ACC/AHA/ESC GUIDELINES
ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text
A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society
France; Poland; United Kingdom; France; The Netherlands; France; Norway; Greece; France; Italy; Portugal; Germany; Spain; Spain
Key Words: ACC/AHA/ESC Guidelines, atrial fibrillation, pacing cardioversion
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Preamble |
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 Top Preamble 1. Introduction2. Definition3. Classification4. Epidemiology and...5. Pathophysiological...6. Causes, associated...7. Clinical evaluation8. Management9. Proposed management...References |
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It is important that the medical profession play a significant role in critically evaluating the use of diagnostic procedures and therapies as they are introduced and tested in the detection, management, or prevention of disease states. Rigorous and expert analysis of the available data documenting absolute and relative benefits and risks of those procedures and therapies can produce helpful guidelines that improve the effectiveness of care, optimize patient outcomes, and favorably affect the overall cost of care by focusing resources on the most effective strategies.
The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have jointly engaged in the production of such guidelines in the area of cardiovascular disease since 1980. The ACC/AHA Task Force on Practice Guidelines, whose charge is to develop, update, or revise practice guidelines for important cardiovascular diseases and procedures, directs this effort. The Task Force is pleased to have this guideline developed in conjunction with the European Society of Cardiology (ESC). Writing committees are charged with the task of performing an assessment of the evidence and acting as an independent group of authors to develop or update written recommendations for clinical practice.
Experts in the subject under consideration have been selected from all 3 organizations to examine subject-specific data and write guidelines. The process includes additional representatives from other medical practitioner and specialty groups when appropriate. Writing committees are specifically charged to perform a formal literature review, weigh the strength of evidence for or against a particular treatment or procedure, and include estimates of expected health outcomes where data exist. Patient-specific modifiers, comorbidities, and issues of patient preference that might influence the choice of particular tests or therapies are considered as well as frequency of follow-up and cost-effectiveness. When available, information from studies on cost will be considered; however, review of data on efficacy and clinical outcomes will constitute the primary basis for preparing recommendations in these guidelines.
The ACC/AHA Task Force on Practice Guidelines and the ESC Committee for Practice Guidelines make every effort to avoid any actual, potential, or perceived conflict of interest that might arise as a result of an outside relationship or personal interest of the writing committee. Specifically, all members of the Writing Committee and peer reviewers of the document are asked to provide disclosure statements of all such relationships that might be perceived as real or potential conflicts of interest. Writing committee members are also strongly encouraged to declare a previous relationship with industry that might be perceived as relevant to guideline development. If a writing committee member develops a new relationship with industry during their tenure, they are required to notify guideline staff in writing. The continued participation of the writing committee member will be reviewed. These statements are reviewed by the parent Task Force, reported orally to all members of the writing committee at each meeting, and updated and reviewed by the writing committee as changes occur. Please refer to the methodology manuals for further description of the policies used in guideline development, including relationships with industry, available online at the ACC, AHA, and ESC World Wide Web sites (http://www.acc.org/clinical/manual/manual_introltr.htm, http://circ.ahajournals.org/manual/, and http://www.escardio.org/knowledge/guidelines/Rules/). Please see Appendix I for author relationships with industry and Appendix II for peer reviewer relationships with industry that are pertinent to these guidelines.
These practice guidelines are intended to assist healthcare providers in clinical decision making by describing a range of generally acceptable approaches for the diagnosis, management, and prevention of specific diseases and conditions. These guidelines attempt to define practices that meet the needs of most patients in most circumstances. These guideline recommendations reflect a consensus of expert opinion after a thorough review of the available, current scientific evidence and are intended to improve patient care. If these guidelines are used as the basis for regulatory/payer decisions, the ultimate goal is quality of care and serving the patient's best interests. The ultimate judgment regarding care of a particular patient must be made by the healthcare provider and the patient in light of all of the circumstances presented by that patient. There are circumstances in which deviations from these guidelines are appropriate.
The guidelines will be reviewed annually by the ACC/AHA Task Force on Practice Guidelines and the ESC Committee for Practice Guidelines and will be considered current unless they are updated, revised, or sunsetted and withdrawn from distribution. The executive summary and recommendations are published in the August 15, 2006, issues of the Journal of the American College of Cardiology and Circulation and the August 16, 2006, issue of the European Heart Journal. The full-text guidelines are published in the August 15, 2006, issues of the Journal of the American College of Cardiology and Circulation and the September 2006 issue of Europace, as well as posted on the ACC (www.acc.org), AHA (www.americanheart.org), and ESC (www.escardio.org) World Wide Web sites. Copies of the full-text guidelines and the executive summary are available from all 3 organizations.
Sidney C. Smith Jr, MD, FACC, FAHA, FESC, Chair, ACC/AHA Task Force on Practice Guidelines.
Silvia G. Priori, MD, PhD, FESC, Chair, ESC Committee for Practice Guidelines.
