Incidence and Prevalence

Atrial fibrillation (AF) is the most common sustained arrhythmia, with the incidence of 3.1 cases in men and 1.9 cases in women per 1000 person-years in the population younger than 64 years, rising to 19.2 per 1000 person-years in those 65 to 74 years, and as high as 31.4 to 38 in octogenarians.¹ A rising proportion of the older population, markedly improved survival from previously fatal cardiovascular conditions, and a recently observed trend toward a continuous increase in the incidence of AF among younger age groups will result in a considerable increase in the number of patients with AF over the next 4 decades. The Framingham Study in the United States and the Rotterdam Study in Europe have estimated lifetime risk for development of AF to be 1 in 4 for men and women aged 40 years and older.^2,3 Projected data from national databases have predicted that the number of patients with AF in the United States is expected to reach 5.6 to 15.9 million by 2050, particularly if the incidence of AF continues to rise (Figure 42-1).^4–6 A similar increase in the proportion of population with AF is likely to be seen in Western Europe.^3,7 However, even these projections may represent conservative estimates because of silent and short transient episodes of AF, which are likely to be diagnosed more frequently because of increased awareness of the arrhythmia, improved diagnostic tools, and a wider use of implantable rhythm-control or rhythm-monitoring devices.⁸

FIGURE 42-1 Estimates of the number of individuals with atrial fibrillation in the United States by 2050.

(Data from Go AS, Hylek EM, Phillips KA, et al: Prevalence of diagnosed atrial fibrillation in adults: National implications for rhythm management and stroke prevention. The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study, JAMA 285:2370–2375, 2001; Miyasaka Y, Barnes ME, Gersh BJ, et al: Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence, Circulation 114:119–125, 2006; and Naccarelli GV, Varker H, Lin J, Schulman KL: Increasing prevalence of atrial fibrillation and flutter in the United States, Am J Cardiol 104:1534–1539, 2009.)

Age, Gender, and Ethnicity

A series of epidemiologic studies have identified age to be one of the major determinants of risk of developing AF, with odds of 1.1 to 5.9 depending on the initial age and morbidity of a cohort studied and the duration of follow-up.^9–12 In the Framingham Heart Study, the risk of AF was increased approximately twofold per decade of age in both men and women.¹¹ Increased rates of AF related to age are attributed to inherent changes in the atria occurring with aging (e.g., fatty metamorphosis, myocyte degeneration, fibrosis), accumulation of risk factors, and progression of the underlying disease.

Men are affected almost twice as often and are diagnosed with AF at a younger age compared with women, but recent analyses have suggested that women with AF have more comorbidities, higher mortality rate, and higher risk of stroke and treatment-related complications (e.g., proarrhythmia or bleeding) compared with their male counterparts.^11–15

The prevalence of AF is higher in white populations.^16–19 In the Atherosclerosis Risk in Communities (ARIC) Study, age-adjusted incidence rates of AF were highest in white men and lowest in black women (7.45 and 3.67 per 1000 person-years, respectively).¹⁷ In the health survey of 664,754 U.S. veterans, white men were significantly more likely to have AF compared with all other races except Pacific Islanders (odds ratio [OR] compared with blacks, 1.84; vs. Hispanics, 1.77; vs. Asians, 1.41; vs. Native Americans, 1.15; P < .001).¹⁸ The prevalence and distribution of associated risk factors also depended on ethnicity. Thus white men were more likely to have valvular heart disease, coronary artery disease (CAD), and congestive heart failure (CHF); blacks had the highest prevalence of hypertension; and Hispanics had the highest prevalence of diabetes. Racial differences remained after adjustment for age, body mass index, and underlying pathology. In a meta-analysis of seven randomized clinical trials in patients with acute coronary syndrome (ACS), the prospectively collected information on the development of AF indicated that the rates of AF were lower in Asian patients than in white patients (4.7% vs. 7.6%; OR, 0.65; 95% confidence interval [CI], 0.50 to 0.84; P = .001).¹⁹ This contradicts the finding of a greater prevalence of unfavorable risk factors for AF in nonwhite populations.²⁰ Nonwhite races have also been reported to be at higher risk of intracranial hemorrhage as a complication of anticoagulation therapy (hazard ratio [HR], with whites as referent, 4.06 for Asians, 2.06 for Hispanics, and 2.04 for blacks).²¹ Thus the link between ethnicity and risk of AF as well as the therapy for AF remains to be further investigated.

Heart Failure

An increasing number of surviving patients with left ventricular impairment has led to CHF emerging as one of the leading risk factors for AF associated with a threefold to almost sixfold increase in the risk of AF.^10,12,13 The prevalence of AF associated with CHF varies from 4% to 50%, depending on New York Heart Association (NYHA) class (Figure 42-3).²² The occurrence of CHF in middle age confers an 8% risk of developing AF over a 10-year period if the patient’s age at time of CHF diagnosis was 55 to 64 years, which rises to more than 30% if CHF was diagnosed at age 45 to 54 years.¹³

FIGURE 42-3 Prevalence of atrial fibrillation in selected heart failure studies. NYHA, New York Heart Association. Study acronyms: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity; Congestive Heart Failure: Survival Trial of Antiarrhythmic Therapy; Cardiac Insufficiency Bisoprolol Study; Carvedilol or Metoprolol European Trial; Cooperative North Scandinavian Enalapril Survival Study; Danish Investigations of Arrhythmia and Mortality on Dofetilide; Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina; Metoprolol CR/XL Randomised Intervention Trial in Heart Failure; I-PRESERVE, Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction; SOLVD-P, Studies of Left Ventricular Dysfunction–Prevention; SOLVD-T, Studies of Left Ventricular Dysfunction–Treatment; Vasodilator-Heart Failure Trial.

CHF may precipitate AF by increasing volume and pressure load, which leads to atrial dilation and stretch and altered atrial electrophysiology, including shortening of the atrial effective refractory period, a major determinant of the arrhythmia. Hypertrophy of atrial myocytes and patchy fibrosis result in numerous areas of conduction delay or block favoring micro–re-entry. Calcium overloading and activation of stretch-mediated ion channels increase the likelihood of afterdepolarizations and triggered activity in the atria.

Diastolic left ventricular dysfunction with subsequent increases in filling pressures, which is common in older adults, mediates atrial remodeling and is associated with a 5.26-fold increased risk of AF.²³ The incidence of AF in patients with CHF and preserved left ventricular systolic function is 20% to 30%.²⁴

Hypertension

Hypertension is the most prevalent condition associated with AF, with a rate of approximately 70% (see Figure 42-2). It is a firmly established risk factor for the development of AF, as shown by many epidemiologic surveys, and increases the risk of AF by a factor of 1.5 to 2.^10–13 The risk has been shown to rise proportionally to the level of blood pressure, although iatrogenic hypotension has been linked to AF, suggesting a J-shaped relationship between blood pressure and AF.^12,25,26

Myocardial Infarction

AF is a common complication of ACS, occurring de novo in 6% to 15% of patients with myocardial infarction (MI); the incidence is higher (10% to 20%) if patients with a history of atrial tachyarrhythmias are included.²⁷ Patients with ST-segment elevation MI (STEMI) are more likely to develop AF compared with patients with other types of ACS (8% vs. 6.4%), and the presence of early left ventricular systolic dysfunction and CHF has been consistently shown to increase the likelihood of AF by a factor of 1.58 to 3.28.^27,28

Previous MI was associated with an increased risk of subsequent AF by a factor of 1.4 to 3.62, but this association is less well established for CAD without MI because these two entities have not been adequately distinguished in epidemiologic studies.^9,10,12 It is reasonable to consider CAD, particularly with evidence of reversible ischemia, a risk factor because it may promote formation of the substrate for AF (e.g., due to atrial ischemia).

Diabetes

Diabetes mellitus has been identified as a risk factor for AF. In the Framingham Heart Study, diabetes mellitus was associated with a 1.4-fold increased risk of AF in men and 1.6-fold increase in women.¹⁰ Its relevance as a risk factor has been confirmed in recent population-based surveys and meta-analyses of randomized controlled studies. A report from the Veterans Health Administration Hospitals database with 845,748 participants has shown that type 2 diabetes increases the risk of AF by a factor of 2.13.²⁹ A systematic review of 11 studies involving 108,703 cases of AF in more than 1.6 million individuals has revealed that patients with diabetes have a 40% greater risk of AF compared with their nondiabetic counterparts.³⁰

The cause-and-effect association between diabetes and AF has not been fully elucidated as, for example, no substantial evidence that type 1 diabetes increases risk of AF exists. Patients with type 2 diabetes mellitus often have other comorbidities and risk factors that may predispose to AF, such as older age, hypertension, CHF, CAD, obesity, and sleep apnea, and the effect of confounding is significant. Although hyperglycemia may directly affect the electrophysiological properties of the atria, causing intra-atrial conduction delay and promoting structural remodeling by activation of the AGE-RAGE (advanced glycation end product–receptor for AGE) system and upregulation of circulating tissue growth factors, insulin resistance associated with type 2 diabetes may also be an important contributor.^31,32

Cardiomyopathies

AF occurs in association with hypertrophic cardiomyopathy in 18% to 28% of patients, with an annual incidence of 2%.^33,34 The prevalence of AF is higher in patients older than 50 years with evidence of left ventricular systolic dysfunction, and its occurrence is associated with limiting symptoms and increased morbidity from CHF (a threefold increase) and stroke (an 8- to10-fold increase) and an almost quadrupled mortality rate. A genetic predisposition to AF is seen in some forms of hypertrophic cardiomyopathy: an Arg663His mutation in the β-cardiac myosin heavy chain gene has been identified in patients with a specific phenotype of familial hypertrophic cardiomyopathy presenting with moderate septal left ventricular hypertrophy, predominantly localized in the proximal segment of the interventricular septum, and a 47% prevalence of AF.³⁵

Dilated cardiomyopathy (DCM) can promote AF via the same mechanisms as CHF of ischemic etiology; that is, atrial overload, stretch, and fibrosis. Some types of mutations in the lamin A/C gene linked to DCM have also been shown to be associated with increased risk of progressive conduction system disease, atrial myopathy, and AF.³⁶

Pre-excitation Syndrome

AF is found in 30% of patients with Wolff-Parkinson-White (WPW) syndrome and is associated with increased risk of sudden cardiac death (SCD).³⁷ Unlike the atrioventricular (AV) node, accessory pathways usually exhibit rapid, nondecremental conduction, and if the effective refractory period of an accessory pathway is short (<250 ms), this may result in a rapid ventricular response during AF, with subsequent degeneration to ventricular fibrillation (VF). In some patients with an accessory pathway or a dual AV node, AV re-entrant tachycardia (AVRT) and AV node re-entrant tachycardia (AVNRT) can trigger AF.

Thyrotoxicosis

Thyrotoxicosis has a classic, but relatively minor, association with AF, whereas latent hyperthyroidism, which has been shown to be associated with an almost threefold increase in the age-adjusted incidence of AF in the Framingham Heart Study, is likely to have a greater impact in the general population.³⁸ In the prospective population-based Rotterdam Study in older individuals, free thyroxine levels within the normal range showed a graded association with risk of AF (HR for highest vs. lowest quartile, 1.62).³⁹ Convincing evidence that hypothyroidism may increase risk of AF does not exist.⁶

Smoking

Smoking as a risk factor has been debated, but recent analyses from the Atherosclerosis Risk in Communities (ARIC) and the Rotterdam studies have provided evidence linking smoking to the risk of AF in the general population, with a hazard ratio of 1.51 to 2.05 in current smokers and 1.32 to 1.49 in former smokers.^40,41 In the highest tertile of accumulated smoking amount (>675 cigarette-years), the incidence of AF was 2.1 times greater than in those who never smoked.

Alcohol

High alcohol intake has been consistently associated with risk of AF, but the effects of light or moderate consumption are less clear, and some have suggested a neutral or even protective effect. A recent systematic review has reported a monotonic dose-response causal relationship between alcohol and onset of AF.⁴² Compared with nondrinkers, individuals consuming 24, 60, and 120 g of alcohol daily had relative risk of 1.08, 1.44, and 2.09, respectively (men), and 1.07, 1.42, and 2.02, respectively (women). Recent meta-analysis of 14 studies has shown that for each 10-mg increase per day in alcohol intake, the risk of AF increased by 1.08 (95% CI, 1.05 to 1.10; P < .001).⁴³

Caffeine

In addition to a series of case reports, recent analyses from the Framingham Heart Study, the Danish Diet, Cancer, and Health Study, and the Women’s Health Study found no association between caffeine intake and the incidence of AF.^44–46 In a canine model with enhanced AF inducibility caused by the stimulation of the ganglionated plexi, the presence of caffeine reduced the propensity for AF.⁴⁷ It is possible that excessive caffeine consumption may trigger AF in individuals with a predominantly adrenergically mediated mechanism of the arrhythmia, but this association could not be detected in the epidemiologic studies.

