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Hunter Mwansa, MD,
St. Vincent Charity Medical Center, Case Western Reserve University, Cleveland, OH
Sula Mazimba, MD, MPH, Division of Cardiovascular Medicine, University of Virginia Health System, Charlottesville, VA
Glen D. Solomon, MD, FACP, Professor and Chair, Department of Internal Medicine, Wright State University Boonshoft School of Medicine, Dayton, OH
Atrial fibrillation (AF) is the most common arrhythmia, affecting nearly 34 million people globally in 2010. In the United States, it is estimated to reach 12.1 million by 2030. Associated with increased morbidity and mortality, AF is characterized by uncoordinated atrial electrical activity leading to compromised ventricular filling and hemodynamic instability.
• AF is commonly categorized based on the temporal nature of the disorder: paroxysmal, acute, or chronic; its response to cardioversion: persistent vs. permanent; and the presence or absence of structural heart disease: valvular vs. nonvalvular.
• Pathophysiologic mechanisms include genetic predisposition, and anatomical and electrophysiologic abnormalities, which may be primary or secondary to conditions such as valvular heart disease, heart failure, hypertension, diabetes mellitus, obstructive sleep apnea, alcohol, and tobacco.
• Thrombogenesis is the most feared consequence of AF leading to cerebral vascular accidents.
• Acute management typically involves beta-blockers, calcium channel blockers and/or digoxin to achieve rate control. Long-term mortality outcomes have been related mostly to appropriate and effective anticoagulation.
This two-part series presents a review of the current evidence on atrial fibrillation. The first part includes its definition, classification, risk factors, comorbidities, evaluation, and acute management of newly diagnosed patients. The second part will focus on long-term management, including risk factor modification, rate and rhythm control measures, stroke risk stratification, and anticoagulation management.
Atrial fibrillation (AF) is one of the most common atrial arrhythmias, and it is associated with increased morbidity and mortality. It is characterized by uncoordinated atrial1 electrical activity that causes impaired atrial contraction and compromised ventricular filling and hemodynamic stability, especially in patients with pre-existing structural heart disease. These hemodynamic consequences of AF depend on the interplay of multiple factors, including atrioventricular dyssynchrony, suboptimal heart rate (either tachycardia or bradycardia), abnormal atrioventricular nodal conduction, presence or the absence of accessory conduction pathways, and sympathetic activation.2,3,4
Electrocardiographically, AF is characterized by irregular R-R intervals and absence of distinct regular P waves (replaced by chaotic oscillatory or fibrillatory P waves) as shown in Figure 1.
Figure 1. Electrocardiogram of a Patient With Atrial Fibrillation
Bold arrows represent R waves; rectangular inserts arranged along the isoelectric line; R-R intervals = distance between consecutive bold arrows; note the variable R-R intervals and lack of meaningful P waves before every R wave.