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1. Introduction |
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TopPreamble1. Introduction2. Definition3. Classification4. Epidemiology and...5. Pathophysiological...6. Causes, associated...7. Clinical evaluation8. Management9. Proposed management...References |
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1.1. Organization of committee and evidence review
Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance, increasing in prevalence with age. AF is often associated with structural heart disease, although a substantial proportion of patients with AF have no detectable heart disease. Hemodynamic impairment and thromboembolic events related to AF result in significant morbidity, mortality, and cost. Accordingly, the American College of Cardiology (ACC), the American Heart Association (AHA), and the European Society of Cardiology (ESC) created a committee to establish guidelines for optimum management of this frequent and complex arrhythmia.
The committee was composed of members representing the ACC, AHA, and ESC, as well as the European Heart Rhythm Association (EHRA) and the Heart Rhythm Society (HRS). This document was reviewed by 2 official reviewers nominated by the ACC, 2 official reviewers nominated by the AHA, and 2 official reviewers nominated by the ESC, as well as by the ACCF Clinical Electrophysiology Committee, the AHA ECG and Arrhythmias Committee, the AHA Stroke Review Committee, EHRA, HRS, and numerous additional content reviewers nominated by the writing committee. The document was approved for publication by the governing bodies of the ACC, AHA, and ESC and officially endorsed by the EHRA and the HRS.
The ACC/AHA/ESC Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation conducted a comprehensive review of the relevant literature from 2001 to 2006. Literature searches were conducted in the following databases: PubMed/MEDLINE and the Cochrane Library (including the Cochrane Database of Systematic Reviews and the Cochrane Controlled Trials Registry). Searches focused on English-language sources and studies in human subjects. Articles related to animal experimentation were cited when the information was important to understanding pathophysiological concepts pertinent to patient management and comparable data were not available from human studies. Major search terms included atrial fibrillation, age, atrial remodeling, atrioventricular conduction, atrioventricular node, cardioversion, classification, clinical trial, complications, concealed conduction, cost-effectiveness, defibrillator, demographics, epidemiology, experimental, heart failure (HF), hemodynamics, human, hyperthyroidism, hypothyroidism, meta-analysis, myocardial infarction, pharmacology, postoperative, pregnancy, pulmonary disease, quality of life, rate control, rhythm control, risks, sinus rhythm, symptoms, and tachycardia-mediated cardiomyopathy. The complete list of search terms is beyond the scope of this section.
Classification of Recommendations and Level of Evidence are expressed in the ACC/AHA/ESC format as follows and described in Table 1. Recommendations are evidence based and derived primarily from published data.
Table 1 Applying classification of recommendations and level of evidenceb
Classification of recommendations
- Class I: Conditions for which there is evidence and/or general agreement that a given procedure/therapy is beneficial, useful, and effective.
- Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of performing the procedure/therapy.
- Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.
- Class IIb: Usefulness/efficacy is less well established by evidence/opinion.
- Class III: Conditions for which there is evidence and/or general agreement that a procedure/therapy is not useful or effective and in some cases may be harmful.
Level of evidence
The weight of evidence was ranked from highest (A) to lowest (C), as follows:
- Level of evidence A: Data derived from multiple randomized clinical trials or meta-analyses.
- Level of evidence B: Data derived from a single randomized trial or nonrandomized studies.
- Level of evidence C: Only consensus opinion of experts, case studies, or standard-of-care.
1.2. Contents of these guidelines
These guidelines first present a comprehensive review of the latest information about the definition, classification, epidemiology, pathophysiological mechanisms, and clinical characteristics of AF. The management of this complex and potentially dangerous arrhythmia is then reviewed. This includes prevention of AF, control of heart rate, prevention of thromboembolism, and conversion to and maintenance of sinus rhythm. The treatment algorithms include pharmacological and nonpharmacological antiarrhythmic approaches, as well as antithrombotic strategies most appropriate for particular clinical conditions. Overall, this is a consensus document that attempts to reconcile evidence and opinion from both sides of the Atlantic Ocean. The pharmacological and nonpharmacological antiarrhythmic approaches may include some drugs and devices that do not have the approval of all government regulatory agencies. Additional information may be obtained from the package inserts when the drug or device has been approved for the stated indication.