Postoperative Atrial Fibrillation

AF may occur in about 30% of patients after isolated coronary artery bypass grafting (CABG), 40% of patients after valve surgery, and 50% of patients after combined coronary artery and valvular surgery.⁴⁸ Most cases of AF occur during the first 3 to 4 days, and more than 90% have a paroxysmal form. Postoperative AF is associated with increased morbidity and mortality rates, largely because of stroke and circulatory failure and longer hospital stay. Atrial flutter (AFL) and atrial tachycardias (ATs), including multi-focal AT, are also common.

Risk factors include conventional clinical variables such as age, hypertension, left ventricular dysfunction, chronic obstructive pulmonary disease (COPD), renal impairment, and specific surgical aspects such as inadequate cardioprotection and hypothermia, right coronary artery grafting, and a longer bypass time.⁴⁹ The incidence of postoperative atrial tachyarrhythmias is lower with minimally invasive techniques.

Other Risk Factors

Pneumonia is a one of the reversible causes of AF, whereas COPD, which is observed in 10% to 15% of patients with AF, increases the propensity to AF, such as by inflammatory mechanisms; therefore it has been identified as a risk factor for AF, although its exact impact is unknown.⁵⁰ The presence of COPD can contribute to progression of AF to a more sustained form.⁵¹

Chronic renal dysfunction has recently been linked to increased risk of AF. In the ARIC study, reduced glomerular filtration rate (GFR), particularly in association with macroalbuminuria, increased risk of developing AF over 1 decade by 13-fold.⁵² In a population-based cohort of African-American and white American adults 45 years or older enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, individuals with chronic renal failure stage 1 to 2, 3, and 4 to 5 had the age-, race-, and gender-adjusted odds ratios for AF of 2.67, 1.68, and 3.52, respectively.⁵³

Congenital heart disease (particularly, atrial septal defect [ASD]) and pre-excitation syndrome caused by accessory pathways are also associated with AF. AT, “incisional” AFL, and AF may occur after surgical repair of congenital heart disease.

Emerging Risk Factors

New risk factors such as obesity (relative risk [RR], 1.2 to 2.3), metabolic syndrome, a prolonged P-R interval on an electrocardiogram (ECG) (RR, 1.2 to 2.7), P-wave duration (1.15 per standard deviation increase), sleep apnea (RR, 2.2 to 3), psychological stress and negative emotions, endurance athletic training (RR, 5.3), visceral adipose tissue (pericardial fat) detected by computer tomography (CT) (RR, 1.11 to 1.18), and tall stature (RR, 1.7 for height >180 cm) have all been reported in association with AF.⁵⁴ A series of biomarkers of inflammation and oxidative stress (cross-reactive protein, interleukin [IL]-6, intercellular adhesion molecule (ICAM)-1, tumor necrosis factor [TNF]-α), hemodynamic stress (atrial natriuretic and brain natriuretic peptides [ANP and BNP]), and cardiac damage (troponin) have emerged as predictors of incident AF.⁵⁴

Genetic Factors

Among many risk factors for AF, genetic predisposition to AF or specific genetically predetermined forms of the arrhythmia have also been identified. Among the participants in the Framingham Heart Study, a parental history of AF increased the risk of AF in the offspring by a factor of 1.4 after adjustment for AF risk factors and AF-related genetic variants (Figure 42-4).⁵⁵ Genetic variation may play even a greater role in the pathogenesis of lone AF (see below). AF in association with known genetic conditions such as Brugada syndrome and short QT interval syndrome is highly prevalent. The genetic substrate for AF ranges from a large kindred with monogenic forms of AF with rare genetic mutations and high penetrance to common genetic polymorphisms in a variety of different genes in general populations.

FIGURE 42-4 A, Incidence of atrial fibrillatin (AF) by the presence or absence of antecedent AF in a first-degree relative in the Framingham Heart Study. B, Incidence of AF ain monozygotic and dizygotic twins in the Danish Twin Study. CI, Confidence interval.

(From Lubitz SA, Yin X, Fontes JD, et al: Association between familial atrial fibrillation and risk of new-onset atrial fibrillation, JAMA 304:2263–2269; and Christophersen IE, Ravn LS, Budtz-Joergensen E, et al: Familial aggregation of atrial fibrillation: a study in Danish twins, Circ Arrhythm Electrophysiol 2:378–383, 2009.)

Monogenic mutations associated with AF have been described in the number of genes encoding several potassium channels (e.g., KCNQ1 and KCNE2, which encode α- and β-subunits, respectively, of the I_Ks channel; KCNA5 and KCNJ2, encoding Kv1.5 and Kir 2.1 channels underlying the I_Kur and I_K1 currents, respectively), and α- and β-subunits of the sodium channels (SCN5A and SCN1/2B) as well as a number of non–ion channel mutations in the nucleoporin gene (NUP155), connexin-40 gene (GJA5), and ANP gene.⁵⁶ However, monogenic forms of AF are rare and, at the population level, AF heritability is likely to be determined by aggregate effects of multiple common genetic variants interacting with environmental factors.

Population-based genome-wide association studies (GWASs) have identified a variety of single-nucleotide polymorphisms near the PITX2 (paired-like homeodomain 2) gene on chromosome 4q25 that almost double the susceptibility to AF in general populations of European and Asian descents.^57,58 Other common variants include ZFHX3 (zinc finger homeobox 3) on chromosome 16q22, and KCNN3 (a calcium-activated, small conductance potassium current, which is also involved in atrial repolarization) on chromosome 1p21.

However, the mechanism by which these genetic variations lead to AF remains unknown. The PITX2 gene encodes a transcription factor expressed in the heart and lungs and is critical for antenatal determination of right-left asymmetry, with one of its isoforms, PITX2C, being involved in the specification of the left atrium and pulmonary vein myocardium and suppression of a default program for sinoatrial node formation in the left atrium. Mutations in PITX2C may be associated with greater chances of ectopic foci occurring in the pulmonary veins triggering AF.

Lone Atrial Fibrillation

Idiopathic or lone AF constitutes approximately half the cases of paroxysmal AF and 20% of persistent AF, particularly in relatively young patients. However, when studied in detail, some may have evidence of inflammation and atrial myocarditis, mild diastolic ventricular dysfunction, subclinical thyroid disease, autoimmune disorders, or sinus node dysfunction. In other words, lone AF may be an indication that a structural defect has not yet manifested to a level that can be detected.

Lone AF poses a higher risk of heritability. Relatives of patients with lone AF are at a substantially increased risk of developing AF compared with the general population, suggesting a Mendelian genetic contribution to the etiology of this common trait. Analysis of the Danish Twin Study has revealed an increased risk of AF among monozygotic twins compared with dizygotic twins (22% vs. 12%), with the heritability of AF estimated at 62% (compared with 80% heritability of height and 35% heritability of the QT interval).^58,59

GWASs have linked an SNP in KCNN3 to a greater risk of lone AF with an odds ratio of 1.52.⁶⁰ The angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism was associated with electrical remodeling in patients with lone AF.⁶¹

Vagally Mediated and Adrenergically Mediated Atrial Fibrillation

The balance between sympathetic and vagal influences plays an important role both in the initiation and prediction of AF. Two types of autonomic-induced AF exist. Adrenergically mediated episodes of AF are typically triggered by exercise and emotional stress (Figure 42-5), commonly associated with polyuria, and occur mainly during the day. Vagally mediated AF is characterized by male predominance, younger age, minimal tendency to progress to permanent AF, and onset at rest or at night. Episodes of vagal AF are typically preceded by progressive bradycardia. β-Blockers are treatment of choice in AF with a predominant adrenergic component but may worsen symptoms in patients with vagally mediated AF.

FIGURE 42-5 A, Prevalence of different types of autonomic trigger patterns in 1517 patients with paroxysmal atrial fibrillation in the European Survey on Atrial Fibrillation. B, An electrocardiogram and a heart rate histogram demonstrating onset of exercise-induced atrial fibrillation preceded by frequent atrial premature beats (arrows) and runs of atrial tachycardia in a 45-year-old man without any structural heart disease. The exercise test was terminated once atrial fibrillation occurred. Note spontaneous termination and recurrence of brief episodes of atrial fibrillation in the recovery phase. Stable sinus rhythm was restored after 32 minutes. HR, Heart rate.

(From De Vos CB, Nieuwlaat R, Crijns HJ, et al: Autonomic trigger patterns and anti-arrhythmic treatment of paroxysmal atrial fibrillation: Data from the Euro Heart Survey, Eur Heart J 29:632–639, 2008.)

However, patients who can be classified in terms of sympathetic or adrenergic forms of AF typically represent the extreme of either sympathetic or parasympathetic influence, and the overall prevalence of typical vagally or adrenergically mediated AF is relatively low. In 1517 patients with paroxysmal AF included in the Euro Heart Survey, vagally mediated AF was found in 6% and adrenergically mediated AF was found in 15%.⁶²

Stroke

The presence of AF has been estimated to increase the risk of stroke by about fivefold.⁷¹ Whereas the effects of hypertension, CAD, and CHF on the risk of stroke become progressively weaker with advancing age, the impact of AF remains significant. In the Framingham Study, the annual risk of stroke attributable to AF among patients aged 50 to 59 years is 1.5% and increases to 23.5% in those older than 80 years.⁷¹ Approximately 15% of neurologically asymptomatic patients enrolled in the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation (SPINAF) study had evidence of one or more previously undiagnosed cerebral infarcts on CT images of the brain.⁷² The risk is considerably higher in patients with previous stroke or TIA.

Strokes associated with AF are usually more severe and confer a high risk of subsequent morbidity, mortality, and poor functional outcome independent of the underlying heart disease. Risk of recurrent stroke is high, particularly within the first year, because of hemostatic abnormalities following the index event. The report from the Framingham Study has revealed that stroke associated with AF was nearly twice as likely to be fatal, and functional deficits were more likely to be severe among survivors.⁷³ Nearly three quarters of stroke victims with AF were severely dependent in activities of daily living (ADLs) compared with about one third of their counterparts with sinus rhythm.

Dementia

Dementia as a consequence of AF has been only recently recognized. Evidence from the large ongoing prospective Intermountain Heart Collaborative Study database, AF was independently associated with all dementia types, and the risk was the highest in the younger group (<70 years), with an HR of 2.2 for vascular dementia, 3.34 for senile dementia, and 2.3 for Alzheimer disease after adjustment for age and comorbidities.⁷⁴ According to data from the Olmsted County, Minnesota, in patients with a mean age of 71 years, the rate of dementia associated with AF was 2.7% at 1 year and 10.5% at 5 years.⁷⁵ The diagnosis of dementia in the presence of AF was associated with a marked increased risk of subsequent mortality by factor of 3.49 in men and 3 in women.

In patients with hypertension and underlying microvascular dysfunction and patients with impaired left ventricular systolic function and CHF, the occurrence of AF may predispose to further impairment of cerebral perfusion and earlier manifestation of dementia. Multiple silent cerebral infarctions, subclinical strokes, and TIAs, as well as microbleeds resulting from the combination of suboptimal blood pressure control and anticoagulation, can be found in a significant proportion of patients with AF and may underlie the early cognitive decline. Other mechanisms operating in AF such as inflammation and endothelial dysfunction are possible contributors.

Tachycardia-Induced Cardiomyopathy

AF may compromise left ventricular systolic function and worsen CHF because of fast, uncontrolled ventricular rates, irregularity of ventricular response, and loss of atrial systolic input. Loss of AV synchrony is associated with impaired diastolic filling, reduced stroke volume, and elevated diastolic atrial pressure, resulting in an approximately 20% reduction in cardiac output.²² An irregular ventricular response further decreases cardiac output and increases right atrial pressure and pulmonary capillary wedge pressure independent of rate. Increased adrenergic stimulation to maintain adequate cardiac output in the setting of heart failure will facilitate AV conduction and favor the progression of cardiomyopathy. AF has been reported to confer a threefold risk of worsening CHF.⁷⁶ In patients with CHF secondary to diastolic dysfunction, the occurrence of AF may be particularly hazardous.

