likely to derive the greatest benefit from rhythm control. The selection of rhythm control or rate control strategies should be individualized and take into consideration the nature, intensity, and frequency of symptoms, patient preferences, comorbid conditions, and the risk of recurrent AF. According to analyses of available data, rhythm control can be an appropriate approach in young AF patients and those with newly diagnosed AF, significant symptoms, poorly controlled ventricular response, or tachycardia-mediated cardiomyopathy. On the other hand, asymptomatic or mildly symptomatic patients, especially those older than 65 years, and women with persistent AF who have hypertension or other underlying heart diseases can be better suited for rate control therapy.

It is important to note that current guidelines do not routinely recommend a rhythm control strategy for reducing the risk of mortality, stroke, or heart failure; rather, the primary indication for rhythm control therapy is for the reduction of symptoms and improvement in quality of life.

Catheter Ablation of Atrial Fibrillation

Catheter ablation of AF provides higher efficacy with comparable safety as antiarrhythmic drug therapy. AF ablation has been shown to significantly improve symptoms, exercise capacity, quality of life, and LV function, even in the presence of concurrent heart disease and when ventricular rate control has been adequate before ablation. Catheter ablation was also found to be associated with better quality of life, higher rates of freedom from both AF and antiarrhythmic medications, and lower rates of AF progression when compared with AVN ablation and biventricular pacing in symptomatic patients with AF and cardiomyopathy (LVEF less than or equal to 40%). Further, a recent study found that catheter ablation of AF superior to medical rate control strategy in patients with idiopathic cardiomyopathy, with significant improvement in the LVEF; restoration of NSR with catheter ablation resulted in significant improvements in LV systolic function, particularly in the absence of ventricular fibrosis on CMR. However, evidence is insufficient to determine whether AF ablation reduces all-cause mortality or stroke. Therefore the primary justification for an AF ablation procedure at this time is the presence of symptomatic AF.

At the current time, patient selection criteria for AF ablation should include weighing risks and potential benefits associated with the procedure, as well as consideration of other factors such as severity of symptoms, quality of life, presence and severity of structural heart disease and other comorbidities, and availability of other reasonable treatment options. In addition, the projected ablation success rate with the operator’s own experience and the tools available to him or her should be taken into consideration.

The ideal candidate for catheter ablation of AF has symptomatic episodes of paroxysmal or persistent AF, has not responded to one or more class I or III antiarrhythmic drugs, does not have severe comorbid conditions or severe structural heart disease, has an LA diameter smaller than 50 to 55 mm and, for those with longstanding AF, has had AF for less than 5 years. Catheter ablation of AF is likely to be of little or no benefit in patients with end-stage cardiomyopathy or massive enlargement of the LA (more than 60 mm), or in patients who have severe mitral regurgitation or stenosis and are deemed inappropriate candidates for valvular intervention. With improvements in the efficacy and safety of the procedure, the inclusion criteria for catheter ablation of AF continue to evolve; expanded indications at many centers now include patients with longstanding persistent AF and those with cardiomyopathy.

Current guidelines recommend catheter ablation in patients with symptomatic paroxysmal or nonparoxysmal AF as a second-line treatment after failure of or intolerance to class I or III antiarrhythmic drug therapy ( Fig. 15.9 ). It is reasonable to use similar indications for AF ablation in selected patients not well represented in clinical trials, including those with heart failure, cardiomyopathy, younger patients (less than 45 years) and older patients (greater than 75 years). However, the risks and benefits of catheter ablation must be carefully assessed in these patients. A lower success rate or a higher complication rate can be expected in AF patients with concomitant heart disease, obesity, sleep apnea, severe LA dilation, longstanding persistent AF, as well as frail, elderly patients.

The 2017 HRS/EHRA/ECAS/APHRS/SOLAECE Indications for Catheter Ablation of Symptomatic Atrial Fibrillation (AF) .

Shown in this figure are the indications for catheter ablation of symptomatic paroxysmal, persistent, and longstanding persistent AF. The class for each indication based on whether ablation is performed after failure of antiarrhythmic drug therapy or as first-line therapy is shown.