Because atrial flutter can precede or coexist with AF, special consideration is given to this arrhythmia in each section. There are important differences in the mechanisms of AF and atrial flutter, and the body of evidence available to support therapeutic recommendations is distinct for the 2 arrhythmias. Atrial flutter is not addressed comprehensively in these guidelines but is addressed in the ACC/AHA/ESC Guidelines on the Management of Patients with Supraventricular Arrhythmias.1
1.3. Changes since the initial publication of these guidelines in 2001
In developing this revision of the guidelines, the Writing Committee considered evidence published since 2001 and drafted revised recommendations where appropriate to incorporate results from major clinical trials such as those that compared rhythm-control and rate-control approaches to long-term management. The text has been reorganized to reflect the implications for patient care, beginning with recognition of AF and its pathogenesis and the general priorities of rate control, prevention of thromboembolism, and methods available for use in selected patients to correct the arrhythmia and maintain normal sinus rhythm. Advances in catheter-based ablation technologies have been incorporated into expanded sections and recommendations, with the recognition that that such vital details as patient selection, optimum catheter positioning, absolute rates of treatment success, and the frequency of complications remain incompletely defined. Sections on drug therapy have been condensed and confined to human studies with compounds that have been approved for clinical use in North America and/or Europe. Accumulating evidence from clinical studies on the emerging role of angiotensin inhibition to reduce the occurrence and complications of AF and information on approaches to the primary prevention of AF are addressed comprehensively in the text, as these may evolve further in the years ahead to form the basis for recommendations affecting patient care. Finally, data on specific aspects of management of patients who are prone to develop AF in special circumstances have become more robust, allowing formulation of recommendations based on a higher level of evidence than in the first edition of these guidelines. An example is the completion of a relatively large randomized trial addressing prophylactic administration of antiarrhythmic medication for patients undergoing cardiac surgery. In developing the updated recommendations, every effort was made to maintain consistency with other ACC/AHA and ESC practice guidelines addressing, for example, the management of patients undergoing myocardial revascularization procedures.
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2. Definition |
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TopPreamble1. Introduction2. Definition3. Classification4. Epidemiology and...5. Pathophysiological...6. Causes, associated...7. Clinical evaluation8. Management9. Proposed management...References |
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2.1. Atrial fibrillation
AF is a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation with consequent deterioration of atrial mechanical function. On the electrocardiogram (ECG), AF is characterized by the replacement of consistent P waves by rapid oscillations or fibrillatory waves that vary in amplitude, shape, and timing, associated with an irregular, frequently rapid ventricular response when atrioventricular (AV) conduction is intact2
(Figure 1). The ventricular response to AF depends on electrophysiological (EP) properties of the AV node and other conducting tissues, the level of vagal and sympathetic tone, the presence or absence of accessory conduction pathways, and the action of drugs.3 Regular cardiac cycles (R-R intervals) are possible in the presence of AV block or ventricular or AV junctional tachycardia. In patients with implanted pacemakers, diagnosis of AF may require temporary inhibition of the pacemaker to expose atrial fibrillatory activity.4 A rapid, irregular, sustained, wide-QRS-complex tachycardia strongly suggests AF with conduction over an accessory pathway or AF with underlying bundle-branch block. Extremely rapid rates (over 200 beats per minute) suggest the presence of an accessory pathway or ventricular tachycardia.
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2.2. Related arrhythmias
AF may occur in isolation or in association with other arrhythmias, most commonly atrial flutter or atrial tachycardia. Atrial flutter may arise during treatment with antiarrhythmic agents prescribed to prevent recurrent AF. Atrial flutter in the typical form is characterized by a saw-tooth pattern of regular atrial activation called flutter (f) waves on the ECG, particularly visible in leads II, III, aVF, and V1 (Figure 2). In the untreated state, the atrial rate in atrial flutter typically ranges from 240 to 320 beats per minute, with f waves inverted in ECG leads II, III, and aVF and upright in lead V1. The direction of activation in the right atrium (RA) may be reversed, resulting in f waves that are upright in leads II, III, and aVF and inverted in lead V1. Atrial flutter commonly occurs with 2 : 1 AV block, resulting in a regular or irregular ventricular rate of 120 to 160 beats per minute (most characteristically about 150 beats per minute). Atrial flutter may degenerate into AF and AF may convert to atrial flutter. The ECG pattern may fluctuate between atrial flutter and AF, reflecting changing activation of the atria. Atrial flutter is usually readily distinguished from AF, but when atrial activity is prominent on the ECG in more than 1 lead, AF may be misdiagnosed as atrial flutter.5
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Focal atrial tachycardias, AV reentrant tachycardias, and AV nodal reentrant tachycardias may also trigger AF. In other atrial tachycardias, P waves may be readily identified and are separated by an isoelectric baseline in 1 or more ECG leads. The morphology of the P waves may help localize the origin of the tachycardias.
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3. Classification |
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TopPreamble1. Introduction2. Definition3. Classification4. Epidemiology and...5. Pathophysiological...6. Causes, associated...7. Clinical evaluation8. Management9. Proposed management...References |
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Various classification systems have been proposed for AF. One is based on the ECG presentation.2
–4 Another is based on epicardial6 or endocavitary recordings or noncontact mapping of atrial electrical activity. Several clinical classification schemes have also been proposed, but none fully accounts for all aspects of AF.7–10 To be clinically useful, a classification system must be based on a sufficient number of features and carry specific therapeutic implications. Assorted labels have been used to describe the pattern of AF, including acute, chronic, paroxysmal, intermittent, constant, persistent, and permanent, but the vagaries of definitions make it difficult to compare studies of AF or the effectiveness of therapeutic strategies based on these designations. Although the pattern of the arrhythmia can change over time, it may be of clinical value to characterize the arrhythmia at a given moment. The classification scheme recommended in this document represents a consensus driven by a desire for simplicity and clinical relevance.