Less commonly, AF with fast, uncontrolled ventricular rates may cause symptomatic left ventricular dysfunction in patients with no or minimal structural heart disease. Such ventricular dysfunction associated with significant heart dilatation and symptoms of heart failure is termed tachycardia-induced cardiomyopathy. It is usually applied to persistent forms of the arrhythmia, and it is generally accepted that sustained ventricular rates of above 120 beats/min may pose a risk but may also occur in individuals with frequent paroxysms, in whom rate control is difficult. Tachycardia-induced cardiomyopathy may reverse completely after sinus rhythm is restored or adequate ventricular rate control is achieved either by pharmacologic or nonpharmacologic means (Figures 42-8 and 42-9).

FIGURE 42-8 Reversal of cardiac enlargement on chest radiographs 3 months after restoration of sinus rhythm.

FIGURE 42-9 Improvement of left ventricular function after rate control and pharmacologic or electrical cardioversion (A), atrioventricular nodal ablation or modification (B), and pulmonary vein isolation/left atrial ablation in the setting of heart failure (C). Asterisks note patients with significantly decreased left ventricular function at baseline.

Hospitalizations

According to some surveys, the number of AF-related hospitalizations almost tripled in 2000 compared with the previous 2 decades and continues to grow, probably because of an increasing proportion of the population surviving to very old age with greatly improved health care. Patients with AF can be admitted for treatment of AF (e.g., cardioversion, initiation of antiarrhythmic drug therapy, or ablation) and cardiovascular adverse events (e.g., proarrhythmia, progression of heart failure, stroke, or MI) or noncardiac causes. Analysis from the Atrial Fibrillation Follow up Investigation of Rhythm Management (AFFIRM) trial has linked cardiovascular hospitalization with increased risk of subsequent death.⁷⁷ The association between cardiovascular hospitalization and adverse outcome has also been reported in the Stockholm Cohort Study of Atrial Fibrillation, which showed that individuals who spent more than 2% of their follow-up period in the hospital with a cardiovascular diagnosis had a significantly higher mortality rate than those who had spent less time in the hospital (36 vs. 8.2 deaths per 100 patient-years).⁷⁸ Time in-hospital greater than 2% increased the risk of subsequent death by a factor of 2.5, and rehospitalization for cardiovascular reason within 3 months increased the risk of death by a factor of 1.4 in the early cohort and 2.43 in the later cohort, for which a better account of therapy was available.

Quality of Life

Patients with AF generally have impaired quality of life compared with healthy control subjects—matched samples from the general population or patients with stable CAD—and is similar on most scales to health impairment seen in patients with MI or CHF and more significant structural heart disease.⁷⁹ The degree of reported reductions in quality of life is determined by the form of AF and the presence of other diseases that may affect the individual perception of health. Thus patients with multiple comorbidities are more likely to report poorer quality of life compared with patients with established AF and those with less significant underlying heart disease. Paroxysmal AF is usually symptomatic and is associated with impaired quality of life. Patients with this variety report better quality of life and had significantly higher scores in physical functioning, vitality, mental health, and emotional health when they perceive themselves to be in sinus rhythm.⁸⁰ Women are more likely to report poor quality of life compared with men, despite comparable severity of underlying pathology. Even patients with asymptomatic AF report a significantly poorer perception of general health and decreased global life satisfaction compared with their healthy counterparts, despite similar scores on all other scales.⁸¹

Both antiarrhythmic drug therapy and ablation-based therapies have been shown to render a significant proportion of AF asymptomatic, which may result in improvement in quality of life. Of interest, when quality of life was compared in patients with AF who were randomly assigned to AV node ablation or AV node modification, ablation was shown to result in a greater improvement in quality of life and reduction of symptoms compared with modification, probably because of better control of the rate and regularity of ventricular response after abolishing fibrillatory conduction to the ventricles.⁸² Recently, several AF-specific quality of life questionnaires have been proposed, but all require validation.^83,84

Silent Atrial Fibrillation

AF is typically associated with a variety of symptoms: palpitations, dyspnea, chest discomfort, fatigue, dizziness, and syncope (Figure 42-10).⁸⁵ The paroxysmal forms are more likely to be symptomatic and frequently present with specific symptoms, whereas the permanent forms are usually associated with less-specific symptoms. However, a substantial proportion of patients may not experience any symptoms or these symptoms may be subtle and may not be reported.

FIGURE 42-10 Distribution of symptoms in different forms of atrial fibrillation.

(Modified from Lévy S, Maarek M, Coumel P, et al, on behalf of the College of French Cardiologists: Characterization of different subsets of atrial fibrillation in general practice in France: The ALFA Study, Circulation 99:3028–3035, 1999.)

The prevalence of sustained silent AF found incidentally during routine physical examinations, preoperative assessments, occupation assessments, or population surveys is believed to be 25% to 30%, but modern implantable rhythm control devices such as pacemakers and implantable cardioverter defibrillators (ICDs) have revealed that up to 50% to 60% may have unsuspected episodes of the arrhythmia, with almost half of these lasting more than 48 hours.^8,86 Patients with unrecognized AF do not receive appropriate preventive therapy and are at greater risk of stroke or, in the case of persistent rapid ventricular rates, tachycardia-induced cardiomyopathy. For example, AF may be found incidentally in about 20% to 25% of admissions for stroke.

Studies that used regular ECG monitoring have demonstrated that up to 90% of recurrences may go unreported by patients but can only be detected by daily transtelephonic ECG transmission (Figure 42-11).⁸⁷ The clinical significance of very short paroxysms of AF, which are difficult to detect by conventional methods of rhythm monitoring but can be logged by implantable device diagnostics, has recently been demonstrated in the The Relationship Between Daily Atrial Tachyarrhythmia Burden from Implantable Device Diagnostics and Stroke Risk (TRENDS) study in patients treated with a pacemaker for sinus node dysfunction.^88,89 AF burden of 5.5 hours or greater on any of 30 prior days doubled the risk of a thromboembolic event.

FIGURE 42-11 A, Diagnostic yield of different methods for monitoring of atrial fibrillation. B, An example of a fast atrial rate episode logged in pacemaker diagnostics in a patient without a history of atrial tachyarrhythmias. ECG, Electrocardiogram.

(From Arya A, Piorkowski C, Sommer P, et al: Clinical implications of various follow up strategies after catheter ablation of atrial fibrillation, Pacing Clin Electrophysiol 30:458–462, 2007.)

Furthermore, an exact definition of “asymptomatic” AF does not exist. A patient may claim to have no symptoms but report feeling much better after cardioversion. Studies have also shown that quality of life is reduced even when a patient is classified as asymptomatic.⁸¹ Level of acceptable symptoms may also vary according to age and comorbidities.

Mortality

Association of AF with death has been demonstrated in epidemiologic studies. Data from the Framingham Study suggest that the risk of death conferred by AF is nearly doubled even in the absence of identifiable structural heart disease.⁹⁰ The risk of death associated with AF is significantly higher in women than in men (OR, 1.9 vs. 1.5). Data from other epidemiologic studies are convincing (Table 42-3). AF is an independent predictor of death in patients with a range of cardiovascular pathologies: CHF, hypertension, MI with left ventricular dysfunction, and ACS. AF increases cause-specific mortality: SCD, death from heart failure, and fatal strokes. A mechanistic basis for the link between AF and each of the components of total mortality does exist (Figure 42-12). Although the exact mechanism by which AF can increase the risk of SCD in the general AF population (apart from rare cases of SCD in WPW syndrome) has not been well established, proarrhythmia from antiarrhythmic drugs and ischemia-induced VT and VF, particularly in patients with severe underlying disease, are plausible explanations.

FIGURE 42-12 Cause-specific morbidity and mortality in patients with atrial fibrillation and hypertension with left ventricular hypertrophy in the Losartan Intervention for End Point Reduction in Hypertension study.

(From Wachtell K, Hornestam B, Lehto M, et al: Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation: The Losartan Intervention for End Point Reduction in Hypertension (LIFE) study, J Am Coll Cardiol 45:705–711, 2005.)

Current data do not offer a definitive answer whether AF truly is an independent risk factor for death or whether it is a marker indicating a sicker patient. However, even lone AF has been reported to entail 4.2-fold increase in all-cause mortality and an almost twofold increase in cardiovascular mortality, including SCD, in the Paris Prospective Study.⁹¹

Costs

The high lifetime risk for AF and increased longevity underscore the important public health burden imposed by AF across the world. The majority of AF expenditure constitutes hospital charges for frequent and often prolonged admissions for AF and particularly its costly complications such as stroke and heart failure. In addition, the cost of caring for patients with other cardiovascular pathologies is significantly higher in the presence of AF. The cost of caring for patients with AF also continues to be significantly higher during the 2 to 3 years after initial hospitalization. The arrhythmia costs of the health care budget in the United Kingdom and has almost doubled (0.9% to 2.4%) over the past 5 years.⁹² Direct cost estimates ranged from $2000 to $14,200 per patient-year in the United States and from to in Europe.⁹² Inpatient care accounts for 50% to 70% of the annual direct costs.

Based on data from the retrospective analysis of three federally funded databases in the United States in 2001, total annual costs for treatment of AF were estimated at $6.65 billion, including $2.93 billion (44%) for hospitalizations for AF, $1.95 billion (29%) for the incremental inpatient cost of AF as a comorbid diagnosis, $1.53 billion (23%) for outpatient treatment of AF, and $235 million (4%) for prescription drugs.⁹³

Epidemiology

Data on the prevalence and incidence of AFL in the general population are limited. The report from the Marshfield Epidemiologic Study Area (MESA), based on a selected sample of 58,820 residents served by the Marshfield Clinic in Wisconsin, suggests that the incidence of AFL is 0.88 per 1000 person-years, but this figure includes 58% of individuals in whom both AFL and AF have been diagnosed.⁹⁴ As a sole arrhythmia, the incidence of AFL is relatively low and clearly stands at less than 1%.

Like that of AF, the incidence of AFL increases markedly with age, from 5 per 100,000 of individuals younger than 50 years to 587 per 100,000 in those older than 80 years. Similar to AF, which is more common in men, AFL is observed 2.5 times more frequently in men than in women (6.06 vs. 2.65 per 100,000 persons aged 70 to 79 years and 9.16 vs. 4.12 per 100,000 persons older than 80 years).

Associated Disease and Prognosis

AFL is commonly associated with organic heart disease (see Figure 42-2). In the MESA population, nearly all cases of AFL were linked to comorbid conditions such as CHF, hypertension, and COPD or occurred in association with a specific precipitating event (i.e., major surgery, pneumonia, or acute MI).⁹⁴ Only 1.7% of cases had no structural cardiac disease or precipitating causes (lone AFL).

AFL and AF share similar risk factors and have the same risk of CHF and thromboembolism in the presence of risk factors for stroke. Similar to AF, AFL is associated with an increase in mortality rate by a factor of 1.7 as a sole arrhythmia and a factor of 2.5 if it coexists with AF (Figure 42-13).⁹⁵

FIGURE 42-13 Kaplan-Meier curves of survival in patients with atrial tachyarrhythmias.

(From Vidaillet H, Granada JF, Chyou PH, et al: A population-based study on mortality among patients with atrial fibrillation or flutter, Am J Med 113:365–370, 2002.)

Interrelationship

Typical AFL is a classic macro–re-entrant arrhythmia that develops from a functional conduction block at the cavotricuspid isthmus.⁹⁶ This mechanism of initiation and maintenance is markedly different from AF, and typical AFL can be cured relatively easily by ablation. Furthermore, AFL and AF respond differently to antiarrhythmic drugs. In this respect, patients with AFL should be distinguished from patients with AF.

