• Paroxysmal AF—episodes of AF terminating spontaneously within 7 days or cardioverted within 48 hours of onset

• Persistent AF—episodes of AF lasting greater than 7 days or cardioverted after 48 hours of onset

• Longstanding persistent AF—continuous AF for longer than 12 months

• Permanent AF—restoration and maintenance of sinus rhythm has either failed or a decision has been made to not attempt rhythm control

Multiple Wavelet Hypothesis

Reentry forms the basis of the multiple wavelet hypothesis.¹³ In this theory, reentrant waves perpetuate and drift in a seemingly random manner subject to heterogeneous excitability properties of adjacent tissue. These wavelets are continuously subject to extinction or generation of new circuits (daughter wavelets). It is possible that multiple wavelets and reentry with fibrillatory conduction have a role in perpetuation of AF, particularly in patients with atrial electroanatomic remodeling.¹⁴

Pulmonary and Thoracic Vein Arrhythmogenesis

The seminal observation that rapid depolarizations from the pulmonary veins (PVs) can initiate and perpetuate AF led to the development of novel mechanistic and therapeutic paradigms.¹⁵ The mechanism by which PVs become arrhythmogenic and initiate AF in some patients and remain dormant in others still is not clear. Genetic predisposition, stretch, neurohormonal milieu, and changes in autonomic tone have all been implicated.

During embryonic development, the common PV is incorporated into the left atrium. An immunohistochemical study demonstrated that the histologic characteristics of the PVs and the smooth-walled portion of the left atrium are identical (Figure 75-3),¹⁶ explaining why the antral regions of the PVs and the posterior left atrium also are arrhythmogenic. There appears to be a dynamic interplay between the PVs and the adjacent left atrium, as the site of rapid electrical activity alternates between the PV and the left atrium.

Nonpulmonary thoracic veins (i.e., the superior and inferior venae cavae), the coronary sinus (CS), and the ligament of Marshall have all been reported to possess arrhythmogenic activity, but less frequently than the PVs. The CS seems to have a particularly complex role; it can harbor triggers of AF and participate in left atrial reentrant circuits.¹⁷ The complex, multilayered structure of the CS and adjacent left atrial myocardium with resultant anisotropy could facilitate reentry. A prior study suggested that the site of fastest electrical activity during AF alternates between the CS and left atrium.¹⁸ In that study, systematic disconnection of the CS from the left atrium rendered AF less likely to be inducible after PV isolation (PVI) in patients with paroxysmal AF. In a recent study, epicardial and endocardial ablation along and in the CS in patients who remained in AF after PVI prolonged AF cycle length and terminated AF in 35% of patients (46% paroxysmal AF, 30% persistent AF).¹⁹ These findings suggest a mechanistic role of the CS in initiation and perpetuation of AF.

High-Frequency Sources and Rotors

High frequency sources or rotors resulting from anisotropic reentry have been proposed as drivers of AF based on optical mapping studies and computer simulation and experimental models.20,21 A recent study using panoramic in vivo mapping of the atria also suggested the presence of rotors as drivers of AF in the human atrium.²² Wavebreak and fibrillatory conduction occur at the periphery of a rotor leading to complex fractionated atrial electrograms (CFAE).²³ Anchor points of rotors may be more prevalent at the antral regions of the PVs. A shorter effective refractory period at sites of autonomic innervation within the PV antrum can also promote development of rotors. Propagation of atrial activity from high-frequency sources results in frequency gradients, such as from the PVs to the left atrium and to the right atrium.²⁴ Elimination of PV tachycardias and ablation of CFAEs can result in a decrease in the frequency content. In persistent AF, reduction in dominant frequency after electrogram-guided ablation predicts maintenance of sinus rhythm.²⁵

Autonomic Innervation

The heart has an intrinsic nervous system and an interactive atrial neural network. Both sympathetic and parasympathetic systems have significant influences, primarily by sympathetic mediated increases in intracellular Ca²⁺ and vagally mediated heterogeneous shortening of atrial ERP promoting reentry.²⁶ Stimulation of ganglionated plexi (GP) promotes PV arrhythmogenicity and inducibility of AF, and GP have been considered as potential targets during ablation.²⁷ However, the precise role of ablation of GP remains to be determined in patients with AF. It is important to note that strategies to ablate CFAEs and GPs are not mutually exclusive because targeted locations frequently overlap.²⁸