The clinician should distinguish a first-detected episode of AF, whether or not it is symptomatic or self-limited, recognizing that there may be uncertainty about the duration of the episode and about previous undetected episodes (Figure 3). When a patient has had 2 or more episodes, AF is considered recurrent. If the arrhythmia terminates spontaneously, recurrent AF is designated paroxysmal; when sustained beyond 7 d, AF is designated persistent. Termination with pharmacological therapy or direct-current cardioversion does not change the designation. First-detected AF may be either paroxysmal or persistent AF. The category of persistent AF also includes cases of long-standing AF (e.g., greater than 1 y), usually leading to permanent AF, in which cardioversion has failed or has not been attempted.
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These categories are not mutually exclusive in a particular patient, who may have several episodes of paroxysmal AF and occasional persistent AF, or the reverse. Regarding paroxysmal and persistent AF, it is practical to categorize a given patient by the most frequent presentation. The definition of permanent AF is often arbitrary. The duration of AF refers both to individual episodes and to how long the patient has been affected by the arrhythmia. Thus, a patient with paroxysmal AF may have episodes that last seconds to hours occurring repeatedly for years.
Episodes of AF briefer than 30 s may be important in certain clinical situations involving symptomatic patients, pre-excitation or in assessing the effectiveness of therapeutic interventions. This terminology applies to episodes of AF that last more than 30 s without a reversible cause. Secondary AF that occurs in the setting of acute myocardial infarction (MI), cardiac surgery, pericarditis, myocarditis, hyperthyroidism, pulmonary embolism, pneumonia, or other acute pulmonary disease is considered separately. In these settings, AF is not the primary problem, and treatment of the underlying disorder concurrently with management of the episode of AF usually terminates the arrhythmia without recurrence. Conversely, because AF is common, it may occur independently of a concurrent disorder like well-controlled hypothyroidism, and then the general principles for management of the arrhythmia apply.
The term ‘lone AF’ has been variously defined but generally applies to young individuals (under 60 y of age) without clinical or echocardiographic evidence of cardiopulmonary disease, including hypertension.11 These patients have a favorable prognosis with respect to thromboembolism and mortality. Over time, patients may move out of the lone AF category due to aging or development of cardiac abnormalities such as enlargement of the left atrium (LA). Then, the risks of thromboembolism and mortality rise accordingly. By convention, the term ‘nonvalvular AF’ is restricted to cases in which the rhythm disturbance occurs in the absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair.
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4. Epidemiology and prognosis |
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TopPreamble1. Introduction2. Definition3. Classification4. Epidemiology and...5. Pathophysiological...6. Causes, associated...7. Clinical evaluation8. Management9. Proposed management...References |
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AF is the most common arrhythmia in clinical practice, accounting for approximately one-third of hospitalizations for cardiac rhythm disturbances. Most data regarding the epidemiology, prognosis, and quality of life in AF have been obtained in the United States and western Europe. It has been estimated that 2.2 million people in America and 4.5 million in the European Union have paroxysmal or persistent AF.12
During the past 20 y, there has been a 66% increase in hospital admissions for AF13–15 due to a combination of factors including the aging of the population, a rising prevalence of chronic heart disease, and more frequent diagnosis through use of ambulatory monitoring devices. AF is an extremely costly public health problem,16,17 with hospitalizations as the primary cost driver (52%), followed by drugs (23%), consultations (9%), further investigations (8%), loss of work (6%), and paramedical procedures (2%). Globally, the annual cost per patient is close to 
3000 (approximately U.S. $3600).16 Considering the prevalence of AF, the total societal burden is huge, for example, about E13.5 billion (approximately U.S. $15.7 billion) in the European Union.
4.1. Prevalence
The estimated prevalence of AF is 0.4% to 1% in the general population, increasing with age.18,19 Cross-sectional studies have found a lower prevalence in those below the age of 60 y, increasing to 8% in those older than 80 y (Figure 4).20–22 The age-adjusted prevalence of AF is higher in men,22,23 in whom the prevalence has more than doubled from the 1970s to the 1990s, while the prevalence in women has remained unchanged.24 The median age of AF patients is about 75 y. Approximately 70% are between 65 and 85 y old. The overall number of men and women with AF is about equal, but approximately 60% of AF patients over 75 y are female. Based on limited data, the age-adjusted risk of developing AF in blacks seems less than half that in whites.18,25,26 AF is less common among African-American than Caucasian patients with heart failure (HF).