However, the close clinical interrelationship between AF and AFL should not be disregarded. In many instances, AFL is preceded by a transitional rhythm in the form of AF of variable duration, which facilitates the occurrence of a functional block between the venae cavae necessary for the maintenance of the AFL macro–re-entrant circuit. Conversely, clinical and experimental studies in postoperative AF and in the canine sterile pericarditis model have demonstrated that a very fast AFL may lead to AF.⁹⁶

The close interrelationship between AF and AFL is reflected in the high prevalence of patients in whom both arrhythmias coexist and the significant proportion of patients (30% to 70%) who develop AF after successful ablation of the cavotricuspid isthmus for AFL, even if AF has never been documented before ablation. In a recent meta-analysis of long-term outcomes of ablation for typical AFL (158 studies, 10,719 patients), the overall incidence of AF was 33.6% during an average follow-up of 15 months; AF occurred in 23.1% of patients with no history of AF and in 52.7% of patients with a history of AF before ablation.⁹⁷ Such a high proportion of patients developing AF within a relatively short time after ablation suggests that AFL may be an early marker of atrial remodeling that forms a substrate for AF. In contrast, antiarrhythmic drugs with sodium channel–blocking properties, such as class IC agents and amiodarone, which slow conduction in the atria, can convert AF into AFL, probably by facilitating the formation of functional block in the right atrium. Ablation of the cavotricuspid isthmus has been effectively used in such patients to prevent the recurrence of AF.

Right Atrium

The dominant feature of this chamber is the large, triangular shaped appendage, which is located anterolaterally (Figures 42-14 and 42-15). Usually, a fat-filled groove, corresponding internally to the terminal crest (crista terminalis), can be seen along the lateral wall. The sinus node is located subepicardially in this groove, close to the superior cavoatrial junction (see Figure 42-15). In most individuals, the node is located anterolaterally in a tadpole shape with the head nearest the junction and the tail penetrating into the musculature of the terminal crest.¹⁰⁵ In approximately 10%, the node is horseshoe shaped and located mediolaterally in the terminal groove.¹⁰⁶ Right atrial musculature often extends superiorly over the wall of the superior vena cava (SVC), unlike inferiorly where atrial muscle fades out or terminates close to the entrance of the inferior vena cava (IVC). Prongs of sinus node tissues often interdigitate with the musculature of the terminal crest and may even extend into the muscular sleeves that surround the SVC (see Figure 42-15).^105,107 The tail portion often fragments into clusters of specialized cells toward the middle or even lower portions of the terminal crest. The prongs and the clusters may have some role in focal atrial tachycardia (AT).

FIGURE 42-14 A, This heart viewed from the right side shows the triangular-shaped appendage of the right atrium. B, An incision parallel to the atrioventricular junction has been made in the right atrial appendage and its parietal wall reflected posteriorly so that the atrial septum is seen en face as if in right anterior oblique (RAO) projection. The parietal wall displays the thin atrial wall between the pectinate muscles that arise from the terminal crest (broken line). The oval fossa is surrounded by a muscular rim. The eustachian valve (EV) guards the orifice of the inferior vena cava. cs, Coronary sinus orifice; IVC, inferior vena cava; SVC, superior vena cava; TV, tricuspid valve.

FIGURE 42-15 This heart viewed from the front shows the myocardial sleeve extending over the outer surface of the superior vena cava (SVC). The distal margin of the sleeve is irregular (white dots). The red dotted line marks the location of the sinus node and the short dotted lines represent prongs of nodal tissues. RA, Right atrial appendage.

The terminal crest demarcates the junction between the rough-walled atrial appendage and the smooth-walled venous (intercaval) appendage on the endocardial surface. Most commonly it is ridgelike and composed of myocardial strands that are aligned longitudinally.¹⁰⁸ An extensive array of pectinate muscles arise nearly perpendicularly from the terminal crest to spread throughout the entire wall of the appendage, reaching to the lateral and inferior walls of the atrium (see Figure 42-14) to the atrial vestibule that separates the appendage from the tricuspid annulus. The pectinate muscles branch into fine and interconnecting muscle bundles. In between the bundles, the wall of the appendage is very thin, almost parchment-like in some cases. Potentially, this arrangement may play a role in initiating intra-atrial re-entry.

The atrial vestibule is the smooth muscular rim that surrounds the tricuspid orifice (see Figure 42-14, B) and the short extensions of its musculature inserting into the atrial surface of the leaflets. Importantly, the inferior to inferolateral segment of the right atrial vestibule, as viewed in left anterior oblique projection, is the anterior part of the cavotricuspid isthmus, the isthmus that is targeted as the zone of slow conduction in common AFL.^109,110 The posterior part of the isthmus contains the terminal ramifications from the terminal crest as it approaches the orifice of the IVC (Figure 42-16).¹⁰⁹ While the anterior part of the isthmus is always muscular, being the atrial vestibule, the middle and posterior parts are highly variable in topography and wall thickness.^111,112 The posterior part adjoining the eustachian valve tends to be composed of fibrous tissues, but the middle part contains variable extents and thicknesses of criss-crossing muscle bundles separated by thin membranous tissue (Figure 42-17). A pouchlike recess, the sub-eustachian sinus, is common and is 5 mm or more deep in 20% of patients.¹¹³ The eustachian valve, which guards the entrance of the IVC, is variably developed. Usually, it is a triangular flap of fibrous or fibromuscular tissue that inserts medially to the eustachian ridge, or the sinus septum, which is the border between the fossa ovalis and the coronary sinus. The free border of the eustachian valve continues as a tendon of Todaro, which runs in the musculature of the sinus septum.¹¹⁴ It is the posterior border of the triangle (of Koch) that delineates the location of the AV node (see Figure 42-16).^115,116 The anterior border is marked by the hinge line of the septal leaflet of the tricuspid valve. Superiorly, the central fibrous body is the landmark for the penetrating bundle of His. Thus the inferior border of the triangle is the orifice of the coronary sinus, together with the vestibule immediately anterior to it. This vestibular portion, also known as the septal isthmus or, more accurately, the paraseptal isthmus (see Figure 42-17), is the area often targeted for ablation of the slow pathway in AVNRT. Although the body of the compact node is located toward the apex of Koch’s triangle, it sends two prongs inferiorly toward the mitral and tricuspid orifices. The rightward extensions have been implicated in this arrhythmia.¹¹⁷ This area also contains the zone of transitional cells that provides the inferior and posterior inputs to the compact node. The so-called fast pathway in AVNRT corresponds to the area of musculature close to the apex of the triangle of Koch. The superior zone of transitional cells and myocardial strands from the anterior limbic band of the fossa ovalis sweep into this area overlying the body of the compact node.

FIGURE 42-16 The endocardium of the right atrium has been removed to display the arrangement of the myocardial strands in the atrial wall. The triangle of Koch is revealed. The orange shape denotes the compact atrioventricular node and its inferior extensions while the bold broken line represents the continuation of the atrioventricular conduction axis. The zone of transitional cells (short orange lines) feeds into the compact node from inferiorly, posteriorly, and superiorly. The asterisk denotes the sub-eustachian sinus. cs, Coronary sinus orifice.

FIGURE 42-17 A, This dissection of the right atrium displays the three isthmuses in the cavotricuspid area. The portion of the isthmus between the coronary sinus (cs) and the tricuspid valve (TV) is the paraseptal isthmus (1). It is the shortest of the three but is nearest to the compact atrioventricular node. The inferior isthmus (2) often includes the pouchlike sub-eustachian sinus (white arrow). The inferolateral isthmus (3) is the longest and passes through some of the distal pectinate muscles arising from the terminal crest. B, The endocardium has been removed to show the morphologic components of the three isthmuses (1, 2, 3). In this heart, the posterior half of the inferior isthmus (2) is mainly a thin fibrous wall, practically devoid of myocardium. EV, Eustachian valve; ICV, inferior vena cava; SCV, superior vena cava.

Left Atrium

Although the left atrium has similar component parts as the right atrium, its fingerlike appendage is distinctive. It can have a variable number of lobes, bends, or branches, but characteristically, the appendage is a cul-de-sac with a narrow opening to the rest of the chamber (Figure 42-18).¹¹⁸ In contrast to the right atrium, no terminal crest or sinus node is present in the left atrium. The so-called ridge (crest) on the endocardial surface between the left atrial appendage (LAA) and the left superior pulmonary vein is an infolding of the atrial wall (Figure 42-19) that contains the remnant of the vein of Marshall and neural elements on the epicardial side. Nearly all the pectinate muscles in the left atrium are confined within the appendage. They form a complicated network lining the endocardial surface. The major part of the atrium, including the septal component, is smooth walled. The smoothest parts are the walls forming the atrial body, the superior and posterior walls that make up the large pulmonary venous component, and the vestibule that is the atrial outlet. Like the right vestibule, the left atrial vestibule also extends a very short distance over the atrial surface of the mitral leaflets. Although appearing fairly uniform, the atrial walls are composed of three or more overlapping “layers” of differently aligned myocardial strands.^98,119,120 The “layers” are not insulated by fibrous tissue sheaths, but abrupt changes in orientations may account for the unusual patterns of conduction.¹²¹ Marked regional variations in thickness are also present.^122,123 A small area of the anterior wall just behind the aorta is usually thin, whereas the superior wall, or dome, is thicker but tends to thin out near the left pulmonary veins.

FIGURE 42-18 A, This heart viewed from the left displays a characteristic fingerlike left atrial appendage. B, Pectinate muscles line the endocardial surface of the appendage. The appendage communicates with the body of the atrium through a narrow orifice (asterisk). LI, Left inferior; LS, left superior pulmonary vein.

FIGURE 42-19 A, The so-called ridge (R) lies between the orifice of the left superior (LS) pulmonary vein and the left atrial appendage (LAA). B, The ridge, when transected, reveals it is an infolding of the atrial wall. MV, Mitral valve.

The transition between the atrium and the vein is smooth. The musculature of the atrial wall extends to varying lengths onto the outside of the venous walls, with the longest sleeves along the upper veins (Figure 42-20).^119,124,125 The right lower veins tend to have the shortest extensions or none at all. The sleeves closest to the venous insertions are thicker and more complete around the vein. Nerve bundles and ganglionated plexi are abundant at the venoatrial junctions and the adjoining walls.^126,127 The margins of the sleeves become thinner and irregular toward the lung hila. Pathologic studies have been inconclusive regarding the role of these myocardial sleeves in triggering AT and AF because they are found in asymptomatic adults as well as in patients with atrial arrhythmias. Like the myocardium of the atrial body, the sleeves also undergo aging changes. Islands of viable myocytes among fibrotic areas are often found (see Figure 42-20).¹²⁵ Myocyte hypertrophy, fibrosis, and sleeve discontinuity are more frequently seen in tissues from patients with AF.¹²⁸ Other studies have shown mainly circularly orientated myocardial fibers with interdigitating longitudinally and obliquely orientated fibers in the sleeves.^101,124 These may set the scene for micro–re-entry.¹²⁹

FIGURE 42-20 A, This right superior pulmonary vein has muscular extensions over its outer surface. Arrows indicate the irregular distal margins and the broken line marks the area of the venoatrial junction. B, This histologic section shows myocardium stained in red and fibrous tissue stained in green. Nerves branches are present at the venoatrial junction (open arrow). The muscular sleeve fades out toward the lung hilum. The enlargement (inset) shows an area of interruption in the sleeve (asterisk) and islands of myocytes amongst fibrous tissue (arrows).

