Classification of Atrial Fibrillation

Atrial fibrillation (AF) has been described in various ways, such as paroxysmal or persistent, lone, idiopathic, nonvalvular, valvular, or self-terminating. Each of these classifications has implications regarding mechanisms, as well as response to therapy. At the initial detection of AF, it may be difficult to be certain of the subsequent pattern of duration and frequency of recurrences. Thus, a designation of first-detected episode of AF is made on the initial diagnosis, irrespective of the duration of the arrhythmia. When the patient has experienced two or more episodes, AF is classified as recurrent. After the termination of an episode of AF, the rhythm can be classified as paroxysmal or persistent. Paroxysmal AF is characterized by self-terminating episodes that generally last less than 7 days. Persistent AF generally lasts longer than 7 days and often requires electrical or pharmacological cardioversion. Permanent AF refers to AF in which cardioversion has failed or AF that has been sustained for more than 1 year, or when further attempts to terminate the arrhythmia are deemed futile. With the advent of catheter ablation interventions for AF, patients with persistent AF for longer than 1 year who are considered for ablation have been referred to as having longstanding persistent AF, to distinguish them from patients with permanent AF in whom attempts to restore normal sinus rhythm (NSR) were unsuccessful or have been abandoned.^1,2

Although useful, this arbitrary classification does not account for all presentations of AF. Paroxysmal AF often progresses to longer, non–self-terminating episodes. Additionally, the pattern of AF can change in response to treatment. AF that has been persistent can become paroxysmal with antiarrhythmic drug therapy, and AF that had been permanent may be cured or made paroxysmal by surgical or catheter-based ablation. Furthermore, the distinction between persistent and permanent AF is not only a function of the underlying arrhythmia but also a reflection of the clinical pragmatism of the patient and physician. The severity of symptoms associated with AF, anticoagulation status, and patient preference all affect the decision of whether and when cardioversion will be attempted. This decision would then affect the duration of sustained AF and could lead to a diagnosis of persistent or permanent AF.³

Mechanism of Atrial Fibrillation

The pathogenesis of AF remains incompletely understood and is believed to be multifactorial. Two concepts of the underlying mechanism of AF have received considerable attention: factors that trigger and factors that perpetuate the arrhythmia. In general, patients with frequent, self-terminating episodes of AF are likely to have a predominance of factors that trigger AF, whereas patients with AF that does not terminate spontaneously are more likely to have a predominance of perpetuating factors. Although such a gross generalization has clinical usefulness, there is often considerable overlap of these mechanisms. The typical patient with paroxysmal AF has identifiable ectopic foci initiating the arrhythmia, but these triggers cannot be recorded in all patients. Conversely, occasional patients with persistent or permanent AF may be cured of their arrhythmia by ablation of a single triggering focus, a finding suggesting that perpetual firing of the focus may be the mechanism sustaining this arrhythmia in some cases.

Advanced mapping technologies, along with studies in animal models, have suggested the potential for complex pathophysiological substrates and modifiers responsible for AF, including the following: (1) continuous aging or degeneration of atrial tissue and the cardiac conduction system; (2) progression of structural heart disease (e.g., valvular heart disease and cardiomyopathy); (3) myocardial ischemia, local hypoxia, electrolyte derangement, and metabolic disorders (e.g., atherosclerotic heart disease, chronic lung disease, hypokalemia, and hyperthyroidism); (4) inflammation related to pericarditis or myocarditis, with or without cardiac surgery; (5) genetic predisposition; (6) drugs; and (7) autonomic effects.²

Substrate for Atrial Fibrillation

AF results from the interplay between a trigger for initiation and a vulnerable EP substrate for maintenance. The fact that most potential triggers do not initiate AF suggests some role for functional and structural substrates in most patients. However, the relative contribution of triggers versus substrate can vary with the clinical context, and the exact nature of the interaction between triggers and substrate remains to be elucidated.⁸

AF commonly occurs in the context of other cardiac or noncardiac pathological conditions, such as valvular disease, hypertension, ischemic heart disease, heart failure, or hyperthyroidism. Depending on the type, extent, and duration of such external stressors, a cascade of time-dependent adaptive, as well as maladaptive, atrial responses develops in order to maintain homeostasis (so-called atrial remodeling), including changes at the ionic channel level, cellular level, or extracellular matrix level, or a combination of these, thus resulting in structural, functional, and electrical consequences. A hallmark of atrial structural remodeling is atrial dilation, often accompanied by a progressive increase in interstitial fibrosis. Atrial arrhythmias, especially AF, are the most common manifestations of electrical remodeling.¹⁰

Increased dispersion in atrial refractoriness and inhomogeneous dispersion of conduction abnormalities, including block, slow conduction, and dissociation of neighboring atrial muscle bundles, are key elements in the development of the substrate of AF. Importantly, different pathological conditions can be associated with a different set of remodeling responses in the atria.¹¹