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In population-based studies, patients with no history of cardiopulmonary disease account for fewer than 12% of all cases of AF.11
,22,27,28 In some series, however, the observed proportion of lone AF was over 30%.29,30
These differences may depend on selection bias when recruiting patients seen in clinical practice compared with population-based observations. In the Euro Heart Survey on AF,31 the prevalence of idiopathic AF amounted to 10%, with an expected highest value of 15% in paroxysmal AF, 14% in first-detected AF, 10% in persistent AF, and only 4% in permanent AF. Essential hypertension, ischemic heart disease, HF (Table 2), valvular heart disease, and diabetes are the most prominent conditions associated with AF.14
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4.2. Incidence
In prospective studies, the incidence of AF increases from less than 0.1% per year in those under 40 y old to exceed 1.5% per year in women and 2% in men older than 80 (Figure 5).25
,32,33 The age-adjusted incidence increased over a 30-y period in the Framingham Study,32 and this may have implications for the future impact of AF.34 During 38 y of follow-up in the Framingham Study, 20.6% of men who developed AF had HF at inclusion versus 3.2% of those without AF; the corresponding incidences in women were 26.0% and 2.9%.35 In patients referred for treatment of HF, the 2- to 3-y incidence of AF was 5% to 10%.25,36,37 The incidence of AF may be lower in HF patients treated with angiotensin inhibitors.38–40 Similarly, angiotensin inhibition may be associated with a reduced incidence of AF in patients with hypertension,41,42 although this may be confined to those with left ventricular hypertrophy (LVH).43–45
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4.3. Prognosis
AF is associated with an increased long-term risk of stroke,47
HF, and all-cause mortality, especially in women.48 The mortality rate of patients with AF is about double that of patients in normal sinus rhythm and linked to the severity of underlying heart disease20,23,33 (Figure 6). About two-thirds of the 3.7% mortality over 8.6 mo in the Etude en Activité Libérale sur la Fibrillation Auriculaire Study (ALFA) was attributed to cardiovascular causes.29 Table 3 shows a list of associated heart diseases in the population of the ALFA study.29
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Mortality in the Veterans Administration Heart Failure Trials (V-HeFT) was not increased among patients with concomitant AF,49
whereas in the Studies of Left Ventricular Dysfunction (SOLVD), mortality was 34% for those with AF versus 23% for patients in sinus rhythm (p less than 0.001).50 The difference was attributed mainly to deaths due to HF rather than to thromboembolism. AF was a strong independent risk factor for mortality and major morbidity in large HF trials. In the Carvedilol Or Metoprolol European Trial (COMET), there was no difference in all-cause mortality in those with AF at entry, but mortality increased in those who developed AF during follow-up.51 In the Val-HeFT cohort of patients with chronic HF, development of AF was associated with significantly worse outcomes.40 HF promotes AF, AF aggravates HF, and individuals with either condition who develop the alternate condition share a poor prognosis.52 Thus, managing the association is a major challenge53 and the need for randomized trials to investigate the impact of AF on the prognosis in HF is apparent.
The rate of ischemic stroke among patients with nonvalvular AF averages 5% per year, 2 to 7 times that of people without AF20,21,29,32,33,47 (Figure 6). One of every 6 strokes occurs in a patient with AF.54 Additionally, when transient ischemic attacks (TIAs) and clinically ‘silent’ strokes detected by brain imaging are considered, the rate of brain ischemia accompanying nonvalvular AF exceeds 7% per year.35,55–58 In patients with rheumatic heart disease and AF in the Framingham Heart Study, stroke risk was increased 17-fold compared with age-matched controls,59 and attributable risk was 5 times greater than that in those with nonrheumatic AF.21 In the Manitoba Follow-up Study, AF doubled the risk of stroke independently of other risk factors,33 and the relative risks for stroke in nonrheumatic AF were 6.9% and 2.3% in the Whitehall and the Regional Heart studies, respectively. Among AF patients from general practices in France, the Etude en Activité Libérale sur le Fibrillation Auriculaire (ALFA) study found a 2.4% incidence of thromboembolism over a mean of 8.6 mo of follow-up.29 The risk of stroke increases with age; in the Framingham Study, the annual risk of stroke attributable to AF was 1.5% in participants 50 to 59 y old and 23.5% in those aged 80 to 89 y.21
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5. Pathophysiological mechanisms |
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5.1. Atrial factors
5.1.1. Atrial pathology as a cause of atrial fibrillation
The most frequent pathoanatomic changes in AF are atrial fibrosis and loss of atrial muscle mass. Histological examination of atrial tissue of patients with AF has shown patchy fibrosis juxtaposed with normal atrial fibers, which may account for nonhomogeneity of conduction.60
–62 The sinoatrial (SA) and AV nodes may also be involved, accounting for the sick sinus syndrome and AV block. It is difficult to distinguish between changes due to AF and those due to associated heart disease, but fibrosis may precede the onset of AF.63
Biopsy of the LA posterior wall during mitral valve surgery revealed mild to moderate fibrosis in specimens obtained from patients with sinus rhythm or AF of relatively short duration, compared with severe fibrosis and substantial loss of muscle mass in those from patients with long-standing AF. Patients with mild or moderate fibrosis responded more successfully to cardioversion than did those with severe fibrosis, which was thought to contribute to persistent AF in cases of valvular heart disease.64 In atrial tissue specimens from 53 explanted hearts from transplantation recipients with dilated cardiomyopathy, 19 of whom had permanent, 18 persistent, and 16 no documented AF, extracellular matrix remodeling including selective downregulation of atrial insulin-like growth factor II mRNA-binding protein 2 (IMP-2) and upregulation of matrix metalloproteinase 2 (MMP-2) and type 1 collagen volume fraction (CVF-1) were associated with sustained AF.65
Atrial biopsies from patients undergoing cardiac surgery revealed apoptosis66 that may lead to replacement of atrial myocytes by interstitial fibrosis, loss of myofibrils, accumulation of glycogen granules, disruption of cell coupling at gap junctions,67 and organelle aggregates.68 The concentration of membrane-bound glycoproteins that regulate cell-cell and cell-matrix interactions (disintegrin and metalloproteinases) in human atrial myocardium has been reported to double during AF. Increased disintegrin and metalloproteinase activity may contribute to atrial dilation in patients with long-standing AF.
