Causes of atrial fibrillation

Sunday, July 19, 2009

Atrial fibrillation (AF) is a relatively common arrhythmia that is frequently associated with atrial enlargement and ventricular dysfunction. It is important clinically because affected patients are at increased risk for mortality (1.5 to 1.9-fold in the Framingham study), for deterioration in hemodynamics due to rate and progressive dysfunction of the left atrium and left ventricle, and for embolic events from atrial thrombi [1,2].

The prevalence and causes of AF, including lone AF, will be discussed here. An overview of the presentation and management of patients with AF is presented separately. (See "Overview of the presentation and management of atrial fibrillation").

PREVALENCE – The prevalence of AF depends upon the population studied as the risk increases with age and with underlying heart disease [3]. AF is uncommon in infants and children, almost always occurring in association with structural heart disease. Healthy young adults are also at low risk; in one report, for example, only five of over 122,000 routinely evaluated, healthy Air Force personnel had AF [4].

Thus, AF is primarily a disease of older subjects [2,3,5-8]. This relationship to age was demonstrated in a cross-sectional study of almost 1.9 million subjects in a health maintenance organization [7]. The following results were noted:

• The overall prevalence of AF was 0.9 percent; 70 percent were at least 65 years old and 45 percent were > or =75 years old.

• The prevalence of AF ranged from 0.1 percent among adults less than 55 years of age to 9 percent in those > or =80 years of age (show figure 1).

• The prevalence was higher in men than women (1.1 versus 0.8 percent), a difference seen in every age group (show figure 1) Among subjects over 50, AF was more frequent in whites than blacks (2.2 versus 1.5 percent).

It was estimated that 2.3 million adults in the United States currently have AF, and that this will increase to 5.6 million by the year 2050, with more than 50 percent being more than 80 years of age.

Similar observations were noted in a longitudinal study in which 3983 male air crew recruits were followed for 44 years [8]. During 154,131 person-years of observation 7.5 percent developed AF. The risk increased with advancing age (from 0.5 per 1000 person-years before age 50 to 9.7 per 1000 person years after age 70) (show figure 2) and with the development of hypertension as well as coronary artery disease with myocardial infarction and angina.

ETIOLOGY – Atrial fibrillation may be paroxysmal or chronic. It is usually associated with underlying heart disease (of almost any cause) that is complicated by heart failure and atrial enlargement, an elevation in atrial pressure, or infiltration or inflammation of the atria. The Framingham Heart Study, for example, performed a prospective evaluation of the echocardiographic predictors of AF in individuals without rheumatic heart disease [9]. Left atrial enlargement was shown to precede and predispose to AF; it has also been associated with an enhanced incidence of stroke and death [10]. .

In an animal model, left atrial enlargement and an increase in left atrial pressure predisposed to AF by reducing both the atrial refractory period and action potential duration [11]. Lowering the left atrial pressure resulted in prompt reversion of AF. Further support for the role of stretch due to volume or pressure overload comes from another animal study in which gadolinium, a blocker of the stretch-activated ion channels in the myocardium, reduced the vulnerability to AF during acute atrial dilatation [12].

Other echocardiographic risk factors for AF in the Framingham Heart Study were increased left ventricular wall thickness and reduced left ventricular fractional shortening were other factors associated with AF [9]. Assessment of left atrial function using transesophageal echocardiography and Doppler is also useful for predicting recurrence after successful cardioversion. (See "Antiarrhythmic drugs to maintain sinus rhythm after cardioversion in atrial fibrillation: Recommendations").

Hypertensive and rheumatic heart disease – In developed countries, hypertensive heart disease is the most common underlying disorder in patients with AF [5]. Rheumatic heart disease is now less frequent. It is, however, associated with a high prevalence of AF [13-15]. One study, for example, evaluated the frequency of AF in approximately 1100 patients with rheumatic heart disease [15]:

• Mitral stenosis, mitral regurgitation, and tricuspid regurgitation – 70 percent

• Mitral stenosis and mitral regurgitation – 52 percent

• Isolated mitral stenosis – 29 percent

• Isolated mitral regurgitation – 16 percent

• Aortic stenosis – about 1 percent unless heart failure is present; AF is usually a late feature in aortic stenosis. (See "Pathophysiology and clinical features of valvular aortic stenosis").

