Atrial Fibrillation: Mechanisms, Clinical Features, and Management

Epidemiology and Societal Impact

AF is a health problem of epidemic proportions with a projected prevalence of over 12 million by 2030 in the United States alone. Population studies have shown that AF confers a significant impairment in quality of life, with a fourfold to fivefold increase in the risk for stroke, a doubling of risk for dementia, tripling of the risk for heart failure, and 40% to 90% increased risk for mortality. AF is an age-dependent disease with its prevalence doubling with each decade over the age of 55 years, independent of known preexisting conditions. Its prevalence is 0.1% in those younger than 55 years, increasing to 9.0% for those aged over 80 years. The lifetime risk for developing AF is approximately 25% in those who have reached the age of 40 years. Men are more frequently affected than women. AF is a costly public health problem at a global level with hospitalization as the primary cost driver. Annual health care expenditures resulting from AF ranges from $6 to $26 billion in the United States alone. Unsurprisingly, costs are strongly influenced by the number of arrhythmia recurrences with one to two recurrences of paroxysmal AF, for example, costing US $6331 and at least three recurrences costing $10,312. In response to the rising tide, there has been an exponential increase in the number of AF ablations being performed ( Fig. 75.1 ).

Classification

After the initial presentation, AF can be categorized according to the American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) guidelines on AF management :

• Paroxysmal AF: episodes terminate spontaneously or with intervention within 7 days of onset.

• Persistent AF: episodes fail to self-terminate within 7 days and often require pharmacologic or electrical cardioversion to restore sinus rhythm.

• Long-standing persistent AF: persistent AF that lasts for longer than 12 months.

• Permanent AF: a term used to identify individuals with persistent AF for whom a combined decision has been made by the patient and clinician to no longer pursue a rhythm control strategy.

The aforementioned definitions apply to recurrent episodes of AF that last longer than 30 seconds. Nonvalvular AF is used to refer to AF that occurs in the absence of moderate-severe mitral stenosis or a mechanical heart valve, and this distinction has important implications for management of thromboembolism risk. The term lone AF refers to patients with paroxysmal, persistent, or permanent AF who have no structural heart disease, but the emerging consensus is that this term does not enrich either the understanding of the mechanism or patient management. Finally, it is apparent that these terms are not mutually exclusive and are insufficient to describe the complexity of the clinical spectrum of AF.

Pathophysiology

A detailed discussion on AF mechanisms (see Chapter 43, Chapter 44, Chapter 45 ), role of autonomic (see Chapter 42 ) and genetic factors (see Chapter 47 ) in AF is presented in detail in earlier chapters; a brief overview is provided here because it is of particular relevance to AF management. The wide range of clinical presentation of AF is fundamentally governed by the variable extent of interaction between AF triggers (or drivers) and the necessary substrate created by electrophysiologically and structurally remodeled atrial tissue capable of supporting and maintaining AF. Haissaguerre et al. in 1998 made the seminal observation that spontaneous initiation of AF often occurred by focal ectopy originating within the pulmonary veins. Such pulmonary vein triggers are thought to be primarily responsible for paroxysmal AF episodes and pulmonary vein isolation has since become the cornerstone of contemporary AF ablation strategies.

In contrast to the proposed mechanism of paroxysmal AF, there is much debate and controversy on the mechanism of persistent and permanent AF, specifically related to factors that promote its sustenance. The conventional paradigm is that persistent and permanent forms of AF are associated with atrial electrical and structural remodeling predicated by underlying atrial fibrosis and maintained by spatial disorganization. ^, More recently, however, Narayan et al. have reported that persistent and permanent AF may be maintained by highly localized drivers or organized sources of reentry (see Chapter 43 ). ^, These localized rotors and focal sources are not necessarily constrained to the pulmonary veins, may be biatrially distributed, and can be targeted with focal ablation. In contrast, other investigators have failed to demonstrate the presence of stable reentrant sources during mapping of patients undergoing cardiac surgery. ^, Allesie et al. have shown that endoepicardial electrical dissociation between the complex three-dimensional myocardial bundle architecture of the atria rather than ectopic focal discharges are responsible for the appearance of so-called drivers. Work from Waldo et al. suggests that persistent or long-standing persistent AF are maintained by continuous collision and merging of activation wavefronts that create the appearance of foci and breakthrough sites with no evidence of reentry. The lack of consensus may be in part because there is no single model of AF that accurately represents the marked heterogeneity of patients represented in these studies. Much further work is necessary to elucidate the mechanism of AF, and it is likely that high-fidelity mapping tools are needed to clarify the complex electrical activation patterns during AF.