Although nodelike cells have been described in murine models, they have never been found human tissues until in the study by Perez-Lugones and colleagues, but controversy remains.^{124,125,130–132} Recently, interstitial cells of Cajal, previously identified as capable of providing pacemaker activity in the gut, were described for the first time in human atrial myocardium. They were found in higher density in the myocardial sleeves of pulmonary veins from patients with AF.^133–135

Atrial Septum and Inter-atrial Connections

Viewed from the right atrium, the endocardial aspect of the true septum is confined to the valve of the fossa ovalis and the raised muscular rim (limbus) that is immediately around it (see Figure 42-14, B). The rim is an infolding of the right atrial wall harboring on its epicardial surface the fatty tissues of the inter-atrial groove. Although belonging to the right atrium, the leftward part of the muscular fold apposing the valve of the fossa continues into the musculature of the left atrial wall. The left atrial aspect of the septum is the valve itself. In most adult hearts, the fossa valve is thin, ranging from 0.4 mm to 3.4 mm. It usually is composed of two myocardial layers separated by fibrous tissue and sandwiched by fatty tissue beneath the endocardial surfaces.^136,137 This arrangement may explain asynchronous and discordant activation of the right and left septal surfaces, as observed by Lemery and colleagues, and may participate in the left septal flutter circuit, as reported by Marrouche and colleagues.^138,139

Muscular continuity between the atria peripheral to the septum is frequently found as bridges in the subepicardium.^101,102,136 In the majority of hearts, the most prominent inter-atrial bridge is Bachmann’s bundle (Fig. 42-21, A). This is a broad muscular band that runs in the subepicardium connecting the anterior right atrial wall of the superior cavoatrial junction with the anterior wall of the left atrium. The myocardial strands in Bachmann’s bundle, as in the terminal crest, are well aligned. The posterior and inferior bridges joining the left atrium to the intercaval area on the right provide the potential for posterior breakthrough of sinus impulse (see Figure 42-21, B).¹³⁹ In one third of hearts, the inferior inter-atrial connection is thicker or as thick as Bachmann’s bundle.¹³⁶ Multiple smaller inter-atrial bridges are frequently present, giving the potential for macro–re-entry. Some connect the muscular sleeves of the right pulmonary veins to the right atrium, and some connect the SVC to the left atrium.^101,120 Inferiorly, further muscular bridges from the left atrial wall often overlie and run into the wall of the coronary sinus.¹²⁰ Fine bridges connecting the remnant of the vein of Marshall to the left atrium have also been demonstrated.¹⁴⁰

FIGURE 42-21 A, The aorta has been pulled forward and the tips of the right and left atrial appendages (RAA, LAA) have been deflected to show the anterior aspect of the atria. Bachmann’s bundle crosses the interatrial groove (arrow) and has mainly parallel alignment with the myocardial strands. B, This heart viewed from the right and inferior aspect has been dissected to reveal a broad band of muscle (open triangle) crossing the interatrial groove (arrow), and smaller interatrial bridges (asterisks). cs, Coronary sinus; IVC, inferior vena cava; LS, left superior; RI, right inferior; RS, right superior pulmonary vein; SVC, superior vena cava.

Pathologic Substrates

In assessing pathologic changes in the myocardium for atrial arrhythmia, consideration must be given to changes associated with normal aging. Further compounding the issue are well-recognized conditions in older adults, such as senile amyloidosis, sick sinus syndrome, CAD, hypertensive heart disease, CHF, which can affect the myocardium as well as conduction tissues. Increased connective tissue, fibro-fatty changes, myocyte degeneration in the myocardium, and fibro-fatty degeneration or fibrosis of the conduction tissues are common. In patients with arrhythmias, some investigators reported increased interstitial fibrosis, myocyte myolysis, and inflammatory infiltrates in AF.^141–144 In addition, recent microinfarcts are more often found in prominent muscle bundles such as the terminal crest and Bachmann’s bundle of AF patients, which suggests that atrial MI may be more common than previously thought.¹⁴⁵

Patients with congenital heart disease are prone to developing arrhythmias as part of the natural history of longstanding hemodynamic alterations. Factors implicated include chronic volume overload, pulmonary hypertension, and ventricular dysfunction. Atrial arrhythmias, AFL, and AF are common in patients who had previous surgical intervention in the atria for congenital heart defects (e.g., ASD), Mustard or Senning procedures for atrial re-direction, or the Fontan procedure. Atrial re-direction procedures for complete transposition of the great arteries require long incision lines and numerous suture lines that result in narrow channels of the myocardium being bounded by incisional scars, or a scar and a natural obstacle, setting the scene for re-entry. The older variants of the Fontan procedure did not exclude the right atrium from high systemic venous pressure. Consequently, the atrium becomes enlarged and hypertrophied. The surgical incisions and subsequent scarring contribute to arrhythmogenesis. Furthermore, in both atrial re-direction and Fontan procedures, suture lines close to the sinus node area risk compromising the sinus node or its blood supply.

Postoperative AF, AFL, or both are common complications following cardiac surgery for acquired heart disease or after thoracotomy. As yet, the pathologic substrates are unclear, but age-related structural changes in the atria, such as dilatation, fibrosis, and loss of conduction tissues, are among the contenders.

Atrial Flutter

AFL is more organized than AF, features a saw-toothed pattern of regular activation that is particularly apparent in leads II, III, and aVF, and does not have an isoelectric baseline between deflections. The rate is typically 240 to 300 beats/min. Major types of AFL include typical (isthmus dependent, clockwise, and counterclockwise AFL) and atypical (isthmus independent) AFL. In the presence of anatomically predetermined slow conduction in the crista terminalis, atrial stimuli wavefront creates unidirectional block in the isthmus and maintains the AFL re-entry circuit. In typical AFL (Figure 42-22) that rotates counterclockwise in the right atrium, the flutter waves are inverted in leads II, III, aVF, and V6 and upright in lead V1. Biphasic or negative deflections in V1 are less common. Leads I and aVL usually have low amplitude deflections.^146,147 When the activation sequence is reversed (clockwise rotation), the flutter waves may be upright in leads II, III, and aVF and inverted in lead V1. Wide negative deflections in lead V1 and a positive flutter wave in V6 are characteristic of clockwise rotation in the right atrium.^146,147 The flutter waves are positive in V6. The surface lead characteristics that differentiate clockwise and counterclockwise AFL are summarized in Table 42-4.

FIGURE 42-22 Twelve-lead electrocardiogram from a young athlete showing typical counterclockwise atrial flutter ay 300 beats/min with 3 : 1 atrioventricular block. Note the presence of left ventricular hypertrophy.

Table 42-4 Predominant Flutter Wave Morphology in Typical Clockwise and Counterclockwise Right Atrial Flutter

Counterclockwise Atrial Flutter

The silent isoelectric zone of the ECG that precedes the negative deflections in the inferior leads corresponds to activation of the low right atrium and isthmus between the tricuspid annulus and the IVC and precedes activation of the left atrium, which begins from the lower septum.^146–152 The left atrial activation sequence is the predominant determinant of the flutter wave morphology (Figure 42-23, A).

FIGURE 42-23 A, Typical counterclockwise atrial flutter. The F waves are negative in leads II, III, aVF, and V6 and positive in V1, corresponding to the wavefront traveling down the lateral wall of the right atrium, through the eustachian ridge, and up the interatrial septum. B, Reverse (clockwise) atrial flutter. Note the reverse polarity of the F waves: positive in leads I, II, III, avF, and V6 and biphasic in V1.

In typical counterclockwise right AFL, the left atrium is activated from both the inferior septum and the superior septum.¹⁴⁸ The posterior wall is activated preferentially from the inferior septum, and the anterior wall is activated from the superior septum. Activation of the lateral wall of the left atrium reflects variable inputs from both regions. Studies showed that left atrial activation coincided with the negative component in leads I, II, III, aVF, and V6 and the first flat or slowly rising component in V1. Activation of the lateral wall of the right atrium coincided with the positive deflections in leads I, V1, and V6 and the upstroke component in the inferior leads. The plateau duration in lead III correlated with the time required for conduction through the isthmus between the tricuspid annulus and the IVC.

In studies using body surface mapping with simultaneous endocardial mapping, the flutter wave cycle length could be divided into three time segments.¹⁵¹ Caudocranial activation of the right atrial septum occurred in conjunction with proximal-to-distal activation along the coronary sinus and corresponded to the initial segment of the flutter wave. Craniocaudal activation of the right atrial free wall occurred during the intermediate portion of the flutter wave, and activation of the lateral sub-eustachian isthmus occurred during the terminal flutter wave.

Difficulties with Electrocardiogram Interpretation

The interpretation of AFL morphologies depends on a sufficient degree of AV block to separate the flutter wave from ventricular activation and repolarization. Atypical forms of AFL with diverse flutter wave morphologies that do not have a standard nomenclature complicate ECG assessments. Sometimes, the flutter wave morphology is low in amplitude or may be obscured by ventricular repolarization when the ventricular response is rapid. ECGs of atypical right atrial macro–re-entrant circuits can be difficult to interpret.^152,153 Complex forms of left atrial macro–re-entry, which may resemble typical right AFL, tend to have predominantly positive flutter waves in V1.¹⁵⁴ Several types of atypical AFL were demonstrated, including AFL in the low right atrial free wall, AFL involving the high right atrium (SVC–atrial septum area), and AFL involving two or four pulmonary vein orifices, mitral annulus isthmus, and the fossa ovalis area.

Figure 42-24 was recorded from a patient who had undergone a Fontan operation to treat transposition of the great vessels. The patient developed AFL, which involved rotation around a scar on the lateral aspect of the right atrium.

FIGURE 42-24 Atrial flutter after a Fontan operation. Neither typical nor reverse typical pattern of atrial activation can be seen. It is “incisional” atrial flutter in which the wavefront circulates around the scar.

The differentiation of focal AT from AFL may also be confusing. When AFL is treated with antiarrhythmic drugs, the rate may decrease appreciably and overlap with the rate of focal AT that ranges from 130 to 240 beats/min (rarely 300 beats/min). The isoelectric segment is generally longer, but it may be difficult to distinguish from AFL if the rate is rapid.

Atrial Fibrillation

AF consists of rapid oscillations or fibrillatory waves that vary in size, shape, and timing (Figure 42-25). The ventricular response to AF depends on the electrophysiological properties of the AV node, the effects of drugs, and the balance between sympathetic and parasympathetic tones. The R-R intervals are irregular unless the patient has AV block or a paced rhythm. Paroxysmal AF appears to be highly dependent on initiation by atrial ectopy: 93% of spontaneous episodes of paroxysmal AF were triggered by atrial premature depolarizations, and 6.4% were preceded by typical AFL as documented by 12-lead Holter recordings.¹⁵² The morphology of the initiating P waves was used to estimate the origin of triggering events: 77.5% arose from the left atrium, 2% were of right atrial origin, and 13.5% were nonspecific. Generally, an increase was observed in the frequency of atrial ectopy in the 30 seconds that preceded the onset of AF. The beats that initiated AF had shorter coupling intervals than those that failed to initiate AF.¹⁵⁵ More than half the episodes were also preceded by cycle length variation with short-long sequences. Although there appeared to be qualitative differences in the homogeneity of right atrial activation in paroxysmal AF compared with chronic AF, no consistent ECG criteria have been developed to distinguish the standard 12-lead ECG morphology of chronic and paroxysmal AF.¹⁵⁶

FIGURE 42-25 Twelve-lead electrocardiogram of atrial fibrillation. Note the presence of fibrillatory f waves, better seen in lead V1, that substitute normal P-wave activity, and an irregular ventricular response.

Historical Aspects

In the late 1800s, AF was shown to be the mechanism underlying “delirium cordis,” in which the heart was noted to beat without any apparent regularity. With the subsequent development of electrocardiography and of methods to study cardiac electrophysiology, three basic theories about the mechanism of AF emerged.¹⁵⁷ These mechanisms are illustrated in Figure 42-26.

FIGURE 42-26 Theories of atrial fibrillation mechanisms in the early twentieth century.

Mines and Garrey observed the occurrence of regular re-entry and fibrillation in cardiac tissue preparations and considered AF to be caused by continuous irregular re-entrant activity occurring in a dyssynchronous fashion in various atrial regions (“multiple circuit re-entry”; see Figure 42-26, A). Garrey first put forward the idea that fibrillation requires a critical mass of tissue to support a sufficient number of irregular re-entrant wavefronts to maintain the arrhythmia.

Lewis believed that AF is caused by a single rapid macro–re-entry circuit (see Figure 42-26, B), with wavefronts emanating from the primary “driver” circuit breaking against regions of varying and greater refractoriness, producing “fibrillatory conduction” and the irregular global activity characterizing the arrhythmia.¹⁵⁸ Others held that AF is caused by very rapid activity, with either a single source giving rise to fibrillatory conduction (see Figure 42-26, C) or multiple ectopic foci producing fibrillation by virtue of dyssynchronous activity and colliding wavefronts. In the subsequent years, various lines of evidence pointed to the relevance of multiple circuit re-entry to clinical AF, and from then until relatively recently, multiple circuit re-entry (see Figure 42-26, A) was widely assumed to be the dominant mechanism underlying clinical AF.

Moe refined the concept of multiple circuit re-entry by suggesting that activity during AF need not involve complete re-entry circuits beginning and ending at the same location but, rather, simultaneous wavelets that either extinguish (not contributing to arrhythmia maintenance) or succeed in continuously encountering excitable tissue and maintaining the arrhythmia.¹⁵⁹ Moe viewed the maintenance of AF as a probabilistic function of tissue properties and size, with a minimum temporal density of re-entrant wavelets needed to sustain the arrhythmia.