Atrial fibrosis may be caused by genetic defects like lamin AC gene mutations.69 Other triggers of fibrosis include inflammation70 as seen in cardiac sarcoidosis71 and autoimmune disorders.72 In one study, histological changes consistent with myocarditis were reported in 66% of atrial biopsy specimens from patients with lone AF,62 but it is uncertain whether these inflammatory changes were a cause or consequence of AF. Autoimmune activity is suggested by high serum levels of antibodies against myosin heavy chains in patients with paroxysmal AF who have no identified heart disease.72 Apart from fibrosis, atrial pathological findings in patients with AF include amyloidosis,73,74 hemochromatosis,75 and endomyocardial fibrosis.75,76 Fibrosis is also triggered by atrial dilation in any type of heart disease associated with AF, including valvular disease, hypertension, HF, or coronary atherosclerosis.77 Stretch activates several molecular pathways, including the renin-angiotensin-aldosterone system (RAAS). Both angiotensin II and transforming growth factor-beta1 (TGF-beta1) are upregulated in response to stretch, and these molecules induce production of connective tissue growth factor (CTGF).70 Atrial tissue from patients with persistent AF undergoing open-heart surgery demonstrated increased amounts of extracellular signal-regulated kinase messenger RNA (ERK-2-mRNA), and expression of angiotensin-converting enzyme (ACE) was increased 3-fold during persistent AF.78 A study of 250 patients with AF and an equal number of controls demonstrated the association of RAAS gene polymorphisms with this type of AF.79
Several RAAS pathways are activated in experimental78,80–84 as well as human AF,78,85 and ACE inhibition and angiotensin II receptor blockade had the potential to prevent AF by reducing fibrosis.84,86
In experimental studies of HF, atrial dilation and interstitial fibrosis facilitates sustained AF.86–92 The regional electrical silence (suggesting scar), voltage reduction, and conduction slowing described in patients with HF93 are similar to changes in the atria that occur as a consequence of aging.
AF is associated with delayed interatrial conduction and dispersion of the atrial refractory period.94 Thus, AF seems to cause a variety of alterations in the atrial architecture and function that contribute to remodeling and perpetuation of the arrhythmia. Despite these pathological changes in the atria, however, isolation of the pulmonary veins (PVs) will prevent AF in many such patients with paroxysmal AF.
5.1.1.1. Pathological changes caused by atrial fibrillation
Just as atrial stretch may cause AF, AF can cause atrial dilation through loss of contractility and increased compliance.61 Stretch-related growth mechanisms and fibrosis increase the extracellular matrix, especially during prolonged periods of AF. Fibrosis is not the primary feature of AF-induced structural remodeling,95,96 although accumulation of extracellular matrix and fibrosis are associated with more pronounced myocytic changes once dilation occurs due to AF or associated heart disease.90,97 These changes closely resemble those in ventricular myocytes in the hibernating myocardium associated with chronic ischemia.98 Among these features are an increase in cell size, perinuclear glycogen accumulation, loss of sarcoplasmic reticulum and sarcomeres (myolysis). Changes in gap junction distribution and expression are inconsistent,61,99 and may be less important than fibrosis or shortened refractoriness in promoting AF. Loss of sarcomeres and contractility seems to protect myocytes against the high metabolic stress associated with rapid rates. In fact, in the absence of other pathophysiological factors, the high atrial rate typical of AF may cause ischemia that affects myocytes more than the extracellular matrix and interstitial tissues.