A well-accepted concept is that atrial remodeling is necessary for AF perpetuation. Electrical and structural remodeling are fundamental components. Electrical remodeling includes reduction in atrial effective refractory periods, increased spatial heterogeneity of refractoriness, and conduction slowing. These changes are governed by shortening of the atrial action potential duration, changes in ion channel expression, alteration in cellular coupling mediated by changes in connexin protein expression, changes in atrial conductivity, and the development of fibrosis. Electrical remodeling, however, may only contribute to short-term changes and can reverse quickly. It is thought that the presence of structural remodeling is fundamental to the stability and progression of AF to persistent and permanent forms. These changes can be self-perpetuating, hence the concept of “AF begets AF” as proposed by Wijfells et al. in their seminal study in awake instrumented goats. Increasing AF duration promotes atrial dilation, myocyte hypertrophy, sarcomere loss, glycogen accumulation, and mitochondrial abnormalities and the development of atrial fibrosis. Atrial fibrosis is thought to be a fundamental component of AF sustenance.

Detailed electrophysiologic and electroanatomic studies have documented that many disease processes known to be associated with AF contribute to atrial structural remodeling, including aging, sinus node dysfunction, conditions of chronic atrial stretch (for example, atrial septal defects, mitral stenosis, heart failure, ventricular pacing), systemic and pulmonary hypertension, obesity, and obstructive sleep apnea. ^, The common paradigm that emerges is that these conditions are associated with atrial remodeling manifesting as global and regional conduction slowing and the development of atrial fibrosis. More recently, there has been recognition of patients who have advanced fibrotic atrial cardiomyopathy even before the advent of AF, and this disease entity may have a pathophysiologic mechanism that is distinct from AF itself promoting development of fibrosis. This so-called fibrotic atrial cardiomyopathy appears to be a specific disease/syndrome that supplies substrates for AF, atrial tachycardia, sinus node disease, atrioventricular (AV) node disease, and thromboembolic complications.

The autonomic nervous system also plays an important role in AF initiation and maintenance (see Chapter 42 ). The pulmonary veins and the pulmonary vein–left atrial junction are richly innervated by autonomic nerves. A dynamic relationship between the parasympathetic and sympathetic nervous system plays a critical role in the initiation of AF from the pulmonary veins. AF onset can be preceded by altered autonomic activity or changes in autonomic balance. Autonomic neural remodeling contributes to positive feedback loops that are thought to be essential for AF persistence and recurrence; remodeling of this sort may be a major reason that AF can maintain itself in the first few hours. Simultaneous sympathovagal discharges may also contribute to the mechanism of AF associated with heart failure.

There is also increasing appreciation that there is a large genetic contribution to AF (see Chapter 47 ). A history of AF in a family member is associated with a 40% increase risk for AF. The majority of monogenic causes of AF are attributed to gain-of-function mutations in potassium channels or their subunits with an expected shortening of atrial refractory periods. Variations in sodium channel subunits, gap junction proteins, and several developmentally related transcription factors also play an important role in the development of familial AF. Genome-wide association studies have identified several genetic loci containing single-nucleotide polymorphisms throughout the genome that are associated with AF. These studies have yielded novel insights into mechanisms of AF in different populations and may ultimately provide novel therapeutic targets.

Investigations

An outline of potential investigations is shown in Table 75.2 . AF is readily detected on electrocardiography (ECG) as fibrillatory waves that may be “coarse” or “fine” ( Fig. 75.2 ). More importantly however, the ECG may give clues to etiology, such as left ventricular hypertrophy (hypertension), and associated conditions that may increase risks for antiarrhythmic drug therapy, such as conduction disease (bundle branch block, slow ventricular response in the absence of atrioventricular nodal blocking agents), sinus node dysfunction, and QT interval prolongation (proarrhythmia risk; see Chapter 102 ).