Allessie subsequently added a quantitative element to Moe’s reasoning by emphasizing the importance of the wavelength (Figure 42-27). The wavelength (see Figure 42-27, A and B) is the distance traveled by a cardiac impulse during the refractory period (refractory period ± conduction speed) and indicates the shortest path length that can maintain re-entry. In circuits shorter than the wavelength, the head of the impulse will impinge on a still-refractory tail after one cycle, and the impulse will die out. According to Allessie’s “leading circle” concept of functional re-entry, functional re-entry circuits naturally form around a perimeter equal to the wavelength.¹⁶⁰ Allessie postulated that shorter wavelengths favor AF maintenance by increasing the number of simultaneous functional re-entrant circuits that the atria can accommodate (see Figure 42-27, C). A corollary of this notion is that multiple circuit re-entry AF can be terminated or prevented by increasing the refractory period and consequently the wavelength, thereby reducing the number of circuits possible and making AF maintenance less likely (see Figure 42-27, D).¹⁶¹ By contrast, factors that reduce the wavelength (such as short refractory periods and slow conduction) should favor AF.¹⁶² Atrial dilatation should also favor re-entry by increasing atrial size and thereby increasing the number of circuits that the atria can accommodate (see Figure 42-27, E).¹⁶³ Heterogeneity in refractory properties should favor AF by promoting the fractionation of impulses into multiple re-entrant wavefronts.

FIGURE 42-27 A, The role of the wavelength (WL) in determining minimum circuit size for re-entry and the size of functional re-entry circuits according to the leading circle concept. B, In atria of normal size with normal wavelength values, the atria cannot support multiple circuit re-entry; even if atrial fibrillation is induced, it usually stops spontaneously. C, If the wavelength is reduced (e.g., by vagal stimulation or electrical remodeling), enough circuits can be accommodated to maintain atrial fibrillation (AF) even in normal atria. D, Drugs that increase refractory period increase wavelength and circuit size, thereby making AF harder to sustain, promoting cardioversion and sinus rhythm maintenance. E, If the atria are enlarged and have short wavelengths, AF tends to be very stable and sinus rhythm very hard to produce and maintain.

In recent years, more sophisticated models of functional re-entry have been developed, such as the “spiral wave” model. A spiral wave involves continuous activity in a spiral pattern, somewhat like a hurricane. It differs from a leading circle in that the center of the spiral wave re-entry is excitable but not activated (like the eye of a hurricane), and the perpetuation of activity is determined by the angle of curvature of radiating activity. The consequences of the spiral wave activity concept for the initiation and maintenance of AF are poorly understood at the moment; therefore the leading circle remains the point of reference for understanding multiple circuit re-entry.

Recently, a significant increase in longitudinal dissociation, consisting of lines of block running parallel to the atrial muscle has been found during intraoperative epicardial mapping in patients with persistent AF as opposed to patients with acutely included AF (Figure 42-28).¹⁶⁴ The amount of dissociation was sixfold greater in longstanding persistent AF, suggesting that it may play a role in the self-perpetuation of the arrhythmia.

FIGURE 42-28 Intraoperative epicardial wave maps of the right atrium of three patients with acute AF (A) and 3 patients with persistent AF (B).The boundaries between the waves are plotted next to the wave maps. Gray pixels indicate interwave time differences of ≤12 ms (collision). Black pixels indicate time differences >12 ms (block).

(FromAllessie MA, de Groot NM, Houben RP, et al: Electropathologic substrate of long-standing persistent atrial fibrillation in patients with structural heart disease: Longitudinal dissociation, Circ Arrhythm Electrophysiol 3:606–615, 2010.)

Electrical Remodeling

A key concept in understanding AF is that of electrical remodeling.¹⁶⁵ It has become obvious over the past few years that atrial electrical properties are altered by sustained AF such that the atria become more susceptible to the initiation and maintenance of the arrhythmia.¹⁶⁶ The primary factor driving AF-induced remodeling appears to be AT, and similar changes can be produced by other atrial tachyarrhythmias such as AFL and AT. Electrical remodeling occurs in a time-related fashion following the onset of AF and likely involves a series of adaptations stimulated by increased cellular calcium (Ca²⁺) loading from the increased rate of activation, with Ca²⁺ entering the cell with each activation.¹⁶⁷ The electrophysiological changes caused by tachycardia-induced atrial electrical remodeling are summarized in Figure 42-29.

FIGURE 42-29 Mechanisms involved in atrial electrical remodeling induced by atrial fibrillation (AF). Similar mechanisms operate for any form of atrial tachycardia. Atrial tachycardia increases intracellular calcium (Ca) loading, which initiates a series of physiologic changes, some of which (e.g., decreased _ICa) reduce cellular Ca²⁺ entry and prevent potentially lethal Ca²⁺ overload. Protection against Ca²⁺ overload comes at the expense of decreased wavelength (WL), which promotes AF. ^ICA^L, L-type calcium current; Na, sodium; ^IAPD, action potential duration.

Short-term changes involve functional alterations, primarily Ca²⁺ current (I_Ca) inactivation, that reduce the action potential duration (APD), the refractory period, and the wavelength and thereby promote AF. Longer-term changes include alterations in the production of ion channel proteins, among which a key alteration appears to be downregulation in the L-type Ca²⁺ current (I_Ca.L) that maintains the plateau of the action potential and triggers cardiac contraction.¹⁶⁸ I_Ca.L downregulation reduces APD and attenuates APD adaptation to rate, which is largely caused by tachycardia-dependent I_Ca.L reduction (that normally reduces APD at fast rates). In addition, sodium (Na⁺) current also appears to be reduced, decreasing conduction velocity, and the intercellular coupling channel protein, connexin 40, is reduced in a heterogeneous fashion. The resulting heterogeneous reductions in atrial wavelength make AF more likely to sustain itself and increase the vulnerability of the atria to AF re-induction should the arrhythmia be terminated.

The concept of atrial electrical remodeling caused by AF is very important because it explains why paroxysmal AF tends to become chronic, why longer-lasting AF is more difficult to treat, and why AF recurrence is particularly likely the first few days after electrical cardioversion. However, for remodeling to occur, AF needs to be sustained for significant periods. Therefore other mechanisms must be involved in triggering and maintaining AF before remodeling can occur.

Structural Remodeling

Autopsy studies of atrial tissues from patients with AF often show extensive atrial fibrotic changes, particularly in association with conditions such as mitral valve disease, CHF, and senescence. Recent clinical studies suggest that patients with AF have activation of the atrial renin-angiotensin system and related mitogen-activated protein kinases with profibrotic actions. In an animal model of CHF, sustained AF can be induced fairly readily, with an underlying substrate that involves local conduction abnormalities related to intense atrial interstitial fibrosis. AF in this model sometimes has the appearance of macro–re-entry with fibrillatory conduction, consistent with the mechanism illustrated in Figure 42-26, B.¹⁶⁹ In addition to causing abnormalities in conduction, structural remodeling is often associated with atrial dilatation, favoring AF, as illustrated in Figure 42-27, E. Cellular electrical properties are also altered in CHF but not in the same way as with atrial tachycardia-induced electrical remodeling.¹⁶⁹ APD is not shortened, so the wavelength is not reduced; however, the activity of the Na⁺-Ca²⁺ exchange current (NCX) is increased. The NCX exchanges Ca²⁺ accumulated in the cell during the action potential for extracellular Na⁺, with one intracellular Ca²⁺ ion exchanged for three extracellular Na⁺ ions. Thus, the NCX carries one net positive charge into the cell with each cycle. When NCX activity is enhanced, delayed afterdepolarizations (DADs) and triggered ectopic activity can result. CHF therefore favors AF both by creating a structural substrate for atrial re-entry and by producing a functional basis for atrial ectopic activity that can trigger re-entry.

Significance of Ectopic Activity

Many patients with AF have enhanced atrial ectopic activity originating in the pulmonary vein region. These ectopic foci can promote AF both by triggering atrial re-entry in the presence of a susceptible substrate and by causing rapid atrial tachycardias that cause electrical remodeling, which then creates the re-entrant substrate for AF. Less commonly, ectopic activity in patients with AF can originate in other atrial sites such as the venae cavae and the ligament of Marshall, an anatomic remnant structure close to the great cardiac vein. Irrespective of the site of origin of atrial ectopy, effective ablation of the ectopic site can prevent AF recurrence, indicating its importance in the pathophysiology of the arrhythmia.

Determinants of the Ventricular Response

In addition to the physiological factors controlling the occurrence and maintenance of atrial arrhythmia in AF, a very important determinant of the clinical manifestations is the ventricular response rate. The two largely independent determinants of the ventricular response are (1) the rate and regularity of atrial activity, particularly at the entry to the AV node; and (2) the refractory properties of the AV node itself. The pattern of atrial input is an important determinant of the ventricular response, but decreases in atrial rate do not always cause a reduced ventricular response. The central, compact portion of the AV node is composed of tissue with a slow, I_Ca,L-dependent upstroke (“slow-channel tissue”). Conduction through slow-channel tissue is not all or none: Impulses entering the AV node during its relatively refractory period can penetrate partway and then die out, leaving the AV node partially refractory for the next impulse. Thus, not only does the impulse fail to conduct, but it makes it more difficult for the next impulse reaching the AV node to conduct as well. This “concealed conduction” means that a very rapid, irregular input into the AV node can be associated with a lower ventricular response rate than a slower, more regular atrial activation pattern. Drugs that slow the atrial rate during AF, such as class IC antiarrhythmic agents, can, therefore, sometimes produce a paradoxical and potentially dangerous increase in the ventricular response rate.

The second important determinant of the ventricular response is the functional state of the AV connection. Normally, it is the refractory properties of the slow-channel tissue in the AV node that determine the ventricular response. Drugs that interfere with conduction through slow channel tissues, such as I_Ca.L-antagonists (diltiazem or verapamil), β-adrenoceptor antagonists (which oppose the conduction-enhancing effect of background β-adrenergic tone), and digitalis (which acts by vagal enhancement), increase the filtering function of the AV node and slow the ventricular response rate. Unlike slow-channel tissue, with a refractory period determined largely by the time required for recovery of I_Ca.L following depolarization, the refractory period of “fast-channel” tissues (with I_Na-dependent upstrokes) is determined by APD. APD (and consequently the refractory period) of fast-channel tissues decreases markedly at faster rates. Thus, when the atria are connected to the ventricles by an accessory bypass tract of fast-channel tissues (as in WPW syndrome), the bombardment of the bypass tract at very rapid rates during AF may result in very short refractory periods and dangerously rapid ventricular response rates caused by conduction across the accessory pathway during AF.

Synthesis of Physiological Determinants in Atrial Fibrillation

Figure 42-30 presents a synthesis of the physiological determinants of AF described earlier. Ectopic activity plays an important role by triggering re-entry and AF in the presence of a vulnerable substrate such as that created by structural remodeling. In addition, continuous atrial ectopic activity can generate ATs that cause atrial electrical remodeling, which produces a substrate for AF. Thus ectopic activity can result in both the substrate for AF (atrial remodeling) and the trigger that acts on the substrate to cause the arrhythmia. Other atrial tachyarrhythmias (including AFL, AVRT, and AVNRT) can also cause tachycardia-dependent remodeling and produce a substrate for AF, accounting (at least in part) for the occurrence of AF in association with these arrhythmias in some patients. If AF is induced by any mechanism, electrical remodeling will ensue, causing heterogeneous wavelength decreases that promote multiple circuit re-entry. Thus, electrical remodeling tends to make multiple circuit re-entry the final common pathway of AF, irrespective of the initial mechanism of the arrhythmia. As discussed earlier, even though AF may begin as macro–re-entry with fibrillatory conduction (as in some cases of experimental heart failure–related AF) or as a rapidly discharging focus with fibrillatory conduction, by the time patients get medical attention, they may already have multiple circuit AF because of remodeling.

FIGURE 42-30 Synthesis of physiological determinants of atrial fibrillation (AF) and its consequences in terms of the ventricular response. WPW, Wolff-Parkinson-White syndrome; AV, atrioventricular.

Recent discoveries regarding AF mechanisms cast an interesting light on the theories of AF in the early twentieth century, as illustrated in Figure 42-26. Recent work suggests that all the original ideas regarding AF mechanisms are probably accurate for some subsets of patients. Furthermore, the subsequent dominance of the multiple circuit re-entry concept is also well founded, since electrical remodeling acts to make multiple circuit re-entry the final common pathway of AF in many cases. The dynamic nature of AF mechanisms needs to be considered to understand the mechanisms of the arrhythmia and to optimize therapy in any given patient.