AF is commonly categorized based on the temporal nature of the disease (paroxysmal, acute, or chronic), response to cardioversion (persistent vs. permanent), or whether there is the presence or absence of specific mitral valvular disease (valvular vs. nonvalvular).5,6 Other classification methods exist, but the above mentioned have therapeutic implications and affect outcomes. For example, catheter ablation therapy has better outcomes in patients with paroxysmal AF than in those with persistent AF, although this does not necessarily translate into improved mortality.7
Interestingly, both paroxysmal and persistent AF may occur in a single patient, and it is not exactly clear how long patients stay in sinus rhythm following successful cardioversion. Further, patients with non-paroxysmal AF (other patterns of AF) have demonstrated higher rates of thromboembolism compared to those with paroxysmal AF (hazard ratio [HR] = 1.38; 95% confidence interval [CI], 1.19-1.61;
P < 0.001) and death (HR = 1.22; 95% CI, 1.09-1.37; P < 0.001).8 Table 1 gives a descriptive summary of AF when characterized by its presentation, duration, and termination, either spontaneously or following cardioversion. AF can be categorized further as valvular and nonvalvular. Valvular AF occurs in the setting of moderate-to-severe mitral stenosis and/or the presence of a mechanical valve, as recently redefined by the 2019 American College of Cardiology (ACC)/American Heart Association (AHA) focused update of the 2014 guidelines on the management of AF. Nonvalvular AF does not signify implicit absence of valvular disease and includes patients with valvular abnormalities below the threshold required for inclusion under valvular AF.6 This classification of AF dictates whether a patient receives a vitamin K antagonist (VKA) or non-vitamin K oral anticoagulant (NOAC) to reduce the risk of stroke and systemic embolism. Except for dabigatran, which proved harmful, none of the NOACs have been evaluated for safety and efficacy in patients with valvular AF. The RE-ALIGN (Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients After Heart Valve Replacement) trial was a prospective multicenter phase II dose-validation study of dabigatran vs. warfarin therapy in patients aged 18-75 years with either a mechanical mitral and/or aortic valve replacement within seven days of surgery (cohort A) or a mechanical mitral and/or mechanical aortic valve replacement more than three months before randomization (cohort B). The study closed prematurely because of prohibitively high thromboembolic and bleeding events in the dabigatran group.9,10
Only VKAs, specifically warfarin, have proven safety and efficacy in patients with valvular AF. Nevertheless, NOACs are effective at reducing stroke and systemic embolism among patients with valvular abnormalities other than moderate-to-severe mitral stenosis and mechanical valves, including those with valvuloplasties and bioprosthetic valves. They also compared well with warfarin in several clinical trials, except for differences in bleeding rates.11,12,13
AF is the most common arrhythmia, with estimates of global prevalence in 20.9 million men and 12.6 million women for the year 2010.14,15 In 2010, estimates of the prevalence of AF in the United States were 2.7 million to 6.1 million16,17 and is projected to reach 12.1 million in 2030.15 The rise in the prevalence of AF is attributable to a combination of factors, including an increasingly older U.S. population,18 improved disease detection made possible by widespread use of cardiac diagnostic and monitoring devices (Holter monitors, loop recorders, pacemakers, etc.), and increases in the prevalence of predisposing conditions for AF, such as cardiovascular disease (e.g. myocardial infarction [MI], valvular heart disease [VHD], heart failure [HF], hypertension [HTN]),19 obesity, obstructive sleep apnea (OSA), obesity hypoventilation syndrome (OHS), chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM), and chronic kidney disease (CKD). AF prevalence increases with age and is highest among elderly patients older than 80 years of age, among whom it has previously been estimated at 8%.20
Notwithstanding the higher prevalence of predisposing factors for AF among black U.S. residents, the risk of incident AF was highest among whites when compared to blacks (HR = 0.84; 95% CI, 0.82-0.85; P < 0.001), Hispanics (HR = 0.78; 95% CI, 0.77-0.79; P < 0.001), and Asians (HR = 0.78; 95% CI, 0.77-0.79; P < 0.001) in a cohort of hospitalized patients followed over a median period of 3.2 years.21 This race-risk factor AF paradox has been investigated before, and current evidence suggests that Caucasian ancestry and genetic factors might play a bigger role in the pathogenesis of AF given the predominantly higher AF risk among these cohorts, even in the absence of cardiovascular comorbidities.21 Furthermore, blacks with implanted cardiac devices did not demonstrate a higher burden of AF compared to Caucasians.22 The lifetime risk of AF in adults of European descent also has increased, from about one in four adults to one in three adults.23 The increased risk of AF among Caucasians also was observed in the recent ARIC (Atherosclerosis Risk in Communities) study that evaluated ethnic differences in the lifetime risk of AF.24
AF is associated with an increased burden of morbidity, including HF, MI, stroke, gastrointestinal (GI) bleeding, and death. Rates of these complications increase with age (e.g. rates of death, HF, MI, stroke, and GI bleeding for populations aged 67-69 years and 85-89 years were 28.8%, 11.0%, 3.3%, 5.0%, and 4.4%, and 67.0%, 15.8%, 4.4%, 8.9%, and 6.6%, respectively) until age ≥ 90 years.25
AF incurs a huge financial burden and was estimated to cost $26 billion in 2005 alone.25 Its association with reversible lifestyle risk factors calls for attention to address these potential precursors and effective treatment of the disease to prevent and/or reduce complications associated with the disease.