Table 75.2

Investigation and Focus in the Assessment of a Patient With Atrial Fibrillation

Type of Examination or Investigation	Key Points of Focus
History and physical examination	Identify hypertension, hyperthyroidism, congestive heart failure, valvular disease
Electrocardiogram	Measure resting ventricular response; identify associated cardiac conditions such as left ventricular hypertrophy, prior myocardial infarction, sinus node dysfunction, QT prolongation, presence of an accessory pathway
Exercise testing	Identify coronary artery disease; measure ventricular response to exertion
Ambulatory monitoring	Identify suspected atrial fibrillation (AF) if symptoms are infrequent or sporadic; correlate symptoms to arrhythmia; calculate ambulatory ventricular response and AF burden
Echocardiogram	Identify valvular disease, left atrial size, ventricular function, associated left ventricular hypertrophy
Electrophysiology study	Identify triggers for AF, such as supraventricular tachycardias
Chemistries	Measure thyroid and renal function, ensure electrolytes (especially potassium and magnesium in the normal range)

Ambulatory monitoring can play a critical role in the diagnosis of AF, especially if events are sporadic or associated with thromboembolic events in the absence of documented AF. Monitoring devices can provide continuous, symptom-driven, or autotriggered recordings and can be used for extended periods, often 30 days (see Chapter 62 ). Internally placed miniature autotriggered monitors can allow prolonged monitoring (up to several years) and allow rapid wireless data transmissions. Because atrial fibrillation may be silent, autotriggered or continuous monitoring for several weeks may be necessary to detect arrhythmia paroxysms and assess the burden of AF. In patients with cryptogenic stroke, implantable monitors detected AF in 12% at 1-year follow-up versus 2% of patients with periodic monitoring. Patients with pacemakers and defibrillators should have these regularly interrogated for atrial high-rate episodes, which should be confirmed by atrial ECG to be AF. There has been a proliferation of home ECG recording devices purchased directly by patients that have algorithms to detect AF (see Chapter 63 ). Simultaneous ECG recording and irregular pulse detection had a positive predictive value for an AF episode of 0.84.

When AF is newly diagnosed, further evaluation is warranted (see Table 75.2 ), usually including transthoracic echocardiography recommended to look for valvular and structural heart disease, ventricular hypertrophy, and ventricular dysfunction and to evaluate left atrial size, which may indicate the degree of AF chronicity. Exercise testing (with or without imaging as indicated) should be considered to exclude coronary artery disease (CAD) in association with AF. Although CAD rarely is a direct cause of AF, its presence limits suitability for class I antiarrhythmic drugs (discussed later). Exercise testing may also be useful to evaluate proarrhythmic potential of antiarrhythmic medications, assess heart rate control with exertion, and unmask a potential trigger for AF.

The role of formal electrophysiology (EP) study in AF is limited and is usually performed in the context of catheter ablation. Nevertheless, in young patients, it is useful to exclude supraventricular tachycardias (SVTs), such as atrioventricular nodal reentry or atrioventricular reentry, which can be the initiating cause of AF and which are identified in 4% to 10% of patients with AF who undergo EP study after being referred for pulmonary vein isolation. Ablation of SVT without pulmonary vein isolation prevents AF recurrences in many patients. A paroxysmal SVT causing AF is, however, uncommon in the general AF population and invasive evaluation for this cause should be reserved for patients whose symptoms, monitoring, or young age at onset suggest possible SVT.

Treatment

Key issues in AF management are control of symptoms through rate or rhythm control with medications or catheter ablation, management of thromboembolism risk, and identification and management of associated conditions that can exacerbate AF. Furthermore, treatment can be divided into acute and long-term management strategies. It is well appreciated that common disorders, such as hypertension, obesity, obstructive sleep apnea, valvular or infiltrative heart disease, diabetes, thyroid disorders, drug use (smoking and alcohol), and acute illnesses (for example, electrolyte abnormalities, infection), can trigger AF and worsen control. Risk factor management has a critical role in reducing AF burden and symptom severity, as well as improving arrhythmia control. Multiple risk factors probably have a cumulative effect on promoting substrate for AF.