Even in the setting of lone AF, whereby no structural heart disease is apparent, there is accumulating evidence that occult abnormalities (e.g., patchy fibrosis, inflammatory infiltrates, loss of myocardial voltage, conduction slowing, altered sinus node function, and vascular dysfunction) can be observed and likely represent an early stage of atrial remodeling contributing to the substrate of AF.¹²

Atrial Remodeling in Atrial Fibrillation

It is well known from clinical practice that AF is a progressive arrhythmia. Eventually, in 14% to 24% of patients with paroxysmal AF, persistent AF will develop, even in the absence of progressive underlying heart disease. Furthermore, conversion of AF to NSR, electrically or pharmacologically, becomes more difficult when the arrhythmia has been present for a longer period. In fact, the arrhythmia itself results in a cascade of electrical and structural changes in the atria that are themselves conducive to the perpetuation of the arrhythmia (“AF begets AF”), a process known as remodeling.²⁰ Recurrent AF can potentially lead to irreversible atrial remodeling and eventually permanent structural changes that account for the progression of paroxysmal to persistent and finally to permanent AF, characterized by the failure of electrical cardioversion or pharmacological therapy, or both, to restore and maintain NSR. Even after cessation of AF, these abnormalities persist for periods that vary in proportion to the duration of the arrhythmia.^17,21

Changes in atrial EP features that are induced by AF can occur through alterations in ion channel activities that cause partial depolarization and abbreviation of atrial refractoriness. These changes promote the initiation and perpetuation of AF (electrical remodeling) and the modification of cellular Ca²⁺ handling, which causes contractile dysfunction (contractile remodeling), as well as atrial dilation with associated structural changes (structural remodeling). Electrical remodeling can potentially begin within a few hours after the onset of AF, whereas the structural changes are slower, likely starting after several weeks.¹⁷

Electrical remodeling results from the high rate of electrical activation. The EP changes typical of atrial myocytes during AF are shortening of the atrial refractory period and action potential duration, reduction in the amplitude of the action potential plateau, and loss of response of action potential duration to changes in rate (abnormal restitution). Whereas the normal atrial action potential duration shortens in response to pacing at shorter CLs, AF results in loss of this rate dependence of atrial action potential duration, and the atrial refractory period fails to lengthen appropriately at slow rates (e.g., with return to NSR). These changes can explain the increased duration 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.^2,20 Tachycardia-induced changes in refractoriness are spatially heterogeneous, and there is increased variability both within and among various atrial regions that may promote atrial vulnerability and AF maintenance and provide a substrate for reentry.

The mechanism for electrical remodeling and shortening of the atrial refractory period is not entirely clear. Several potential explanations exist, including ion channel remodeling, angiotensin II, and atrial ischemia. Shortening of the atrial action potential can be caused by a net decrease of inward ionic currents (Na⁺ or Ca²⁺), a net increase of outward currents (K⁺), or a combination of both. The decrease of I_CaL seems to be responsible for shortening of the atrial action potential, whereas the decrease of I_to is considered to result in loss of physiological rate adaptation of the action potential. The reduction in I_CaL can be explained by a decreased expression of the L-type Ca²⁺ channel α_1C subunit, likely as a compensatory mechanism to minimize the potential for cytosolic Ca²⁺ overload secondary to increased Ca²⁺ influx during the rapidly repetitive action potentials during AF. Verapamil, an L-type Ca²⁺ channel blocker, was shown to prevent electrical remodeling and hasten complete recovery without affecting inducibility of AF, whereas intracellular Ca²⁺ overload, induced by hypercalcemia or digoxin, enhances electrical remodeling. Electrical remodeling can be attenuated by the sarcoplasmic reticulum’s release of the Ca²⁺ antagonist ryanodine, a finding suggesting the importance of increased intracellular Ca²⁺ to the maladaptation of the atrial myocardium during AF. Angiotensin II may also be involved in electrical and atrial myocardial remodeling, and angiotensin II inhibitors may prevent atrial electrical remodeling. Angiotensin-converting enzyme inhibitors reduce the incidence of AF in patients with left ventricular (LV) dysfunction after myocardial infarction 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.^10,11

Furthermore, persistent AF can result in other changes within the atria, including gap junctional remodeling, cellular remodeling, and sinus node remodeling. Gap junctional remodeling is 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.²⁰ Cellular remodeling is caused by the apoptotic death of myocytes with myolysis, which may not be entirely reversible. 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.²⁰

Sustained AF has also been associated with structural changes, such as myocyte hypertrophy, myocyte death, impaired atrial contractility, and atrial stretch and dilation, which act to reduce conduction velocity.²⁰ Atrial dilation increases electrical instability by shortening the effective refractory period and slowing atrial conduction.¹⁰ These structural changes, many of which probably are irreversible, appear to occur more slowly, over periods of weeks to months.