The pathophysiology and mechanisms responsible for initiation, propagation, and perpetuation of AF are not completely understood. Currently proposed mechanisms suggest an interplay of factors that include genetic susceptibility to developing AF and anatomic and electrophysiologic abnormalities that may be primary (rarely) and/or secondary effects of prolonged exposure to the known risk factors (e.g. VHD, chronic HF, HTN, DM, OSA, alcohol, tobacco, etc.).
There is evidence to suggest a strong heritable component to AF. Relatively early onset AF, apparently independent of cardiovascular disease, has been observed in young patients with a strong family history of AF.26,27 Early onset AF in young patients with heritable channelopathies and cardiomyopathies with underlying monogenic mutations also has been described. For example, a mutation in the gene encoding the pore-forming α-subunit (KCNQ1) of the cardiac IKs channel on chromosome 11 that causes a shortened refractory period and increased function of the channel has been implicated in persistent AF observed in these patients.28
Familial AF is most likely polygenic, mediated by an interplay of multiple gene mutations, and is currently a subject of ongoing research.29,30,31 It is likely a phenotypic manifestation of the atrial action potential changes and atrial arrhythmogenic remodeling may occur in patients with these gene polymorphisms.32,33 Patients with these gene variants also have been reported to have a heightened risk for cardioembolic or ischemic strokes, possibly from silent AF.34
Several risk factors for AF, as well as AF itself, can cause progressive cardiac damage with accompanying fibrosis. Physiologic stress arising from pressure overload acting alone or in concert with an activated renin-angiotensin aldosterone system (RAAS) in the setting of VHD, chronic HF, and hypertension may lead to structural changes that culminate in atrial myocardial damage and ensuing repair via activation of fibroblasts, connective tissue deposition, and ultimately cardiomyocyte and interstitial fibrosis.35-38 This remodeling may result in the creation of atrial ectopy and re-entry circuits, alteration of conduction pathways, and electrical dissociation related to the juxtaposition of normal myocytes with fibrotic tissue that act together to propagate and perpetuate AF.39,40 Evidence also exists of atrial fatty infiltration and cardiomyocyte inflammation, necrosis, and amyloid deposition in AF patients with concomitant risk factors, such as obesity and advanced age.41,42
Etiologically, two principle scientific constructs have been advanced to explain AF. First, AF is thought to involve an interplay of ectopic foci that cause rapid firing, which may be sustained by local re-entry. Commonly, these ectopic foci are located in muscular sleeves extending from the left atrium into the distal pulmonary veins, but they also are found less frequently in the distal superior vena cava as it enters the right atrium, ligament of Marshall, and other parts of both atria.43,44,45 These foci of ectopic atrial electrical activity have been implicated in the initiation of AF, and this has been demonstrated in individuals with paroxysmal AF without evidence of underlying structural heart disease44 and patients who revert to AF after successful cardioversion.46 The exact mechanisms underpinning the initiation of ectopic and rapid electrical activity have not been fully elucidated. There is some evidence to suggest that the alteration of autonomic tone characterized by either sympathetic or parasympathetic (vagal) hyperactivity, as observed during intense physical exercise and during sleep, respectively, may precede paroxysms of AF.47 Whereas sympathetic overdrive leads to increased intracellular calcium, which possibly creates triggers and increased automaticity, parasympathetic overdrive causes increased susceptibility to re-entry because of activation of acetylcholine-mediated potassium ion channels that cause heterogeneous shortening of the atrial action potential and refractory period.48 Sympathetic activation may play a role in AF that occurs in postoperative settings, although the major drivers behind this form of AF are possibly inflammation and oxidative stress.49,50
Postoperative AF commonly complicates cardiac surgery, with incidence estimates of about 15-30% after coronary bypass surgery and 30-60% after cardiac valve replacement.51,52 Catheter-directed radiofrequency ablation can be an effective intervention in subjects with these ectopic foci, particularly for those that are localized to the distal pulmonary veins.45