(From Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm . 2017;14:e275–e444.)

It is important to recognize that there are still no randomized controlled data demonstrating that a patient’s stroke risk is reduced by ablation. Therefore AF catheter ablation should not be performed with the sole intent of obviating the need for anticoagulation.

Complications of catheter ablation can have catastrophic outcomes in certain patients, including those with severe obstructive carotid artery disease, cardiomyopathy, aortic stenosis, nonrevascularized left main or three-vessel coronary artery disease, severe pulmonary arterial hypertension, or hypertrophic cardiomyopathy with severe LV outflow obstruction. Another relative contraindication is a history of major lung resection because of the severe impact of potential PV stenosis. Furthermore, because of the risk of thromboembolic events during the procedure and in the early postoperative period, patients who cannot be anticoagulated during and for at least 2 months after the ablation procedure should not be considered for catheter ablation of AF. Also, catheter ablation should not be performed in patients with an LAA thrombus or a recently implanted LAA closure device.

Surgical Ablation of Atrial Fibrillation

The classic Cox-maze procedure involves creating a series of incisions in the left and right atria designed to direct the propagation of the sinus impulse through both atria while interrupting the multiple macroreentrant circuits thought to be responsible for AF. This procedure is the most effective means of curing AF, eliminating the arrhythmia in 75% to 95% up to 15 years after surgery. Improvements and simplifications of the surgical technique culminated in the Cox-maze III procedure, which became the gold standard for the surgical treatment of AF. Nonetheless, because of its complexity, technical difficulty, and risk of mortality and other complications, the maze procedure did not gain widespread acceptance.

To simplify the procedure, the standard cut-and-sew surgical technique has been replaced with linear epicardial ablation using unipolar or bipolar RF ablation, cryoablation, laser, high-frequency ultrasound, or microwave energy. Most surgical epicardial ablation procedures have been performed in conjunction with mitral valve surgery; the combination of mitral valve repair and cure of AF can enable selected patients to avoid life-long anticoagulation.

Current surgical instrumentation now enables minimally invasive approaches to be performed epicardially on the beating heart through mini-thoracotomies with video assistance. Bipolar RF is the predominant energy source used, and bilateral PV isolation is the most common lesion set, with some approaches adding ganglionic plexus ablation, as well as exclusion of the LAA. However, despite elimination of the need for median sternotomy and cardiopulmonary bypass, these procedures are still relatively invasive. To minimize the invasiveness of the procedure further, a totally thoracoscopic approach has been developed. Although multiple series described high success rates for paroxysmal AF (89% at 12 months of follow-up), success has been limited in patients with persistent and longstanding persistent AF (25% to 87%). In one report, the overall complication rate was 10%, with a perioperative mortality rate of 1.8%.

More extensive ablation lines, in addition to PV antral isolation and ganglionic plexus ablation, as well as documentation of complete PV isolation by demonstration of EP entrance or exit block, conduction block across ablation lines, and the detection and confirmation of ablation of the parasympathetic component of the ganglionic plexuses, are being evaluated to improve outcome. Some series reported a single procedure success rate of 86% at 1 year without the use of antiarrhythmic drugs.

Surgical ablation of AF is recommended in patients undergoing concomitant open heart surgery (whether ablation is performed after failure of antiarrhythmic drug therapy or as first-line therapy and regardless of the duration of the arrhythmia). Such an approach is also reasonable in patients undergoing closed cardiac surgery (e.g., coronary bypass or surgery) ( Fig. 15.10 ).

The 2017 HRS/EHRA/ECAS/APHRS/SOLAECE Indications for Surgical Ablation of Atrial Fibrillation (AF) .