Contractile remodeling is likely caused by downregulation of I_CaL (resulting in reduced release of Ca²⁺ 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 sinus node dysfunction and bradyarrhythmias caused by reduced sinus node automaticity or prolonged sinoatrial conduction. The phenomenon of sinus node remodeling may contribute to the episodes of bradycardia seen in the tachycardia-bradycardia syndrome and may reduce sinus rhythm stability and increase the stability of AF.²⁰ 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 features 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 result in 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. Therefore, rather than AF begets AF, one can vary that theme: “PV-induced paroxysmal AF begets PV-induced chronic AF.”²²

Atrial tachycardia (AT)–induced 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.²

If NSR is restored within a reasonable period of time, 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.

Role of Autonomic Nervous System in Atrial Fibrillation

Cardiac function is modulated by both the extrinsic and the intrinsic cardiac autonomic nervous systems. The extrinsic (central) system is composed of the vagosympathetic system from the brain and spinal cord to the heart. The intrinsic system is composed of a large network of autonomic cardiac ganglia buried throughout the epicardial fat within the pericardial space. Groups of several cardiac ganglia comprise plexuses that coalesce in specific locations, and different groups of ganglia have different sites of innervation throughout the heart. Atrial ganglia contain afferent neurons from the atrial myocardium and from the central autonomic nervous system, and efferent cholinergic and adrenergic neurons, with heavy innervation of the PV myocardium and the atrial myocardium surrounding the ganglionic plexuses. Additionally, an extensive array of interconnecting neurons creates a communication network among the different ganglionic plexuses, as well as between the ganglionic plexuses and the atrium and PV myocardium. The intrinsic system receives input from the extrinsic system but acts independently to modulate numerous cardiac functions, including automaticity, contractility, and conduction.^23,24

Several studies have suggested that both divisions of the autonomic nervous system are involved in the initiation, maintenance, and termination of AF, with a predominant role of the parasympathetic system. Electrical stimulation of autonomic nerves on the heart itself can facilitate the induction of AF. Increased vagal tone is frequently involved in the onset of AF in patients with structurally normal hearts. Parasympathetic stimulation shortens the atrial refractory period, increases the dispersion of refractoriness, and decreases the wavelength of reentrant circuits that facilitate initiation and perpetuation of AF. Long-term vagal denervation of the atria renders AF less easily inducible in animal experiments, presumably because of increased EP homogeneity. On the other hand, vagal stimulation results in maintenance of AF, and catheter ablation of the parasympathetic autonomic nerves entering the RA from the SVC prevents vagally induced AF in animal models. Sympathetic stimuli also shorten the atrial refractory period and increase the vulnerability to AF.^23,25

Spatial heterogeneity of refractoriness can also be produced by the heterogeneity of autonomic innervation. It has been well established that vagal innervation of the atria is heterogeneous and vagal stimulation can precipitate AF as a result of heterogeneity of atrial refractoriness. Heterogeneity of sympathetic neural inputs also plays a role in AF. In animal models, sympathetic atrial denervation facilitates sustained AF, and AF induced by rapid RA pacing is associated with nerve sprouting and a heterogeneous increase in sympathetic innervation. Enhanced sympathetic activity can promote automaticity, delayed afterdepolarization–related AT, and focal AF. Sympathetic stimulation also shortens atrial refractoriness and may facilitate the induction of AF in patients with structural heart disease, in whom possible heterogeneous sympathetic denervation leads to increased refractoriness heterogeneity.

Experimental evidence suggests that the electrical properties of the PVs are also modulated by changes in autonomic tone.⁶ Anatomical studies revealed that the LA and PVs are innervated by adrenergic and cholinergic nerve fibers. A collection of ganglia is localized on the posterior wall of the LA between the superior PVs. Subsequent studies found that ganglionated plexuses clustered at the PV entrances (within fat pads) could be stimulated without atrial excitation. For patients with PV foci, a primary increase in adrenergic tone followed by a marked vagal predominance was reported just prior to the onset of paroxysmal AF. A similar pattern of autonomic tone was reported in an unselected group of patients with paroxysmal AF and various cardiac conditions.²⁵ Activation of the ganglionic plexuses at the PV-LA junction can potentially result in conversion of PV ectopy to AF. Furthermore, ablation of the ganglionated plexuses located at the atrial entrances or antra of the PVs can potentially abolish or reduce AF inducibility.