Coronary disease – AF is not commonly associated with coronary heart disease (CHD) unless it is complicated by acute myocardial infarction or heart failure. However, because of the high prevalence of coronary disease in the population, CHD is a common cause of AF. Atrial fibrillation occurs transiently in up to 20 percent of patients with an acute myocardial infarction (MI), presumably due to atrial ischemia or atrial stretching secondary to heart failure; these patients tend to have larger infarcts and generally but not always have been reported to have a poorer prognosis [16-21]. (See "Supraventricular arrhythmias after myocardial infarction").

In the GUSTO-I trial of over 40,000 patients with an acute MI, AF was present in 2.5 percent on admission electrocardiogram (ECG) and 7.9 percent after enrollment [17]. The unadjusted mortality rate was higher in the patients with AF at both 30 days (14.3 versus 6.2 percent) and one year (21.5 versus 8.6 percent). However, the adjusted odds ratio for AF was only 1.3. Similar findings – increased mortality that was mostly due to other adverse risk factors, such as older age and a higher prevalence of heart failure or serious ventricular arrhythmias – have been noted in other studies [20,21].

The incidence of AF is much lower in patients with chronic stable CHD [22,23]. In the Coronary Artery Surgical Study (CASS), which included over 18,000 patients with angiographically documented coronary artery disease, chronic AF was present in only 0.6 percent [23]. It was associated with age greater than 60, male sex, mitral regurgitation, and heart failure; there was no association between AF and the number of coronary arteries involved.

CASS and other studies found that AF was an independent predictor of increased mortality in patients with stable CHD. In CASS, the relative risk was 1.98 at seven years [23].

Given the low incidence of AF in CHD and in those with an acute MI, a common problem is the need for coronary care unit admission for patients with recent onset AF. This issue was addressed in a series of 245 patients with new onset AF admitted to the coronary care unit; only five had elevated cardiac enzymes diagnostic of an acute myocardial infarction [24]. All five had at least two of the following clinical features: left ventricular hypertrophy on the ECG, an old MI on the ECG, typical angina pectoris, or duration of symptoms less than four hours. It was not clear whether the MI precipitated the AF or AF and the rapid ventricular rate caused ischemia and an MI.

A prospective cohort study consisted of 255 patients who presented to a single-center emergency department with the primary diagnosis of AF; 190 were admitted to the hospital, 109 of whom underwent a standard "rule-out MI" protocol, and six of whom had an acute infarct [25]. The presence of ST segment elevation or major ST segment depression (>2 mm) was a reliable marker of an acute MI (sensitivity and specificity of 100 and 99 percent, respectively), while chest pain and ST segment depression <2 mm were common but had limited use for predicting an infarction.

In summary, chronic CHD is an uncommon cause of AF unless there are associated factors such as CHF or hypertension. AF is rarely a manifestation of an acute MI or ischemia in the absence of other signs or symptoms of CHD.

Other forms of heart disease – The observed incidence of AF in other forms of heart disease includes:

• Atrial septal defect – 19 percent in adults [26]. However, the incidence of AF is related to age, ranging in one series from 15 percent for those aged 40 to 60, to 61 percent for those over the age of 60 [27].

AF also occurs in other forms of congenital heart disease that affect the atria, including Ebstein's anomaly and patent ductus arteriosus, and after surgical correction of some other abnormalities, including ventricular septal defect, Tetralogy of Fallot, pulmonic stenosis, and transposition of the great vessels.

• Hypertrophic cardiomyopathy – 10 to 28 percent [28,29]. The prognostic importance of AF in these patients is unclear. In one report of 202 patients, for example, patients with AF had a worse prognosis:16 percent experienced premature, often sudden, death and 15 year survival was reduced (76 versus 97 percent in those without AF) [29]. In contrast, another study found no increase in mortality risk with AF; symptomatic deterioration occurred in most patients with acute AF, a change that was reversed with the restoration of sinus rhythm or control of the ventricular rate [30].

• Dilated cardiomyopathy – 15 to 20 percent [31,32]. The prognostic importance of AF in such patients depends upon the severity of myocardial dysfunction. AF does not increase morbidity or mortality in patients with mild to moderate heart failure [31], but is an independent risk factor for total and sudden death mortality in patients with advanced heart failure, especially those with lower left ventricular filling pressures due to vasodilator and diuretic therapy [32].

• Binge drinkers with or without an underlying alcoholic cardiomyopathy – up to 60 percent [33]. Most of the cases occur over weekends or holidays when alcohol intake is increased, a phenomenon that has been termed "the holiday heart syndrome." (See "Alcoholic cardiomyopathy").