Shown in this figure are the indications for surgical ablation of paroxysmal, persistent, and longstanding persistent AF. The class for each indication based on whether ablation is performed after failure of antiarrhythmic drug therapy or as first-line therapy is shown. The indications for surgical AF ablation are divided into whether the AF ablation procedure is performed concomitantly with an open surgical procedure (such as mitral valve replacement), a closed surgical procedure (such as coronary artery bypass graft [CABG] surgery), or as a stand-alone surgical AF ablation procedure performed solely for treatment of AF. AVR, Aortic valve replacement.

(From Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm . 2017;14:e275–e444.)

Currently, stand-alone and hybrid surgical AF ablation can be considered for symptomatic patients with AF who were refractory to one or more attempts at catheter ablation or who are not candidates for catheter ablation (e.g., patients not candidates for long-term anticoagulation and those with an LA thrombus). Although surgical ablation was found in one report to have superior efficacy to catheter ablation, the complication rate after surgical ablation was higher. Hence, the decision to recommend surgical AF ablation before considering catheter ablation for patients with symptomatic AF refractory to drug therapy and no other indication for cardiac surgery remains controversial, and it should be based on institutional experience with both techniques, the relative outcomes and risks of each in the individual patient, as well as patient preference (see Fig. 15.10 ). Given the degree of patient discomfort, longer hospitalizations and recovery times, and the risk of bleeding following surgery, most patients prefer catheter to surgical ablation.

Other Nonpharmacological Approaches for Rhythm Control

Atrial antitachycardia pacing.

Several pacing algorithms have been developed to inhibit the initiation of AF episodes. These include continuous atrial pacing just faster than the intrinsic sinus rate, overdrive atrial pacing after a PAC, algorithms for preventing pauses after PACs, and overdrive atrial pacing after the termination of an episode of AF to suppress an early arrhythmia recurrence. A multitude of studies tested the efficacy of those algorithms and showed no consistent reduction in AF burden or improvement in AF symptoms. Similarly, dual-site atrial pacing and atrial septal pacing site did not show benefits.

Modern pacemakers are equipped with a variety of atrial antitachycardia pacing (ATP) algorithms designed to terminate atrial tachyarrhythmias. ATP is delivered at an atrial CL shorter than the detected arrhythmia with the administration of a number of pulses of fixed duration (burst pacing), or sequences at progressively shorter intervals (ramp pacing) to abort episodes of AFL or AT. Prior generations of ATP algorithms demonstrated a modest efficacy (30% to 60%) in terminating slow regular ATs, less effective with rapid ATs, and ineffective at treating established AF. Further, the clinical impact of these algorithms on the burden of the arrhythmia is small. It is important to note that, besides the need for organized atrial tachyarrhythmias, the efficacy of ATP is crucially reliant on early detection of AT and correct rhythm classification by the device.

More recently, a new-generation atrial ATP (“reactive ATP”) was developed to target atrial tachyarrhythmias at onset (when the atrial CL is relatively long) and after any change in rate or regularity when the episode may be most amenable to termination by pacing. Transitions toward more regular or slower rhythms are not infrequent (reportedly occurring in 64% of atrial tachyarrhythmia episodes), even after hours following the onset of the arrhythmia. Unlike standard ATP algorithms, reactive ATP continues to monitor atrial rhythm and watches for any change in rate or regularity, and then opportunistically applies ATP when the episode is most amenable to termination by pacing ( eFig. 15.5 ). In a recent study, reactive ATP reduced the risk of progression of AF to permanent or persistent AF.

Examples of Atrial Antitachycardia Pacing (ATP) .

Upper panel, Ramp ATP therapy delivered during atrial fibrillation fails at terminating the arrhythmia. Lower panel, In the same patient, ramp ATP therapy delivered when the tachycardia transitions into a more organized and slower arrhythmia successfully terminates the tachycardia and restores atrial-paced rhythm within 2 seconds of ATP delivery. AF, Atrial fibrillation; AP, atrial-paced event; AT, atrial tachycardia; TD, tachycardia detection; TP, tachycardia pacing; TS, tachycardia-sensed; VP, ventricular-paced event; VS, ventricular-sensed event.