Role of the Pulmonary Veins in Atrial Fibrillation

There is little controversy now that the PVs play a major role in triggering and maintaining AF, as established by animal and human models, especially in the setting of paroxysmal AF. First, fibrillatory conduction is likely initiated by rapid discharges from one or several focal sources within the atria; in most patients with AF (94%), the focus is in one of the PVs (Fig. 15-1). Extra-PV sites can also trigger AF, but this occurs in a few cases, likely no more than 6% to 10% of patients. AF is also perpetuated by microreentrant circuits, or rotors, that exhibit high-frequency periodic activity from which spiral wavefronts of activation radiate into surrounding atrial tissue. Conduction becomes slower and less organized with increasing distance from the rotors, likely because of atrial structural remodeling, resulting in fibrillatory conduction. Interestingly, the dominant rotors in AF are localized primarily in the junction between the LA and PVs. One study also demonstrated that the PV-LA region has heterogeneous EP properties capable of sustaining reentry (microreentry or macroreentry). Finally, vagal inputs may be important in triggering and maintaining AF, and many of these inputs are clustered close to the PV-LA junction. Thus, the PVs play a critical role in triggering and maintaining AF.

The role of PVs in the initiation and perpetuation of persistent AF seems less prominent than in the setting of paroxysmal AF, likely secondary to the electrical and structural remodeling associated with persistent AF. Non-PV triggers occur more commonly, and the reentry sites required for AF perpetuation are more often found outside the PV-LA junction in persistent AF than in paroxysmal AF.

Epidemiology

AF is the most common sustained arrhythmia encountered in clinical practice. It accounts for approximately one-third of hospitalizations for cardiac rhythm disturbance. AF affects 1% to 2% of the general population, and it has been estimated that 2.3 million people in the United States and 4.5 million in the European Union have paroxysmal or persistent AF. However, the true prevalence of AF is probably higher given the common occurrence of asymptomatic (silent) AF.²⁶

The prevalence of AF increases with age. AF is uncommon in childhood except after cardiac surgery. It occurs in less than 1% of individuals younger than 60 years, but in approximately 6% of those older than 65 years, and in more than 10% of those older than 80 years. The median age of patients with AF is approximately 75 years, and approximately 75% of patients with AF are 65 years of age or older.

The lifetime risk of the development of AF at age 40 years has been estimated to be approximately 25%. The age-adjusted prevalence is higher in men. Blacks have less than half the age-adjusted risk of developing AF than whites.²⁷ Given the increasing prevalence of AF with age, coupled with our aging population, the number of affected U.S. residents is expected to increase to nearly 16 million by 2050.

AF is a progressive disease. Approximately half of individuals who experience an initial episode of AF will eventually develop recurrent AF, typically within the first 2 years of follow-up. AF progresses from paroxysmal to persistent despite antiarrhythmic therapy in approximately 10% at 1 year, in 25% to 30% at 5 years, and in more than 50% beyond 10 years. Furthermore, progression from paroxysmal and persistent AF to permanent AF occurs in up to 34% of patients at 4 years after initial diagnosis. Maintenance of sinus rhythm is progressively more difficult as the duration of persistent AF increases. Only 40% to 60% of patients with persistent AF of less than 1 year’s duration remain in sinus rhythm 1 year after initiation of antiarrhythmic drug therapy, despite multiple cardioversions, whereas patients with persistent AF of more than 3 year’s duration have only a 15% likelihood of long-term sinus rhythm. Increased age, diabetes, and heart failure are among potential predictors of progression to permanent AF. Lone AF is less likely to progress.²⁸

AF is associated with an increased long-term risk of stroke, heart failure, hospitalization, and all-cause mortality, especially in women, even after controlling for CHADS₂ score and other covariables. The mortality rate of patients with AF is approximately double that of patients in NSR and is linked to the severity of underlying heart disease.^27,29

Clinical Risk Factors Predisposing to Atrial Fibrillation

As noted, AF can be related to a transient reversible cause, such as thyrotoxicosis, acute myocardial infarction, acute pericarditis, recent cardiac surgery, acute pulmonary disease, alcohol intake, or electrocution. In these cases, AF is generally eliminated by treatment of the underlying precipitating condition.

AF is thought to be secondary to underlying structural heart disease in more than 70% of patients and is the final arrhythmic expression of a diverse family of diseases. AF derives from a complex continuum of predisposing factors that appear to involve disease processes that contribute to the triggering of AF (e.g., sympathetic and parasympathetic nervous systems [neurogenic AF], predisposing arrhythmias, ectopic foci in PVs), increase atrial distention (e.g., valvular heart disease, hypertension, and heart failure), decrease the ratio of atrial myocyte to fibrotic tissue, possibly including an increased rate of apoptotic cell death (e.g., hypertension and ischemic heart disease), disrupt transmyocyte communications (e.g., pericarditis and edema), increase inflammatory mediators (e.g., pericarditis and myocarditis), or alter energy and redox states that modulate the function of ion channels and gap junctions.