Second, the hypothesis of multiple wavelets and rotors suggests that AF is perpetuated by the occurrence of multiple wavelets that propagate within larger abnormal atrial tissue with refractory and conduction heterogeneity that render them highly arrhythmogenic and self-sustaining.53 Propagation of these wavelets is sustained so long as their number remains above a certain threshold.39
It is often said that “AF begets AF.” This is because AF leads to other electrophysiological changes within the atrial substrate. For example, AF induces shortening of the atrial action potential refractory period and AF cycle length, which, if persistent, is associated with atrial remodeling that can further perpetuate AF.54,55,56
The duration of antecedent persistent AF is inversely associated with the time a patient stays in sinus rhythm post cardioversion. In light of these pathophysiological insights, avoiding irreversible atrial remodeling through early therapy initiation may be an important therapeutic consideration. However, there is no evidence that a universal rhythm control approach over a rate control strategy has mortality benefit.57
One of the most dreaded consequences of AF is cerebral vascular accident (CVA) due to thromboembolism. Atrial remodeling, including dilatation, and functional abnormalities associated with AF promote a suitable milieu for the formation of thrombi with potential for systemic propagation. Stasis of blood (due to atrial hypocontractility), atrial endothelial damage, and an inflammatory milieu all converge to produce a procoagulant state that may account for thromboembolism seen in AF.58,59
Atrial hypocontractility is probably the most important factor in AF-related thrombogenesis because there is a heightened risk of thromboembolism post cardioversion due to delayed return of atrial contractility in the setting of atrial myocardial stunning.
Table 2 shows some risk factors and clinical conditions associated with AF. It is important to note that some of these risks and clinical comorbidities are potentially reversible. Interventions aimed at addressing them may, therefore, prevent incident AF and potentially cure concomitant AF. For example, catheter ablation may effectively treat AF associated with Wolff-Parkinson-White (WPW) syndrome, atrial nodal (AV) reentrant tachycardia, and atrial ectopic tachycardia.60
The diagnosis of AF requires evidence of AF on ECG (see Figure 1), noninvasive ambulatory rhythm monitors (e.g. Holter monitors, event recorders), pacemakers, defibrillators, and electrophysiologic studies. Patients may present either asymptomatically or with non-specific symptoms, including palpitations, lightheadedness, fatigue, dyspnea, and chest pain. It is not uncommon for patients, especially those with pre-existing cardiac disease, to present with worsening symptoms of heart failure, angina, and hypotension if the ventricular response is rapid enough to cause hemodynamic instability.
The initial evaluation of patients should focus on obtaining a thorough history of symptoms, risk factors (see Table 2), family history, and a detailed physical examination looking for an irregularly irregular pulse, an irregular jugular venous pulse, and a variation in loudness of the first heart sound (S1). A physical exam may further show a pulse deficit when the heart rate is compared to the peripheral venous pulse as well as murmurs in the presence of underlying cardiac structural disease.
Extracardiac manifestations may reflect either complications of the disease, such as focal neurological deficits in those with AF complicated by cerebrovascular disease, or manifestations of comorbid non-cardiac diseases.
The diagnosis of AF may pose a challenge in some patients and this requires a high index of suspicion, particularly in those with risk factors for the disease and/or those presenting with possible complications of AF, commonly cardioembolic stroke. Long-term cardiac rhythm monitoring devices, e.g. loop recorders, may be warranted in patients suspected of having paroxysmal AF, such as patients with intermittent palpitations and survivors of cryptogenic stroke (stroke of unknown origin) in whom the diagnosis of AF via external cardiac event monitors is inconclusive.71 These devices are effective in diagnosing silent AF in patients with cryptogenic stroke and may help decrease the chances of recurrent stroke.