Currently, pacemaker implantation is not indicated for the sole purpose of prevention or treatment of AF in patients without other indications for pacemaker implantation. Nonetheless, ATP offers a therapeutic option for rhythm control in patients with permanent dual-chamber pacemakers or defibrillators that have this feature.

Hypertension

Hypertension is an independent risk factor for AF and stroke. Although treatment of hypertension has not been consistently shown to decrease AF risk, it is an important component of reducing cardiovascular complications and thromboembolic risk.

Diabetes

Although diabetes is an independent risk factor for the development of AF and thromboembolic complications, there are limited data on diabetes management and AF risk. Intense glycemic control does not appear to directly impact the incidence or course of AF. Nonetheless, optimization of diabetes management and prevention of cardiovascular complications may indirectly reduce risk of AF.

Sleep Disordered Breathing

An independent association exists between AF and obstructive sleep apnea. Therefore AF patients should be actively screened for undiagnosed obstructive sleep apnea and evaluated when clinically suspected. Treatment of sleep apnea, when diagnosed, is an important component of AF management. CPAP therapy is associated with more than 40% relative risk reduction in AF recurrence in patients with obstructive sleep apnea, regardless of the AF treatment strategy (pharmacological or invasive).

Lifestyle Modifications

Lifestyle interventions aimed at maintaining a healthy body weight and cardiorespiratory fitness, in the context of a comprehensive risk factor modification, are recommend for both prevention and management of AF. Weight reduction in overweight and obese AF patients, especially those with type II diabetes and hypertension, can improve management of concomitant cardiometabolic risk factors, and was shown to improve symptoms and reduce AF burden.

In addition, regular, moderate exercise appears to benefit overweight and obese patients with symptomatic paroxysmal or persistent AF. One study found a significant dose-response relationship between baseline cardiorespiratory fitness with a 20% reduction in the risk of AF recurrence for each metabolic equivalent (MET) increase in baseline cardiorespiratory fitness. The benefits gained from cardiorespiratory fitness are additive to the effect of weight loss. Increased cardiorespiratory fitness is associated with beneficial effects on blood pressure, diabetic control, lipid profile, and inflammation, all of which can potentially contribute to reduced AF burden. However, guidelines on appropriate weight loss and fitness targets are still lacking.

Habitual and binge alcohol drinking increases the risk of new-onset AF as well as the risk of arrhythmia progression in patients with AF. Therefore reducing alcohol consumption can potentially be an effective strategy for primary and secondary AF prevention. In this context, however, a safe level of daily alcohol consumption in AF patients has not been established. In addition, appropriate counseling should be provided for smoking cessation and recreational drug abuse.

Primary Prevention

Multiple strategies for preventing postoperative AF have been studied. Prophylaxis of AF using perioperative beta-blockers, amiodarone, and sotalol has shown promising results. However, no strategy completely eliminates the occurrence of postoperative AF.

Rate Versus Rhythm Control

Beta-blockers are the drugs of choice for rate control in patients with postoperative AF. The indications for cardioversion of AF and recommendations for rhythm- versus rate-control strategies are similar to those discussed for nonsurgical patients. When antiarrhythmic drug therapy is required for rhythm control, amiodarone is the drug of choice. Sotalol can be considered if amiodarone is contraindicated. Class IC agents, such as flecainide and propafenone, generally are avoided in these patients given the presence of structural heart disease.

Prevention of Systemic Embolization

Guidelines for stroke prevention in nonsurgical AF patients apply to those with postoperative AF. Most of these patients have multiple stroke risk factors but also increased risk of bleeding in the postoperative phase. Therefore the decision to initiate anticoagulation therapy should be guided by the individual patient’s bleeding risk and CHA2DS2-VASc score. Data are lacking regarding the threshold burden or duration of postoperative AF at which anticoagulation is favored, but AF lasting for longer than 48 hours should prompt strong consideration of anticoagulation therapy. The optimal duration for which anticoagulation must be continued after cessation of postoperative AF is uncertain.