The most frequent causes of acute AF are myocardial infarction (5% to 10% of patients with infarct) and cardiothoracic surgery (up to 50% of patients). The most common clinical settings for permanent AF are hypertension and ischemic heart disease, with the subset of patients having congestive heart failure most likely to experience the arrhythmia. In the developing world, hypertension and rheumatic valvular (usually mitral) and congenital heart diseases are the most commonly related conditions.³⁰

Heart failure is present in 34% of patients with AF, and AF develops in up to 42% of patients with heart failure. AF and heart failure have a grim prognosis, with a 1-year mortality of 9.5% and worsening of heart failure in almost 25%.³¹ In patients with heart failure who are undergoing defibrillator implantation, a history of AF at time of procedure identifies additional risk of heart failure and death, and the new detection of AF afterward is associated with even higher rates of death.³²

There is accumulating evidence demonstrating an independent association between sleep apnea and AF, likely related to the effects of sleep apnea and nocturnal hypoxemia on LA electrical remodeling, fibrosis, and chamber enlargement. AF occurs in 5% of persons with severe sleep apnea and only 1% of those without sleep apnea. The prevalence of at least moderate sleep apnea was reported in up to 32% of patients with lone AF. Furthermore, cross-sectional studies demonstrated that patients with AF had a significantly higher risk of obstructive sleep apnea than matched controls (49% versus 33%), and multivariate analysis demonstrated a strong independent association between sleep apnea and AF (odds ratio, 2.2). Additionally, several prospective studies showed that obstructive sleep apnea predicts the occurrence of future AF. Untreated obstructive sleep apnea was associated with a remarkably high rate of AF recurrence at 1 year compared with patients with unknown sleep apnea status (83% versus 53%). The presence of sleep apnea can also predict a higher rate of early recurrence of PV conduction and AF following catheter ablation of AF.³³ Several investigations identified obesity (found in approximately 25% of patients with AF) as a risk factor for the development of AF, and there exists a linear association between the body mass index and AF risk. Obesity is associated with increased LA size and impaired LV diastolic function, which can potentially explain its predisposition to AF.³⁴

The presence of sinus node dysfunction also predicts an increased risk for AF. Atrial high-rate episodes lasting longer than 5 minutes were noted in 29% of the patients receiving pacemakers for sinus node dysfunction but with no prior history of AF.

In younger patients, approximately 30% to 45% of paroxysmal cases and 20% to 25% of persistent cases of AF occur in the absence of any chronic or acute risk factors for the arrhythmia, a condition referred to as lone AF. Adrenergic and vagotonic forms of paroxysmal AF are uncommon. Nonetheless, patients with lone AF often have attacks against the background of parasympathetic predominance, whereas paroxysms in patients with structural heart disease more usually occur in a sympathetic setting.

Clinical Presentation

AF can be symptomatic or asymptomatic, even in the same patient. Asymptomatic, or silent, AF occurs frequently. In patients with paroxysmal AF; up to 90% of episodes can be unrecognized by the patient, including some lasting more than 48 hours. On the other hand, continuous monitoring with a pacemaker with dedicated functions for AF detection and electrogram storage showed that as many as 40% of patients experienced AF-like symptoms in the absence of AF, whereas 38% of patients with a history of AF had episodes of AF lasting more than 48 hours noted at the time of interrogation even though these patients were asymptomatic. In more than 10% to 25% of patients, however, AF is discovered in the absence of symptoms or after a complication attributable to AF.

Symptoms associated with AF vary, depending on the ventricular rate, the underlying functional status, the duration of AF, the presence and degree of structural heart disease, and the individual patient’s perception. The hemodynamic consequences of AF are related to loss of coordinated atrial contraction, irregularity of ventricular response, and fast heart rate, as well as long-term consequences such as atrial and ventricular cardiomyopathy. Loss of effective atrial contraction can potentially reduce cardiac output by 15% to 20%. These consequences are magnified in the presence of impaired diastolic ventricular filling, hypertension, mitral stenosis, LV hypertrophy, and restrictive cardiomyopathy. Irregularity of the cardiac cycle, especially when accompanied by short coupling intervals, and rapid heart rates in AF can lead to reduction in diastolic filling, stroke volume, and cardiac output.²⁷

Most patients with AF complain of palpitations, chest discomfort, dyspnea, generalized fatigue, or dizziness. Although palpitation, or awareness of the irregularity of the heartbeat, is prominent in more than half of patients with AF, its correlation with documented arrhythmia is unimpressive.³⁵ Furthermore, AF with a chronically rapid heart rate (more than 120 to 130 beats/min) can lead to tachycardia-mediated cardiomyopathy and heart failure. Syncope is an uncommon complication of AF that can occur on conversion in patients with sinus node dysfunction or because of rapid ventricular rates in patients with hypertrophic cardiomyopathy, in patients with valvular aortic stenosis, or in patients with ventricular preexcitation over an accessory pathway. The first presentation of asymptomatic AF can be catastrophic—an embolic complication or acute decompensation of heart failure.^27,35