Aside from changes in atrial dimensions that occur over time, data on human atrial structural remodeling are limited96,100 and difficult to distinguish from degenerative changes related to aging and associated heart disease.96 One study that compared atrial tissue specimens from patients with paroxysmal and persistent lone AF found degenerative contraction bands in patients with either pattern of AF, while myolysis and mitochondria hibernation were limited to those with persistent AF. The activity of calpain I, a proteolytic enzyme activated in response to cytosolic calcium overload, was upregulated in both groups and correlated with ion channel protein and structural and electrical remodeling. Hence, calpain activation may link calcium overload to cellular adaptation in patients with AF.341
5.1.2. Mechanisms of atrial fibrillation
The onset and maintenance of a tachyarrhythmia require both an initiating event and an anatomical substrate. With respect to AF, the situation is often complex, and available data support a ‘focal’ mechanism involving automaticity or multiple reentrant wavelets. These mechanisms are not mutually exclusive and may at various times coexist in the same patient (Figure 7).
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5.1.2.1. Automatic focus theory
A focal origin of AF is supported by experimental models of aconitine and pacing-induced AF102
,103 in which the arrhythmia persists only in isolated regions of atrial myocardium. This theory received minimal attention until the important observation that a focal source for AF could be identified in humans and ablation of this source could extinguish AF.104 While PVs are the most frequent source of these rapidly atrial impulses, foci have also been found in the superior vena cava, ligament of Marshall, left posterior free wall, crista terminalis, and coronary sinus.79,104–110
In histological studies, cardiac muscle with preserved electrical properties extends into the PV,106,111–116 and the primacy of PVs as triggers of AF has prompted substantial research into the anatomical and EP properties of these structures. Atrial tissue on the PV of patients with AF has shorter refractory periods than in control patients or other parts of the atria in patients with AF.117,118 The refractory period is shorter in atrial tissue in the distal PV than at the PV-LA junction. Decremental conduction in PV is more frequent in AF patients than in controls, and AF is more readily induced during pacing in the PV than in the LA. This heterogeneity of conduction may promote reentry and form a substrate for sustained AF.119 Programmed electrical stimulation in PV isolated by catheter ablation initiated sustained pulmonary venous tachycardia, probably as a consequence of reentry.120 Rapidly firing atrial automatic foci may be responsible for these PV triggers, with an anatomical substrate for reentry vested within the PV.
Whether the source for AF is an automatic focus or a microreentrant circuit, rapid local activation in the LA cannot extend to the RA in an organized way. Experiments involving acetylcholine-induced AF in Langendorf-perfused sheep hearts demonstrated a dominant fibrillation frequency in the LA with decreasing frequency as activation progressed to the RA. A similar phenomenon has been shown in patients with paroxysmal AF.121 Such variation in conduction leads to disorganized atrial activation, which could explain the ECG appearance of a chaotic atrial rhythm.122 The existence of triggers for AF does not negate the role of substrate modification. In some patients with persistent AF, disruption of the muscular connections between the PV and the LA may terminate the arrhythmia. In others, AF persists following isolation of the supposed trigger but does not recur after cardioversion. Thus, in some patients with abnormal triggers, sustained AF may depend on an appropriate anatomical substrate.
5.1.2.2. Multiple-wavelet hypothesis
The multiple-wavelet hypothesis as the mechanism of reentrant AF was advanced by Moe and colleagues,123 who proposed that fractionation of wavefronts propagating through the atria results in self-perpetuating ‘daughter wavelets’. In this model, the number of wavelets at any time depends on the refractory period, mass, and conduction velocity in different parts of the atria. A large atrial mass with a short refractory period and delayed conduction increases the number of wavelets, favoring sustained AF. Simultaneous recordings from multiple electrodes supported the multiple-wavelet hypothesis in human subjects.127
For many years, the multiple-wavelet hypothesis was the dominant theory explaining the mechanism of AF, but the data presented above and from experimental127a and clinical127b,127c mapping studies challenge this notion. Even so, a number of other observations support the importance of an abnormal atrial substrate in the maintenance of AF. For over 25 y, EP studies in humans have implicated atrial vulnerability in the pathogenesis of AF.128–132 In one study of 43 patients without structural heart disease, 18 of whom had paroxysmal AF, the coefficient of dispersion of atrial refractoriness was significantly greater in the patients with AF.128 Furthermore, in 16 of 18 patients with a history of AF, the arrhythmia was induced with a single extrastimulus, while a more aggressive pacing protocol was required in 23 of 25 control patients without previously documented AF. In patients with idiopathic paroxysmal AF, widespread distribution of abnormal electrograms in the RA predicted development of persistent AF, suggesting an abnormal substrate.132 In patients with persistent AF who had undergone conversion to sinus rhythm, there was significant prolongation of intra-atrial conduction compared with a control group, especially among those who developed recurrent AF after cardioversion.130
Patients with a history of paroxysmal AF, even those with lone AF, have abnormal atrial refractoriness and conduction compared with patients without AF. An abnormal signal-averaged P-wave ECG reflects slowed intra-atrial conduction and shorter wavelengths of reentrant impulses. The resulting increase in wavelet density promotes the onset and maintenance of AF. Among patients with HF, prolongation of the P wave was more frequent in those prone to paroxysmal AF.133 In specimens of RA appendage tissue obtained from patients undergoing open-heart surgery, P-wave duration was correlated with amyloid deposition.73 Because many of these observations were made prior to the onset of clinical AF, the findings cannot be ascribed to atrial remodeling that occurs as a consequence of AF. Atrial refractoriness increases with age in both men and women, but concurrent age-related fibrosis lengthens effective intra-atrial conduction pathways. This, coupled with the shorter wavelengths of reentrant impulses, increases the likelihood that AF will develop.134,135 Nonuniform alterations of refractoriness and conduction throughout the atria may provide a milieu for the maintenance of AF. However, the degree to which changes in the atrial architecture contribute to the initiation and maintenance of AF is not known. Isolation of the PV may prevent recurrent AF even in patients with substantial abnormalities in atrial size and function. Finally, the duration of episodes of AF correlates with both a decrease in atrial refractoriness and shortening of the AF cycle length, attesting to the importance of electrical remodeling in the maintenance of AF.136 The anatomical and electrophysiological substrates are detailed in Table 4.