Atrial Remodeling

AF leads to electroanatomic remodeling in the atria, which can include a decrease in atrial ERP; an increase in heterogeneity of refractoriness; shortening of action potential duration; changes in ion channel expression, cellular coupling, and conductivity; and development of fibrosis.²⁹ Progressive electroanatomic remodeling of the atria facilitates perpetuation of AF.³⁰ A variety of interventions to interfere with progression of remodeling both as a standalone therapy and also in conjunction with antiarrhythmic drug therapy or catheter ablation for rhythm control is the subject of ongoing research.

Management of Thromboembolic Risk

Atrial fibrillation increases the risk of thromboembolic events by nearly fivefold.³¹ Left atrial mechanical dysfunction and stasis promote thrombus formation in the left atrial appendage. However, approximately 25% of all strokes in patients with AF are due to intrinsic cerebrovascular or atherosclerotic aortic disease.³² A hypercoagulable state with platelet and endothelial dysfunction can exist in patients with AF, with increases in thromboglobulin and platelet factor 4 levels and a trend toward higher fibrinogen levels.³³ Further evidence of systemic involvement includes elevated CRP levels.³⁴ It remains unclear whether the thromboembolic risk in patients with AF is primarily due to a hypercoagulable state, left atrial mechanical dysfunction, or both.

Currently, management of thromboembolic risk associated with AF focuses on the use of antithrombotic agents and involves a three-part evaluation of the thromboembolic risk, bleeding risk, and selection of the appropriate antithrombotic agent.

The risk of thromboembolism is considered similar among patients with paroxysmal, persistent, or permanent AF or atrial flutter. In patients younger than 60 years with lone AF, the benefit of even antiplatelet therapy using aspirin for primary prevention of stroke has not been established.³⁵ In other patients, a commonly used algorithm proposes the classification of risk factors into low, moderate, or high-risk categories and selection of antithrombotic therapy on the composite score based on these risk factors (Table 75-1). The CHADS₂^36,37 (Box 75-1) scoring system has been used to quantify thromboembolic risk in patients with AF by estimating an annual stroke rate based on the presence or absence of five clinical risk factors: heart failure, hypertension, age, diabetes, and previous stroke. The more recent CHA₂DS₂-VASc score³⁸ (Box 75-1) also estimates annual stroke risk and incorporates incremental thromboembolic risk factors, including vascular disease, female sex, and two levels of risk based on age (Box 75-1). This scoring system has been incorporated into the European Society of Cardiology (ESC) guidelines for AF management.

In addition to establishing thromboembolic risk, a patient’s individualized bleeding risk must also be evaluated before selection of therapy. Three bleeding risk algorithms have been validated in patients with AF:

Among these, the HAS-BLED score is simple and readily applicable with identification of manageable risk factors, and it has a high predictive value.⁴² The HAS-BLED score can be used to identify patients with a high risk of bleeding, but it should not be considered prohibitive for antithrombotic therapy as patients with higher bleeding risk often are at higher thromboembolic risk and may still have incremental benefit with appropriate anticoagulation. Rather, a high HAS-BLED score (e.g., 3 or greater) should be used to individualize therapy for each patient, prompting more regular follow-up with higher vigilance for potential bleeding complications. Any reversible risk factor for bleeding should be addressed.

Selection of antithrombotic agents includes antiplatelet therapy (aspirin with or without clopidogrel), vitamin K antagonists (warfarin), and newer anticoagulants such as the direct thrombin inhibitor dabigatran and direct factor Xa inhibitors rivaroxaban and apixaban. These newer agents have been studied primarily in patients with nonvalvular AF.