In some patients, paroxysmal AF can be classified as either vagal or adrenergic, depending on the types of triggers and the temporal distribution of the arrhythmic episodes. Vagal AF typically occurs in young male patients without structural heart disease and characteristically develops during sleep or postprandial. In contrast, patients with adrenergic AF are usually older, often with evidence of underlying heart disease, and the episodes of AF usually occur during the day and are associated with physical or emotional stress. In patients with paroxysmal AF, the prevalence of vagal AF probably ranges between 6% and 25%, whereas that of adrenergic AF ranges between 7% and 16%. Approximately 12% of patients with paroxysmal AF exhibit features of mixed vagal and adrenergic patterns.²⁵

Many patients with persistent or permanent AF have one or more comorbid conditions that can considerably contribute to specific complaints and to overall quality of life. Therefore, it is important to establish a correlation between any symptoms and AF, as well as ventricular response rates. The effect of regulation of ventricular rate during persistent AF or conversion to NSR on a patient’s symptoms and quality of life can help assess the relative contribution of AF to the patient’s complaints. The Canadian Cardiovascular Society Severity in Atrial Fibrillation (CCS-SAF) scale is a simple, five-point semiquantitative scale (Table 15-1) that has been proposed for use at the bedside to assess the functional consequences of symptoms during AF and can provide objective assessment of the patient’s subjective state (analogous to the New York Heart Association [NYHA] congestive heart failure functional class and the CCS angina severity class).³⁵

TABLE 15-1 Canadian Cardiovascular Society Severity of Atrial Fibrillation Scale

Step 1: Symptoms

Identify the presence of the following symptoms: • Palpitation • Dyspnea • Dizziness, presyncope, or syncope • Chest pain • Weakness or fatigue

Step 2: Association Is AF, when present, associated with the foregoing symptoms? For example: Ascertain whether any of the foregoing symptoms are present during AF and are likely caused by AF (as opposed to some other cause). Step 3: Functionality Determine whether the symptoms associated with AF (or the treatment of AF) affect the patient’s functionality (subjective QOL). CCS-SAF Class Definitions Class 0 Asymptomatic with respect to AF Class 1 Symptoms attributable to AF have minimal effect on patient’s general QOL

Prevention of Systemic Embolization

As noted, AF significantly increases the risk of stroke, and the stroke risk appears to be equivalent in paroxysmal and persistent AF and equivalent with a rate control or rhythm control management strategy.

Rate Control

Rate control during AF is important to prevent hemodynamic instability or symptoms such as palpitations, heart failure, lightheadedness, and poor exercise capacity and, over the long-term, to prevent tachycardia-mediated cardiomyopathy and improve quality of life. Beta blockers (e.g., atenolol or metoprolol), diltiazem, and verapamil are recommended for rate control during rest and exercise. Digoxin is not effective during exercise but can be used in patients with heart failure or hypotension or as a second-line agent.

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. Additionally, 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.^27,47

Nevertheless, 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 may 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.^47,55 Of note, lenient rate control does not seem to increase the risk of adverse atrial or ventricular remodeling.

In some patients with tachycardia-bradycardia syndrome, pacemaker implantation can be required to protect from severe bradycardia while allowing the use of AV nodal (AVN) blockers for adequate control of fast ventricular rates during AF (see Fig. 8-4).

AVN ablation and permanent pacemaker implantation are highly effective means of improving symptoms in patients with AF who experience symptoms related to a rapid ventricular rate during AF that cannot be adequately controlled with antiarrhythmic or AVN blockers. AV junction ablation is especially useful when excessive ventricular rates induce a tachycardia-mediated decline in LV systolic function, despite appropriate medical therapy. Additionally, in patients with AF and advanced heart failure requiring cardiac resynchronization therapy, AVN ablation can potentially improve long-term survival, NYHA class, and LV systolic function, even in patients with mean ventricular rates lower than 100 beats/min during AF. In these patients, AVN ablation ensures a high percentage of resynchronized QRS complexes and attenuates cardiac output impairment resulting from R-R interval variability.⁵⁶

Rhythm Control

Restoration and maintenance of sinus rhythm in patients with AF can have several potential benefits, including relief of symptoms, improved functional status and quality of life, prevention of systemic thromboembolism, and avoidance of cardiomyopathy. Reduction in atrial remodeling and retardation of progression of AF, and improvement in LV function also have been described. The impact of rhythm control on mortality, however, remains to be determined.²¹

Unfortunately, complete restoration of sinus rhythm (100% freedom from AF recurrence) often is unachievable with current drug therapies and remains an impractical treatment goal. It has been estimated that the average 1-year recurrence rate associated with amiodarone approximates 35%, and the recurrence rate for other currently available antiarrhythmic drug therapies is even higher (approximately 50%). However, it is likely that individuals with AF can derive benefit from even partial restoration of sinus rhythm, including improvements in symptoms and attenuation of electrical and structural atrial remodeling associated with AF and hence retardation of progression of AF.²¹

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 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 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. There was no difference in the functional status or quality of life. Thus, both rhythm control and rate control are acceptable approaches, and both require long-term anticoagulation for stroke prevention. The trials provided supportive evidence for the rate control option in most patients. The AF-Congestive Heart Failure (AF-CHF) study demonstrated similar results among patients with AF with concomitant heart failure.⁶¹

In a worldwide, prospective, observational survey of management of AF in unselected, community-based patients, clinical outcomes were not influenced by the choice of rhythm control versus rate control. Major cardiovascular outcomes were driven mainly by hospitalizations for arrhythmia or proarrhythmia and other cardiovascular causes and were more dependent on comorbidity than the choice of cardiac rhythm management. Nevertheless, patients receiving rhythm control progressed less rapidly to permanent AF.