History

Symptoms

The ESC and CCS guidelines introduced score systems to quantify the severity of AF-related symptoms and their impact on quality of life: the European Heart Rhythm Association (EHRA) and the Severity of Atrial Fibrillation (SAF) (Table 42-6) scales.^63,170 Both scales are based on a subjective perception of symptoms by the patient and include four and five grades, respectively, ranging from the asymptomatic status to severe symptoms disrupting every day activity and significantly affecting quality of life.

Table 42-6 Assessment of Symptoms Related to Atrial Fibrillation and Impact on Quality of Life by EHRA score and CCS SAF Scale

EHRA CLASS	SYMPTOMS
EHRA I	No symptoms
EHRA II	Mild symptoms; normal daily activity not affected
EHRA III	Severe symptoms; normal daily activity affected
EHRA IV	Disabling symptoms; normal daily activity discontinued

SAF SCORE	IMPACT ON QUALITY OF LIFE
Class 0	No symptoms
Class 1	Minimal effect on quality of life
Class 2	Minor effect on quality of life
Class 3	Moderate effect on quality of life
Class 4	Severe effect on quality of life

CCS SAF, Canadian Cardiovascular Society; Severity of Atrial Fibrillation; EHRA, European Heart Rhythm Association.

From Camm AJ, Kirchhof P, Lip GY, et al: Guidelines for the management of atrial fibrillation: The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC), Europace 12:1360–1420, 2010; Healey JS, Parkash R, Pollak T, et al, for the CCS Atrial Fibrillation Guidelines Committee: Canadian Cardiovascular Society atrial fibrillation guidelines 2010: Etiology and initial investigations, Can J Cardiol 27(1):31–37, 2011.

Many cases of AF are discovered incidentally and are thought to be truly asymptomatic. However, symptoms are often not perceived as physicians tend to focus on palpitations as the most important feature of the arrhythmia, but patients are often more aware of exertional dyspnea, poor exercise tolerance and fatigue, especially if the ventricular rate is slow (see Figure 42-10).⁸⁵ The true impact of the disease may be missed, and patients with longstanding, unrecognized, and untreated arrhythmia may be exposed to high risk of thromboembolic complications or tachycardia-induced left ventricular dysfunction with stroke and heart failure being the first clinical manifestations. Many patients may have both silent and symptomatic bouts of the arrhythmia, and considerable discrepancy exists between reported symptoms and documented rhythms. For example, patients may complain of episodic palpitations when rapid or highly irregular ventricular rates are present but may not be aware of their arrhythmia during slow ventricular rates (Figure 42-31). Therapeutic intervention may render AF asymptomatic or modify the patient’s perception of the arrhythmia.

FIGURE 42-31 Holter monitor tachogram and electrocardiogram strips from a patient with atrial fibrillation. A, Symptomatic episode of the arrhythmia with a rapid ventricular rate response (>200 beats/min). B, Symptomatic episode of the arrhythmia with a slower but irregular ventricular rhythm. C, Asymptomatic episode with a slow ventricular rate response. In such “intermittently symptomatic atrial fibrillation,” the presence of frequent asymptomatic periods can be mistakenly assumed for sinus rhythm. HR, Heart rate.

Electrocardiography

12-Lead Electrocardiogram

The diagnosis of any arrhythmias requires electrocardiographic documentation, the probability of which can be increased by using a standard ECG, rhythm strips obtained during the arrhythmia, ambulatory Holter recording, trans-telephonic or telemetric monitoring, and loop event recorders, including implantable devices.

A proper evaluation of the 12-lead ECG is vital for several reasons. Firstly, the diagnosis must be confirmed (see Figure 42-25), and the type of the arrhythmia should be differentiated, as confusion may arise from other causes of irregular pulse, for example, frequent atrial or ventricular premature beats or intermittent heart block (Figure 42-32). Conversely, a regular, relatively slow pulse can be found in patients with AFL or AT if the ventricular rate is pharmacologically slowed down (see Figure 42-32). AF may coexist with complete heart block where atrial fibrillatory activity is visible as the baseline but where the ventricular rhythm is slow and regular. Second, the presence of pre-excitation syndrome on baseline ECG determines further investigation and management. Third, evidence of left atrial enlargement during sinus rhythm, previous MI, ST-segment and T-wave changes, left ventricular hypertrophy, and axis deviation can be useful in the identification of coexistent disease and assessment of risk of recurrence. Finally, monitoring of the P-R and Q-T intervals and the QRS complex width is essential for the prevention of proarrhythmias during antiarrhythmic drug therapy.

FIGURE 42-32 A, Frequent premature beats can mimic an irregularly irregular rhythm typical for atrial fibrillation. B, Atrial tachycardia with ventricular rates of 140 beats/min before treatment. C, Atrial tachycardia is still present after the initiation of sotalol but ventricular rates are significantly slower (100 beats/min). D, Atrial flutter with constant atrioventricular conduction mimicking a normal, regular pulse.

Holter Monitoring

Ambulatory 24-hour Holter monitoring usually is useful for the diagnosis of frequent paroxysms of the arrhythmia and for the assessment of the effects of rate-slowing agents if rate control was selected as a principal management strategy (Figure 42-33). In some cases, it may provide information pertinent to the principal management of the arrhythmia, as documentation of frequent atrial premature beats or fast atrial tachycardia preceding AF may be crucial for the selection of nonpharmacologic treatment alternatives (Figure 42-34). Digital ambulatory recorders, which enable standard 12-lead configurations similar to that of the digital diagnostic-quality 12-lead ECG machines, may increase diagnostic accuracy.

FIGURE 42-33 A, A Holter monitor heart rate (HR) histogram plotted against time showing at least three paroxysms of atrial fibrillation with fast ventricular rates within 24 hours (arrows). B, A Holter histogram of extremely frequent, multiple short-lived episodes of atrial fibrillation (“incessant” paroxysmal atrial fibrillation). C, A Holter monitor histogram in a patient with permanent atrial fibrillation before treatment. D, The same patient as C during rate control therapy.

FIGURE 42-34 A, A Holter monitor strip showing initiation of atrial fibrillation by atrial premature beats (arrows) B, A Holter electrocardiogram recording of onset of the arrhythmia in a patient with paroxysmal atrial fibrillation. Note the presence of focal atrial tachycardia with a cycle length of 190 to 200 ms, which initiates atrial fibrillation. Because this arrhythmia is likely to originate from the region of the pulmonary veins and may be amenable to radiofrequency catheter ablation, the next step in investigation should be electrophysiological study.

Loop Recorders

When paroxysms of the arrhythmia are infrequent or when asymptomatic episodes are suspected, a loop event recorder with transtelephonic or telemetric facilities can offer long-term, continuous ECG monitoring and event-specific recording. ECG loop recorders have a retrospective (loop) memory, which continuously records and deletes the patient’s ECG. They can be both implantable and external devices and have a patient activation function that allows the patient to activate ECG storage as a result of symptoms and an auto-activation feature that allows the automatic capture of arrhythmic events. The probability of capturing the arrhythmic event varies from 65% to 88% (Figure 42-35).¹⁷¹ Implantable loop recorders are superior to Holter monitoring systems in the diagnosis of very infrequent arrhythmic attacks, determination of onset patterns, identification of asymptomatic arrhythmias, assessment of treatment efficacy, and detection of proarrhythmias.¹⁷²

FIGURE 42-35 A, Currently available implantable loop recorders. B, A rhythm strip from the Reveal XT device (Medtronic Inc.) demonstrating onset of atrial fibrillation. Note an atrial premature beat followed by the run of fast atrial tachycardia, possibly from the pulmonary vein, preceding atrial fibrillation.

(Courtesy A. Vincent, Medtronic Inc., Minneapolis, MN).

One of such devices, Reveal XT (Medtronic Inc., Minneapolis, MN) has been tested in patients who underwent pulmonary vein ablation and has been shown to identify AF recurrences with a 92% positive predictive accuracy.¹⁷³ These devices can be useful in identifying AF as a cause of cryptogenic strokes when no specific risk factors are present.

Exercise Stress Test

Exercise stress test can be used for exclusion of adrenergically mediated or exercise-induced AF and for the assessment of the effectiveness of rate control therapy in patients with permanent AF (Figure 42-36). It is also generally performed in individuals with suspected CAD, especially, if type IC antiarrhythmic drug therapy is planned.

FIGURE 42-36 Inadequate ventricular rate control during exercise in a patient with permanent atrial fibrillation treated with digoxin only. A, Baseline electrocardiogram. B, An electrocadiogram after 1.5 minutes of exercise stress test. C, A tachogram showing a rapid increase in ventricular rates immediately after the beginning of exercise.

Blood Tests

Essential blood tests include a full blood count and hemoglobin, serum electrolytes, including serum potassium and magnesium levels, and the assessment of thyroid function. A lipid profile is often warranted in patients with risk factors for CAD. Of interest, several reports identified the association between low levels of high-density lipoprotein (HDL) cholesterol and risk of AF.¹⁷⁴

Thyrotoxicosis accounts for 1% to 2% of new cases of AF but abnormal thyroid function tests can be found in 4% to 12.5% of AF patients.³⁹ Recognition of a hyperthyroid state is important because cardioversion and long-term maintenance of sinus rhythm are unlikely as long as the underlying condition persists. Thyroid hormones have a direct positive chronotropic effect and may enhance cardiac sensitivity to catecholamines by increasing β-adrenergic receptor density. In some patients, no obvious symptoms of hyperthyroidism are present or only subtle signs of an overactive thyroid are present (apathetic hyperthyroidism), and the arrhythmia can be the only clinical marker of the disease.

Anemia may contribute to dyspnea or may precipitate atrial tachyarrhythmias. The white cell count may suggest the presence of inflammatory mechanisms precipitating the arrhythmia. Measures of the acute phase response, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein, may give further guidance where inflammatory or malignant processes are suspected. Increased levels of C-reactive protein have been associated with the development of AF in the general population and with recurrent AF after cardioversion and may be a marker of the inflammatory mechanism underlying the arrhythmia but currently are only measured for research purposes.¹⁷⁴

Serum liver enzyme levels, in particular that of γ-glutamyltransferase, may be helpful when alcohol is suspected as a cause of AF. Thyroid and liver function monitoring is mandatory during therapy with amiodarone, and creatinine clearance is essential while adjusting the dose of dofetilide.

Imaging

Echocardiography

TTE is essential if active management is contemplated. Valve heart lesions, severe enough to cause AF, are usually evident on clinical examination but may not be discovered. Echocardiographic measurement of left ventricular hypertrophy and left ventricular dysfunction is important for the guidance of prophylactic antiarrhythmic drug therapy in patients with hypertension and CHF. The left atrial volume at the time of mitral valve opening is now routinely measured (Figure 42-37, A). Three-dimensional echocardiography allows assessing left atrial volumes at different phases of the cardiac cycle. TTE can be effectively used to assess left atrial mechanical function, but its sensitivity in diagnosis of an LAA thrombus is low.

FIGURE 42-37 A, A gigantic left atrium in a patient with atrial fibrillation and mitral stenosis. B, Left atrial appendage thrombus (arrow) detected by transesophageal echocardiography in a patient with atrial fibrillation (AF). Note the presence of spontaneous echo contrast in the left atrium. C, A computed tomographic image of cerebral infarct (arrow) in a patient with AF but without neurologic symptoms (silent infarct). D, A computed tomographic image of acute ischemic stroke (arrow) with subsequent hemorrhagic transformation (thick arrow) in a patient with AF. LA, Left atrium; LAA, left atrial appendage; LV, left ventricle.