Once a diagnosis of AF is confirmed, a further workup aimed at identifying possible causes, including laboratory tests and transthoracic echocardiography to identify associated structural heart disease, atrial enlargement, and left ventricular function, must be obtained. Important investigations required in patients diagnosed with AF are shown in Table 3.
It often is challenging to distinguish between new-onset AF and recurrent AF, as it may go unrecognized as asymptomatic disease. Acutely, assessing for hemodynamic instability is a critical first step in dealing with newly diagnosed AF. Clinical evidence of hemodynamic instability, including hypotension, acute coronary syndrome, pulmonary edema, and/or congestive HF, calls for urgent electrical cardioversion. Hemodynamically stable patients presenting with rapid ventricular response (heart rate [HR] > 100 beats/minute) usually require a rate control strategy that employs measures such as the use of intravenous beta-blockers (e.g. esmolol, metoprolol), calcium channel blockers (e.g. diltiazem), and/or digoxin before a patient can be transitioned to oral heart rate control measures for symptomatic treatment and preservation of left ventricular (LV) function. It is important to recognize possible precipitants for the AF and/or tachycardia, such as thyrotoxicosis, anemia, and intercurrent infections, as addressing these might be key to spontaneous restoration of sinus rhythm and/or HR control. In appropriate candidates for the rate control strategy, LV systolic function and concurrent medical comorbidities (e.g. heart failure and chronic pulmonary diseases like COPD and asthma) dictate the therapeutic choice of a beta-blocker, a calcium channel blocker, and/or digoxin. Beta-blockers should be used in patients with chronic HF with reduced ejection fraction (HFrEF) (EF < 40%), as calcium channel blockers have significant inotropic effects that may worsen LV dysfunction and lead to deterioration of HF.73,74,75
Calcium channel blockers are preferred agents in those with chronic reactive airway diseases such as asthma. Acutely, digoxin usually is not a preferred initial choice because it has a slow onset of action and appears less efficacious in achieving rate control than beta-blockers and calcium channel blockers in this setting.76,77,78 Nevertheless, it is an important agent in patients with hypotension and can be a useful adjunct in patients requiring combination therapy for effective rate control. Acutely stabilized patients typically are transitioned to either oral beta-blockers, calcium channel blockers, digoxin, or combination therapy for long-term rate control. These rate controlling medications are listed in Table 4.
Patients who present acutely with pre-excitation should not be managed with AV nodal blocking agents because AV nodal blockade can precipitate rapid conduction through the accessory pathway, leading to degeneration of AF into ventricular fibrillation, sudden cardiac arrest, and death. If they are hemodynamically stable, these patients can be managed with intravenous procainamide or propafenone acutely to control ventricular rates.79,80 These patients, particularly those with an antegrade accessory pathway, may benefit from catheter-directed AF ablation because of its effectiveness in this setting.5,81 Urgent catheter ablation of the accessory pathway is warranted in those who survive a sudden cardiac death. Patients with AF in the setting of pre-existing Ebstein’s anomaly, symptomatic pre-excitation, a short R-R interval (< 250 ms), and the presence of multiple accessory pathways on electrophysiologic studies have an increased risk for death and require catheter-directed ablation of the accessory pathway.
Whatever the choice of therapy, it is important to realize that long-term mortality outcomes in AF mostly have been tied to appropriate and effective anticoagulation. This important aspect of AF management must be addressed alongside the instituted rate and rhythm control measures.
Financial Disclosure: To reveal any potential bias in this publication, and in accordance with Accreditation Council for Continuing Medical Education guidelines, Dr. Wise (editor) reports he is involved with sales for CNS Vital Signs and Clean Sweep. Dr. Mwansa (author), Dr. Mazimba (author), Dr. Solomon (peer reviewer), Mr. Schneider (editor), Ms. Mark (executive editor), Ms. Coplin (editorial group manager), and Ms. Johnson (accreditations manager) report no financial relationships with companies related to the field of study covered by this CME activity.