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. The failure of AFFIRM and RACE 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 the rhythm control methods used. Failure of rhythm control to demonstrate superiority over rate control is caused by failure to achieve maintenance of NSR over the long term. Several trials demonstrated that the success of antiarrhythmic therapy in maintaining NSR is borderline, at best, with increasing failure rates over time. 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.^21,61,62

Achieving and maintaining sinus rhythm 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 appropriate 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, these groups may include young 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 may be better suited for rate control therapy.^21,61,62

Nonpharmacological Approaches for Rhythm Control

Atrial Activity

AF is characterized by rapid and irregular atrial fibrillatory waves (f waves) and a lack of clearly defined P waves, with an undulating baseline that may alternate between recognizable atrial activity and a nearly flat line (Fig. 15-6). Atrial fibrillatory activity is generally best seen in lead V₁ and in the inferior leads. Less often, the f waves are most prominent in leads I and aVL.

The rate of the fibrillatory waves is generally between 350 and 600 beats/min. With up to 600 pulses generated every minute, syncytial contraction of the atria is replaced by irregular atrial twitches. Therefore, the fibrillating atria look like a bag of worms in that the contractions are very rapid and irregular. The f waves vary in amplitude, morphology, and intervals, thus reflecting the multiple potential types of atrial activation that may be present at the same time at different locations throughout the atria. The f waves can be fine (amplitude less than 0.5 mm on ECG) or coarse (amplitude more than 0.5 mm). On occasion, the f waves can be inapparent on the standard and precordial leads, which is most likely to occur in permanent AF. It was initially thought that the amplitude of the f waves correlated with increasing atrial size; however, echocardiographic studies have failed to show a correlation among the amplitude of the f waves, the size of the atria, and the type of heart disease. The amplitude, however, may correlate with the duration of AF.

AF should be distinguished from other rhythms in which the R-R intervals are irregularly irregular. These include multifocal AT (see Fig. 11-1), wandering atrial pacemaker, multifocal PACs, and AT or AFL with varying AV block (see Fig. 12-4). In general, distinct (although often abnormal and possibly variable) P (or flutter) waves are present during these arrhythmias, in contrast to AF. Patients with rheumatic mitral stenosis often demonstrate large-amplitude fibrillatory waves in the anterior precordial leads (V₁ and V₂), which can be confused with AFL. However, careful examination of the fibrillatory waves reveals them to have a varying CL and morphology. The distinction between AF and AFL can also be confusing in patients who demonstrate a transition between these arrhythmias. Thus, AF may organize to AFL or AFL may degenerate to AF (Fig. 15-7). Occasionally, extracardiac artifacts (e.g., 60 cycle/min muscle tremors, as in parkinsonism) can mimic f waves.

Intracardiac recordings demonstrate variability in the atrial electrogram morphology, amplitude, and CL from beat to beat. The different patterns of conduction during AF may be reflected in the morphology of atrial electrograms recorded with mapping during induced AF. Single potentials usually indicate rapid uniform conduction, short intervals between double potentials may indicate collision, long intervals between double potentials are usually indicative of conduction block, and fragmented potentials and complex fractionated atrial electrograms (CFAEs) are markers for pivoting points or slow conduction.

Atrioventricular Conduction during Atrial Fibrillation

The ventricular response in AF is typically irregularly irregular, and the ventricular rate depends on multiple factors, including the EP properties of the AVN, the rate and organization of atrial inputs to the AVN, the level of autonomic tone, the effects of medications that act on the AV conduction ystem, and the presence of preexcitation over an AV BT.

The ventricular rate in untreated patients usually ranges from 90 up to 170 beats/min. Ventricular rates that are clearly outside this range suggest some concurrent problem. Ventricular rates slower than 60 beats/min are seen with AVN disease and can be associated with the sick sinus syndrome, drugs that affect conduction, and high vagal tone, as can occur in a well-conditioned athlete. The ventricular rate in AF can become rapid (more than 200 beats/min) during exercise, with catecholamine excess (Fig. 15-8), parasympathetic withdrawal, thyrotoxicosis, or preexcitation (Fig. 15-9). The ventricular rate can be very rapid (more than 300 beats/min) in patients with the Wolff-Parkinson-White syndrome, with conduction over AV BTs having short anterograde refractory periods.