• Documented pulmonary embolism – up to 10 percent [34].

AF also occurs in other cardiopulmonary diseases including chronic obstructive pulmonary disease [35], peripartum cardiomyopathy [36], lupus myocarditis [37], the cardiomyopathy associated with severe obesity [38], and both idiopathic and uremic pericarditis [39,40].

Thyrotoxicosis – AF occurs in about 20 to 25 percent of older patients with thyrotoxicosis, but is unusual under the age of 30 [41]. Increased beta adrenergic tone may be in part responsible for the development of AF and may also contribute to the rapid ventricular response in this setting. However, excess thyroid hormone increases the likelihood of AF in experimental animals, even in the presence of beta receptor and vagal blockade [42]; it is likely that this observation applies to humans.

The risk of AF is increased up to threefold in patients with subclinical hyperthyroidism (show figure 3) [43]. As a result, serum thyroid stimulating hormone (TSH) should be measured in all patients with AF, even if there are no symptoms suggestive of thyrotoxicosis. Those with low values (<0.5 mU/L with the newer sensitive assays) and normal serum T4 probably have subclinical hyperthyroidism. (See "Subclinical hyperthyroidism"). One report assessed the frequency of hyperthyroidism by measuring serum TSH in 726 patients with recent onset AF [44]. Low TSH values were found in 39 (5.4 percent). Fourteen of these patients were taking thyroxine supplements for previous hyperthyroidism or hypothyroidism.

Treatment generally consists of a beta blocker (such as propranolol) to control the ventricular rate, and correction of the hyperthyroid state [41]. Spontaneous reversion to sinus rhythm usually occurs within six weeks in patients under the age of 60 who are rendered euthyroid; older patients show an age-related decline in the frequency of spontaneous reversion [41]. Attempted electric or pharmacologic cardioversion is not indicated while the patient is thyrotoxic, since AF usually recurs in this setting.

As with other causes of AF, thyrotoxic patients are at some risk for embolic events and anticoagulation may be warranted in certain cases. (See "Anticoagulation to prevent embolization in chronic atrial fibrillation: Recommendations").

Autonomic dysfunction – The autonomic nervous system may be involved in the initiation and maintenance of AF. Heightened vagal or sympathetic tone can induce AF, the former occurring most commonly in athletic young men with slow heart rates during rest or sleep [45] and the latter often being seen in men or women during exercise or other activity [46]. Abnormal autonomic activity also may be important in patients with recurrent episodes of paroxysmal AF. (See "Paroxysmal atrial fibrillation").

Coronary artery bypass graft – AF occurs in 5 to 40 percent of patients in the early postoperative period following coronary artery bypass graft surgery [47,48]. Although the arrhythmia is usually self-limited, it may be associated with embolic stroke or adverse hemodynamics. More importantly, postoperative AF increases the length and cost of hospitalization [49,50].

A number of risk factors have been identified:

• The likelihood of developing AF may be increased if beta blockers are discontinued preoperatively [48,49].

• Significant stenosis of the right coronary artery is an independent and powerful predictor of AF after CABG [51].

• Other factors associated with a risk of postoperative AF include increased age, lower ejection fraction, and alterations in autonomic balance with an increase in sympathetic tone [52].

Cardiac valvular surgery – AF occurs after valve surgery in 37 to 64 percent of patients [53,54]. Independent predictors for AF include advanced age, mitral stenosis, and left atrial enlargement [53].

Noncardiac surgery – AF is less common after noncardiac surgery. In one series of 4181 patients over the age of 50 who were in sinus rhythm prior to surgery, the incidence of perioperative AF was 4.1 percent; most episodes occurred within the first three days after surgery [55].

Cardiac transplantation – AF frequently occurs in the denervated transplanted heart, often in the absence of significant rejection. In one study of 88 patients, for example, AF occurred 23 times in 21 recipients (24 percent) and was associated with an increased risk of subsequent death [56].

Association with other types of paroxysmal supraventricular tachyarrhythmias – Spontaneous transition between typical atrial flutter and AF has been observed, although little is known about the mechanism of this conversion [57]. Changes in the electrophysiology of the atrial myocardium may be important, with the development of multiple wavelets, rather than the single wavefront seen in atrial flutter. An alternative explanation is that AF is initiated by atrial premature beats originating from ectopic foci located in the pulmonary veins or crista terminalis [58]. (See "Electrocardiographic and electrophysiologic features of atrial fibrillation-I" and see "Electrocardiographic and electrophysiologic features of type I atrial flutter").