Transesophageal echocardiography (TEE) is capable of providing high-quality images of cardiac structure and function and is the most sensitive and specific technique to detect the presence of thrombi in the left atrium and the LAA, which have been found in 5% to 15% of patients with AF prior to cardioversion (see Figure 42-37, B).¹⁷⁵ TEE has proved to be useful in the stratification patients with AF and AFL with regard to risk of ischemic stroke and has been suggested for the guidance of elective cardioversion.¹⁷⁶

Anticoagulation

Pathogenesis of Stroke in Atrial Fibrillation

Absence of organized mechanical contraction of fibrillating atria with a consequent increase in atrial pressure, atrial stretch, and dilation caused by multiple pathophysiological mechanisms compensating for reduced cardiac output, generate conditions for blood stasis and thrombus formation (Figure 42-39).¹⁸⁰ Atrial stretch results in the increased production of ANP and decreased secretion of vasopressin, which may cause hemoconcentration within the fibrillating atria. A hypercoagulable state and increased platelet activation have been found in association with AF, adding to the risk of thrombus formation. Endothelial injury and systemic inflammation are also contributory factors. The left atrium andthe LAA, particularly because of its anatomic features (distensibility and trabeculations), are the main source of cardioembolic emboli in AF.¹⁸¹ With TEE, left atrial thrombi can be found in about 14% of patients with AF or AFL, even if they were effectively anticoagulated, and spontaneous echocardiographic contrast can be seen in 52% of patients.^{176–178,181} The LAA is the source of thrombi in 80% to 90% of patients.¹⁸²

FIGURE 42-39 Pathogenesis of thrombus formation in atrial fibrillation. AF, Atrial fibrillation; ANP, atrial natriuretic peptide; LA, left atrium; LAA, left atrial appendage.

Risk Stratification

Stroke

A number of models have been devised to predict the risk of stroke and the likelihood of benefit from therapy with either warfarin or aspirin. Patients with valvular AF (mitral valve stenosis or prosthetic valves) are considered high risk, independently of other risk factors, and anticoagulation is mandatory in this patients.¹⁸³ Major risk factors for stroke in nonvalvular AF were identified on the basis of the pooled analysis of 1593 untreated patients from five primary-prevention trials of warfarin (known as Atrial Fibrillation Investigators’ risk stratification model) and the results from 2012 participants from the aspirin arms of the Stroke Prevention in Atrial Fibrillation I to III (SPAF) studies.^184–186 Both reports have shown that hypertension, prior stroke or TIA, diabetes, and advanced age are all associated with increased risk of stroke. The SPAF investigators also introduced left ventricular dysfunction and female gender as risk factors. According to these schemes, patients with no major risk factors have a 0.9% to 1% probability of stroke, those with 1 (or 2) risk factors are at moderate risk, which is estimated at 2.6% to 5.7%, and individuals with more than 2 risk factors have a risk of stroke of 7.1% to 8.1%. All subsequent risk stratification schemes used a combination of these factors.

The most widely accepted CHADS₂ scheme is an amalgamation of individual risk factors: congestive heart failure, hypertension, age >75 years, diabetes mellitus, each of which is assigned one point, and prior stroke or TIA, which is given 2 points (hence, the subscript “2”).^185–187 The CHADS₂ score system was designed to simplify the determination of stroke risk in general practice. Using this system, the stroke rate per 100 patient-years without anti-thrombotic therapy is expected to increase by a factor of 1.5 for each 1-point increase from 1.9 for a score of 0, to 18.2 for the highest score of 6 (Table 42-8).

Table 42-8 CHADS₂ Stroke Risk Stratification in Nonvalvular Atrial Fibrillation

HISTORY	CHADS2 RISK SCORE
Prior stroke or TIA	2
Age >75 years	1
Hypertension	1
Diabetes mellitus	1
Heart failure	1

CHADS2 SCORE	ADJUSTED STROKE RATE (%/YEAR) (95% CI)
0	1.9 (1.2-3.0)
1	2.8 (2.0-3.8)
2	4.0 (3.1-5.1)
3	5.9 (4.6-7.3)
4	8.5 (6.3-11.1)
5	12.5 (8,2-17.5)
6	18.2 (10.5-27.4)

CHADS₂, Cardiac failure, hypertension, age, diabetes, stroke [doubled] risk stratification system; TIA, transient ischemic attack; CI, confidence interval.

From Gage BF, Waterman AD, Shannon W, et al: Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation, JAMA 285:2864–2870, 2001; and Van Walraven WC, Hart RG, Wells GA, et al: A clinical prediction rule to identify patients with atrial fibrillation and a low stroke risk while taking aspirin, Arch Intern Med 163:936–943, 2003.

Although it provides a valuable first step in identifying patients for whom anticoagulation is mandatory, the CHADS₂ scheme allows a rather crude estimate of stroke risk as it does not take into consideration less validated risk factors such as gender, age between 65 and 75 years, the presence of obstructive artery disease (coronary, carotid, peripheral), chronic kidney dysfunction and proteinuria, and thyrotoxicosis. Furthermore, it underappreciates the importance of advanced age (>75 years), which is probably a more powerful risk factor than previously thought. Some of these factors have been incorporated in the CHA₂DS₂VASc system adopted by the ESC guidelines (Table 42-9).¹⁸⁷

Table 42-9 CHA₂DS₂VASc Stroke Risk Stratification in Nonvalvular Atrial Fibrillation

HISTORY	CHA2DS2VASC RISK SCORE
Congestive heart failure or left ventricular dysfunction	1
Hypertension	1
Age ≥75 years	2
Diabetes mellitus	1
Stroke, TIA, or thromboembolic vascular disease (CAD, CArD, PAD)	2
Age 65-74 years	1
Gender (female)	1

CHA₂DS₂VASc, Cardiac failure, hypertension, age (doubled), diabetes, stroke (doubled); vascular disease: myocardial infarction, aortic plague, peripheral arterial disease; CAD, coronary artery disease; TIA, transient ischemic attack; CArD, complex aortic plaque disease; PAD, pulmonary artery disease.

The advantage of the CHA₂DS₂VASc system is that is appears to perform best identifying patients at truly low risk of stroke and those who would benefit from anticoagulation but who would be deemed as low risk by other risk stratification systems (Figure 42-40).

FIGURE 42-40 Performance of the CHA₂DS₂VASc risk stratification scheme compared with other currently used risk stratification systems. Note that CHA₂DS₂VASc scheme better identifies patients with truly low risk of thromboembolic events.

(From Lip GY, Nieuwlaat R, Pisters R, et al: Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The Euro heart survey on atrial fibrillation, Chest 137:263–272, 2010.)

Although TEE is not routinely used for this purpose, it can offer further refining of risk stratification based on specific findings such as an enlarged LAA with reduced inflow and outflow velocities and thrombi and complex aortic plaque (thick >4 mm, mobile, pedunculated).¹⁸⁸ Assessment of indexes of hypercoagulability and endothelial dysfunction or damage (e.g., von Willebrand factor, P-selectin, fibrin, D-dimer, thrombomodulin) for prediction of stroke in AF remains a research tool.

Therapy

Warfarin

Warfarin, a vitamin K antagonist, reduces the synthesis of biologically inactive forms of thrombin and clotting factors VII, IX and X, which requires vitamin K. Anticoagulation with adjusted-dose warfarin (target INR, 2.5; range, 2 to 3) is recommended in all patients at risk but without a contraindication. This strategy is also pertinent for patients with moderate risk on the basis of an individualized approach that balances the risks and benefits of oral anticoagulation or aspirin, but preference should be given to warfarin. Warfarin has consistently reduced the risk of ischemic stroke or systemic embolism by about two thirds compared with no treatment and by 30% to 40% compared with aspirin in high-risk patients with AF (Figure 42-41).¹⁹³ The number needed to treat (NNT) to prevent one stroke has been estimated to be 100 patient-years for those at low risk (≤2% per year) compared with 25 patient-years for those at high risk (≥6% per year).

FIGURE 42-41 Performance of new antithrombotic therapies versus standard treatment for the prevention of stroke and systemic embolism associated with atrial fibrillation.

International Normalized Ratio Monitoring

Despite it proven efficacy, warfarin is substantially underused (Table 42-11). Warfarin has a narrow therapeutic window, and its management is complicated by multiple drug interactions and variations in dietary intake of vitamin K, prompting regular, and sometimes intense, monitoring of coagulation parameters and dose adjustment, and stringent control of diet, alcohol, and co-medications. Warfarin has a relatively slow onset of action (2 to 7 days), and early thrombogenic risk increases because of the depletion of natural anticoagulation proteins C and S. Intracranial bleeding is the most serious complication with warfarin, as it is associated with high mortality or disability rates.

Table 42-11 Use of Warfarin for Prevention of Atrial Fibrillation–Related Stroke in Epidemiologic Studies

Genetic determination of the response to warfarin also exists. Patients with variant alleles (CYP2C9*2 and CYP2C9*3) of the liver cytochrome P-450 2C9 (CYP2C9) isoenzyme, which is involved in warfarin metabolism, are slow metabolizers of warfarin and can be exposed to higher concentrations of the drug and the associated risk of over-anticoagulation. Conversely, individuals with polymorphisms in the gene encoding for the vitamin K epoxide reductase complex 1 (VKORC1), which is the target protein for warfarin, exhibit increased resistance or a greater sensitivity to warfarin.¹⁹⁸ Although it is possible to screen patients for their potential response to warfarin by using genetic testing, it is limited by associated costs and availability.

Strict INR control is essential to ascertain the highest efficacy and safety of anticoagulation with warfarin, but it is difficult to achieve for the reasons mentioned above. The intensity of anticoagulation with an INR in the range between 2 and 3 is considered to achieve maximum efficacy in the prevention of stroke and an acceptable level of risk of bleeding (Figure 42-43).¹⁹⁹ A population-average model estimated that INR should be maintained within the therapeutic range for at least 60% of the time on therapy to ensure any benefit from anticoagulation; below this threshold, little benefit of anticoagulation exists.²⁰⁰ Compared with the recommended INR values, INR less than 2 confers a 3.6-fold increased risk of stroke in patients younger than 75 years and a twofold increased risk in those older than 75 years, whereas INR above 4 is associated with an exponential increase in bleeding risk. Self-monitoring of INR has a limited applicability.⁴³

FIGURE 42-43 A, Left atrial appendage (LAA)–occluding devices currently available or under investigation. B, Transesophageal echocardiogram showing a patent LAA before implantation of the Watchman (Atritech) LAA occluder system. C, No blood flow in the LAA after implantation.

FIGURE 42-42 Effects of intensity of anticoagulation on incidence rates of ischemic stroke and intracranial hemorrhage in a cohort of 13,355 patients with atrial fibrillation. INR, International normalized ratio.

(Modified from Hylek EM, Go AS, Chang Y, et al: Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation, N Engl J Med 349:1019–1026, 2003.)

Left Atrial Appendage Occluder Devices

A meta-analysis of 23 studies in approximately 5000 subjects with rheumatic or nonrheumatic AF in settings of cardiac surgery, autopsy, or TEE, which revealed that LAA thrombi were found in 57% cases of rheumatic AF and 91% of nonrheumatic AF, has set the stage to investigate the benefit of LAA occlusion.²⁰⁶ LAA excision is often performed adjunct to open-heart surgery in patients with AF. LAA ligation or ectomy via thoracoscopy or a limited sternotomy is not widely used, but new tools are under development. Transcatheter devices are discussed in detail in Chapter 98. Early studies showed the feasibility and safety of a percutaneous LAA transcatheter occluder (PLAATO, ev3 Inc., Plymouth, MN).²⁰⁷ Successful occlusion of LAA was achieved in 90% of patients, with acceptable perioperative morbidity and mortality rates. The incidence of stroke was 2.3% per year compared with the 6.6% per year expected rates of stroke with no warfarin administration warfarin according to the CHADS₂. Several other devices (see Fig. 42-43) are currently under investigation (see Chapter 98).

The performance of the Watchman device (Atritech, Plymouth, MN) against dose-adjusted warfarin has been tested in the Protection in Patients with Atrial Fibrillation (PROTECT-AF) study of 800 patients with a CHADS₂ score of 1 or less.²⁰⁸ After implantation, warfarin was continued for 45 days to allow endothelialization of the device. Warfarin was discontinued and replaced with aspirin and clopidogrel for 6 months if TEE at 45 days showed either no or minimal flow into the LAA and no thrombus and no clinical events occurred. At 45 days, 85% of patients in the device group were able to discontinue warfarin. The primary composite endpoint of all strokes, systemic thromboembolism, and cardiovascular or unexplained death and systemic thromboembolism occurred at a rate of 3 per 100 patient-years in the device group and 4.4 per 100 patient-years in the warfarin group. However, the primary safety endpoints, which included peri-procedural events (stroke and long-term bleeding or device embolization) were more common in the device group (7.4 vs. 4.4 per 100 patient-years), with pericardial tamponade occurring in 5.5%. This has been explained by a steep learning curve; in the subsequent Continued Access Protocol (CAP) registry, the incidence of pericardial effusion decreased to 1.1%.²⁰⁹ The performance of the device will be further tested in several randomized controlled studies and registries (Table 42-13).