The compact AVN is located anteriorly in the triangle of Koch. There are two distinct atrial inputs to the AVN, anteriorly via the interatrial septum and posteriorly via the crista terminalis. Experiments in a rabbit AVN preparation demonstrated that propagation of impulses during AF through the AVN to the His bundle (HB) is critically dependent on the relative timing of activation of septal inputs to the AVN at the crista terminalis and interatrial septum. Other investigators showed that the ventricular response also depends on atrial input frequency.

Concealed conduction likely plays the predominant role in determining ventricular response during AF. The constant bombardment of atrial impulses into the AVN creates substantial and varying degrees of concealed conduction, with atrial impulses that enter the AVN but do not conduct to the ventricle, thus leaving a wake of refractoriness encountered by subsequent impulses. This also accounts for the irregular ventricular response during AF. Although the AVN would be expected to conduct whenever it recovers excitability after the last conducted atrial impulse, which would then be at regular intervals, the ventricular response is irregularly irregular because of the varying depth of penetration of the numerous fibrillatory impulses approaching the AVN, leaving it refractory in the face of subsequent atrial impulses.

Alterations of autonomic tone can have profound effects on AVN conduction. Enhanced parasympathetic and sympathetic tone have negative and positive dromotropic effects, respectively, on AVN conduction and refractoriness. An additional factor is the use of AVN blocking agents such as digoxin, Ca²⁺ channel blockers, or beta blockers. There also may be a circadian rhythm for both AVN refractoriness and concealed conduction that accounts for the circadian variation in ventricular rate.

QRS Morphology

The QRS complexes during AF are narrow and normal unless AV conduction is abnormal because of functional (rate-related) aberration, preexisting bundle branch block (BBB; see Fig. 15-6), or preexcitation over an AV BT (see Fig. 15-9).

Aberrant conduction commonly occurs during AF. Aberrancy is caused by the physiological changes of the conduction system refractory periods that are associated with sudden changes in heart rate. The refractoriness of the HPS tissue is directly related to the preceding R-R interval. Thus, there can be aberrant conduction as the result of a long R-R interval followed by a short cycle. In this scenario, the refractory period of the bundles increases during the long R-R interval (long cycle). The QRS complex that ends the long pause will be conducted normally but is followed by a prolonged refractory period of the bundle branches. If the next QRS complex occurs after a short coupling interval, it can be conducted aberrantly because one of the bundle branches is still refractory as a result of a lengthening of the refractory period (the Ashman phenomenon). The gross irregularity of ventricular response during AF yields an abundance of different R-R intervals; therefore, the long-short cycle sequence occurs commonly, and the Ashman phenomenon is seen frequently during AF. Right BBB (RBBB) aberrancy is more common than left BBB (LBBB) aberrancy, because the right bundle branch has a longer refractory period at slower heart rates. The left anterior fascicle is also frequently involved, often in combination with RBBB. In contrast, functional aberration is uncommon in the HB, the left posterior fascicle, or the main left bundle. Moreover, CLs preceding the pause may also affect the chance for aberrancy after the pause.

The aberrancy caused by the Ashman phenomenon can be present for one beat and have a morphology that resembles a premature ventricular complex (PVC), or it can involve several sequential complexes, suggesting VT. The persistence of aberrancy may reflect a time-dependent adjustment of refractoriness of the bundle branch to an abrupt change in CL, or it may be the result of concealed transseptal activation.

Although functional BBB is common in AF, PVCs are even more frequent, and it is important to differentiate between aberrant ventricular conduction and VT when repetitive wide QRS complexes occur during AF. The presence or absence of a long-short cycle sequence may not be helpful in differentiating aberration from ectopy for two reasons. Although a long cycle (pause) sets the stage for the Ashman phenomenon, it also tends to precipitate ventricular ectopy. Moreover, concealed conduction occurs frequently during AF, and therefore it is never possible to determine exactly when a bundle branch is activated from the surface ECG.

The proper diagnosis of aberrant conduction is a continuing challenge, but it can usually be accomplished by careful analysis of the rhythm strip and application of certain criteria. An aberrantly conducted beat caused by BBB generally has the pattern of a classic bundle branch or fascicular block. A PVC is usually followed by a longer R-R cycle, indicating the occurrence of a compensatory pause, the result of retrograde conduction into the AVN and anterograde block of the impulse originating in the atrium. The presence of long R-R cycles after the wide QRS complex that have identical CLs also suggests a ventricular origin (see Fig. 10-3). Furthermore, the absence of a long-short cycle sequence associated with the wide or aberrant QRS complex suggests that it is of ventricular origin. Aberrancy is not present if, with inspection of a long ECG rhythm strip, there are R-R interval combinations that are longer and shorter than those associated with the wide QRS complex. Also, a ventricular origin is likely if there is a fixed coupling interval between the normal and wide QRS complexes (Fig. 15-10).