The clinical impression has long existed that AF is common in patients with paroxysmal supraventricular tachycardia (PSVT). This was illustrated in a report that evaluated 169 patients who presented with PSVT and were followed by clinic visits and transtelephonic ECG monitoring during symptomatic episodes [59]. Nineteen percent had an episode of AF during a mean follow-up of 31 months; 6 percent within one month; 9 percent within four months, and 12 percent within one year. Neither the mechanism nor the rate of the PSVT was associated with the time to occurrence of AF.

AF occurring in patients with PSVT may be mediated by enhanced vagal tone, as determined by baroreflex sensitivity, or an increase in dispersion of right atrial refractory periods during PSVT [60]. Radiofrequency ablation to prevent PSVT does not guarantee subsequent freedom from AF [61].

AF also occurs in 10 to 34 percent of individuals with the Wolff-Parkinson-White syndrome [62,63]. The etiology of AF in this setting may be retrograde conduction via the accessory pathway of a premature beat, stimulating the atrial myocardium during its vulnerable period. Ablation of the accessory pathways reduces the incidence of subsequent AF [64,65].

Medications – Certain medications, such as theophylline and caffeine, can cause or contribute to the development of AF [66]. In addition, increased vagal tone can induce AF [45]; thus, drugs that increase vagal tone, such as digitalis, may be share this effect.

Familial – A familial form of atrial fibrillation has been reported that is transmitted in an autosomal dominant fashion [67]. Genetic linkage analysis localized the responsible gene to chromosome 10q in the region of 10q22-q24.

LONE ATRIAL FIBRILLATION – Some patients without structural heart disease have paroxysmal or stable AF, a disorder that has been termed lone atrial fibrillation. In different reports, lone AF has accounted for 19 to 31 percent of patients with AF [5,68]. Affected patients are younger than those with structural heart disease, are often male, have few symptoms, are refractory to maintaining sinus rhythm, and generally have a good prognosis, particularly if they are under the age of 60 [69-73]. A study from the Mayo Clinic, for example, found that 2.7 percent of patients with AF were under the age of 60 and had no apparent heart disease or hypertension; the incidence of stroke in this group was only 1.3 percent in 15 years [72].

However, the relatively benign prognosis in lone AF may not apply to older patients. A prospective report from the Framingham Study evaluated patients who were primarily (90 percent) over the age of 60, some of whom were also hypertensive [74]. In this subset of patients, there was a four-fold increase in stroke compared to patients in sinus rhythm.

It is still uncertain whether some or all patients with lone AF should receive prophylactic anticoagulation in an attempt to prevent systemic embolization. Although the role of warfarin is uncertain, these patients might benefit from aspirin. (See "Anticoagulation to prevent embolization in chronic atrial fibrillation: Recommendations").

Pathophysiology – The pathophysiology of lone AF is not well understood. Differences in electrophysiologic properties have been identified between patients with recurrent episodes of lone paroxysmal AF and controls [75,76]. Many of these patients have AF at night while asleep, suggesting that enhanced vagal tone may contribute in individuals who are predisposed because of abnormalities in the atrial myocardium. In animal models, increasing vagal tone prolongs the duration of episodes of AF and result in sustained AF [77]. This is most likely due to shortening of the atrial refractory period. Interestingly, a reduction in vagal tone also may be arrhythmogenic [78].

In addition to electrophysiologic alterations, abnormalities in left atrial histology have also been observed in patients with lone AF. As an example, one study of 12 patients with the disorder found that all atrial biopsy specimens were abnormal versus no observed abnormalities in atrial specimens from a control group of 11 patients without a history of AF [79]. Pathologic evidence of healed myocarditis was seen in one-half of lone AF patients, and active myocarditis, patchy fibrosis, or a noninflammatory localized cardiomyopathy were frequently observed in the remainder.

Another mechanism for lone AF is a "sick sinus syndrome." Such patients have underlying electrophysiologic abnormalities of the atrial myocardium, and it is possible that AF occurs as an escape or end-stage arrhythmia as a result of the sinus node dysfunction [80-82].

PAROXYSMAL ATRIAL FIBRILLATION – Paroxysmal AF refers to episodes that generally last less than three days. These episodes frequently recur and can eventually progress to chronic AF. The causes of paroxysmal AF are similar to those described above for chronic AF. (See "Paroxysmal atrial fibrillation").


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