Follow-Up of Patients With Postoperative Atrial Fibrillation

Follow-up is recommended at 6 to 12 weeks after surgery to evaluate the presence of persistent or paroxysmal AF and reassess management strategy. Ambulatory cardiac monitoring should be considered to screen for asymptomatic paroxysmal arrhythmias. The optimal frequency and intensity of cardiac rhythm monitoring beyond the 3-month period are not known. If AF is documented, long-term anticoagulation should be considered based on the CHA2DS2-VASc score, and the need for rate versus rhythm control should be reassessed. If there is no evidence of symptomatic or asymptomatic AF beyond the immediate postoperative period, discontinuation of antiarrhythmic drug therapy, if initiated after cardiac surgery, is recommended.

Ventricular Preexcitation During Atrial Fibrillation

The presence of a grossly irregular, very rapid ventricular response (more than 250 beats/min) with QRS duration longer than 120 milliseconds during AF rarely results from conduction over the AVN and strongly implies conduction over an AV BT (see Fig. 15.14 ). At very fast heart rates, there is usually a tendency toward regularization of the R-R intervals; therefore distinguishing preexcited AF from VT or preexcited SVT can be difficult. However, careful measurement always discloses definite irregularities. Moreover, very rapid and irregular VTs are usually unstable and quickly degenerate into VF. Thus, when a rapid, irregular wide QRS complex tachycardia is noted in a patient who has a reasonably stable hemodynamic state, preexcited AF is the most likely diagnosis.

The ability to conduct rapidly over an AV BT is determined primarily by the intrinsic conduction and refractoriness properties of the AV BT. However, as with AVN conduction, factors such as spatial and temporal characteristics of atrial wavefronts during AF, autonomic tone, and concealed conduction influence activation over the AV BT. Very rapid AV conduction during AF can occur in the presence of AV BTs with very short refractoriness, especially when normal conduction through the AVN and HPS is blocked (as occurs with AVN blocking drugs) and ventricular activation occurs only via the rapidly conducting BT, which would then eliminate retrograde concealment into the BT. This would result in extremely rapid ventricular rates, possibly more than 300 beats/min, which can occasionally degenerate into VF.

Regular Ventricular Rate During Atrial Fibrillation

Regular ventricular rate during AF indicates associated abnormalities. A regular, slow ventricular rhythm during AF suggests a junctional or ventricular rhythm, either as an escape mechanism with complete AV block or as an accelerated pacemaker activity with AV dissociation ( see Fig. 9.27 ). Rarely, the R-R interval can be regularly irregular and show group beating with the combination of complete heart block and a lower nodal pacemaker with a Wenckebach type of exit block. Patients with severe underlying heart disease may develop the combination of AF and VT, leading to a rapid, regular, wide QRS complex tachycardia.

Effect of Digitalis Toxicity on the Ventricular Response

With increasing degrees of digitalis toxicity, high-grade but not complete AV block during AF initially leads to single junctional or ventricular escape beats. Higher degrees of AV block result in such a small number of atrial impulses being conducted that the lower pacemaker takes over, thus leading to an escape junctional or ventricular rhythm with a regular R-R interval for two or more cycles. On occasion, the junctional rate can increase, possibly because of digitalis-induced triggered activity, and it is called nonparoxysmal junctional tachycardia. Increasing digitalis toxicity can result in a Wenckebach exit block and give the appearance of an irregular ventricular rhythm with restoration of AF conduction, but the rhythm shows repetitive group beating because of the exit block. Complete AV block is marked by a regular escape rhythm with no conducted beats, a finding that may lead to the erroneous assumption that the patient has converted to NSR. Infrequently, impulses from the lower pacemaker travel alternately down the right and left bundle branches or alternate fascicles of the left bundle branch, resulting in a bidirectional tachycardia. This arrhythmia, which is also frequently a reflection of marked digitalis toxicity, may appear to be ventricular bigeminy. In true bigeminy, however, the ventricular beat in the bigeminal pattern is premature. In comparison, the R-R interval is regular with a bidirectional tachycardia because all the beats arise from a single pacemaker.