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5.1.3. Atrial electrical remodeling
Pharmacological or direct-current cardioversion of AF has a higher success rate when AF has been present for less than 24 h,137
whereas more prolonged AF makes restoring and maintaining sinus rhythm less likely. These observations gave rise to the adage ‘atrial fibrillation begets atrial fibrillation’. The notion that AF is self-perpetuating takes experimental support from a goat model using an automatic atrial fibrillator that detected spontaneous termination of AF and reinduced the arrhythmia by electrical stimulation.138 Initially, electrically induced AF terminated spontaneously. After repeated inductions, however, the episodes became progressively more sustained until AF persisted at a more rapid atrial rate.138 The increasing propensity to AF was related to progressive shortening of effective refractory periods with increasing episode duration, a phenomenon known as EP remodeling. These measurements support clinical observations139 that the short atrial effective refractory period in patients with parox-ysmal AF fails to adapt to rate, particularly during bradycardia. Confirmation came from recordings of action potentials in isolated fibrillating atrial tissue and from patients after cardioversion.140 The duration of atrial monophasic action potentials was shorter after cardioversion and correlated with the instability of sinus rhythm.141
Tachycardia-induced AF may result from AV node reentry, an accessory pathway, atrial tachycardia, or atrial flutter.142–144 After a period of rapid atrial rate, electrical remodeling stimulates progressive intracellular calcium loading that leads to inactivation of the calcium current.145,146 Reduction of the calcium current in turn shortens the action potential duration and atrial refractory period, which may promote sustained AF. The role of potassium currents in this situation is less clear.145 Electrical remodeling has also been demonstrated in PV myocytes subjected to sustained rapid atrial pacing, resulting in shorter action potential durations and both early and delayed afterdepolarizations.147
In addition to remodeling and changes in electrical refractoriness, prolonged AF disturbs atrial contractile function. With persistent AF, recovery of atrial contraction can be delayed for days or weeks following the restoration of sinus rhythm, which has important implications for the duration of anticoagulation after cardioversion. (See Section 8.1.4, Preventing Thromboembolism.) Both canine and preliminary human data suggest that prolonged AF may also lengthen sinus node recovery time.148,149 The implication is that AF may be partly responsible for sinus node dysfunction in some patients with the tachycardia-bradycardia syndrome.
Reversal of electrical remodeling in human atria may occur at different rates depending on the region of the atrium studied.150 When tested at various times after cardioversion, the effective refractory period of the lateral RA increased within 1 h after cardioversion, while that in the coronary sinus was delayed for 1 wk. In another study, recovery of normal atrial refractoriness after cardioversion of persistent AF was complete within 3 to 4 d,151 after which there was no difference in refractoriness between the RA appendage and the distal coronary sinus. The disparities between studies may reflect patient factors or the duration or pattern of AF before cardioversion.
5.1.4. Counteracting atrial electrical remodeling
Data are accumulating on the importance of the RAAS in the genesis of AF.145 Irbesartan plus amiodarone was associated with a lower incidence of recurrent AF after cardioversion than amiodarone alone,39 and use of angiotensin inhibitors and diuretics significantly reduced the incidence of AF after catheter ablation of atrial flutter.152 Amiodarone may reverse electrical remodeling even when AF is ongoing,153 and this explains how amiodarone can convert persistent AF to sinus rhythm. Inhibition of the RAAS, alone or in combination with other therapies, may therefore prevent the onset or maintenance of AF43 through several mechanisms. These include hemodynamic changes (lower atrial pressure and wall stress), prevention of structural remodeling (fibrosis, dilation, and hypertrophy) in both the LA and left ventricle (LV), inhibition of neurohumoral activation, reduced blood pressure, prevention or amelioration of HF, and avoidance of hypokalemia. Treatment with trandolapril reduced the incidence of AF in patients with LV dysfunction following acute MI,36 but it remains to be cl