Although the bleeding risk is higher, warfarin is superior to aspirin in reducing thromboembolic events.⁴³ Aspirin plus clopidogrel has bleeding rates similar to warfarin, but it is less effective in preventing thromboembolism.⁴⁴ Current American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guidelines for antithrombotic therapy are displayed in Table 75-1 and recommend consideration of warfarin in patients with one or more moderate thromboembolic risk factor. Recent ESC guidelines have incorporated the CHA₂DS₂-VASc algorithm and recommend oral anticoagulation unless contraindicated for a score of 2 or greater, and they suggest consideration for a score of 1 based on the bleeding risk and patient preference.⁴⁵

Recent studies demonstrated the noninferiority or superiority of newer anticoagulants compared with warfarin. Dabigatran was reported to have a similar or lower stroke and major bleeding risk and a decrease in hemorrhagic strokes compared with warfarin, without a difference in overall mortality.⁴⁶ Rivaroxaban is noninferior to warfarin in stroke prevention with similar overall bleeding risk, but is associated with fewer intracranial and fatal hemorrhages.⁴⁷ Apixaban is superior to warfarin in stroke prevention with a lower risk of hemorrhagic complications.⁴⁸ Other potential advantages of newer anticoagulants over warfarin include faster onset of action, no need for dietary restrictions, and potentially more time in the therapeutic range with proper compliance. It has been recognized that patients taking warfarin might not be in the optimal therapeutic anticoagulation range in up to 59% to 68% of the time.⁴⁹ Limitations of the newer anticoagulant agents include lack of specific reversal agents, dose adjustment requirements in elderly patients and in patients with renal insufficiency, cost, and limited long-term safety data compared with warfarin. The latest ESC guidelines recommend the use of these newer anticoagulant agents as the preferred anticoagulant therapy for patients with AF (Figure 75-4).

Other options for stroke prevention, particularly in patients with contraindications to anticoagulation, are surgical or percutaneous left atrial appendage exclusion or occlusion. Reductions in the long term risk for stroke after surgical exclusion of the left atrial appendage, even among patients with high baseline risk factors and many who discontinued anticoagulation following surgery, have been reported.⁵⁰ Surgical morbidity and mortality should be carefully considered. A high prevalence of residual communication between the left atrium and appendage after both surgical and percutaneous exclusion has been recognized; however, it is not clear whether this is associated with an increased risk of stroke.

Percutaneous techniques of left atrial appendage closure include endocardial deployment of an appendage occlusion device and epicardial ligation of the left atrial appendage with endocardial guidance (LARIAT; SentreHeart, Redwood City, CA). Clinical trials are underway in assessing the efficacy and safety of percutaneous left atrial appendage occlusion devices (Watchman, Atritech, Plymouth, MN; Amplatzer Cardiac Plug, St. Jude Medical, MN). Early studies suggested a significant effect of operator experience and a learning curve in minimizing the risk of complications. A single-center study evaluating the use of the LARIAT device demonstrated a high 1-year complete appendage closure rate (98%) with limited procedural complications.⁵¹ Limitations to the use of this device include the exclusion of patients with previous cardiac surgery or unfavorable appendage anatomy and the potential challenges and risk of obtaining percutaneous pericardial access. Large-scale randomized trials will be necessary to determine whether there will be a reduction in the risk of stroke.

Antiarrhythmic drug (AAD) use to maintain sinus rhythm has not been demonstrated to reduce the risk of stroke. However, early observational studies have suggested that stroke risk in the absence of anticoagulant therapy after successful catheter ablation of AF may be similar to the general population, at least in patients who have not had a prior stroke and are younger than 65 years.52,53 Another study showed that an older cohort (≥65 years) following successful ablation of AF also had a stroke rate of 0.7% per year even after discontinuing warfarin (Figure 75-5).⁵⁴ However, these findings remain to be confirmed in longer-term and larger scale trials.

Rate Versus Rhythm Control

In the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study, 4060 patients 65 years or older with AF and other risk factors for stroke or death were randomized to a rate or rhythm control strategy.⁵⁵ On an intention-to-treat analysis, there was a trend toward higher overall mortality in the rhythm control group (P = .08). Subsequent post hoc analyses suggested that potential adverse effects of AAD therapy might have negated any beneficial effects of sinus rhythm.⁵⁶ An on-treatment analysis demonstrated that maintenance of sinus rhythm and warfarin use were associated with a decrease in mortality, whereas AAD therapy was associated with an increase in mortality.⁵⁷ In the Rate Control versus Electrical Cardioversion (RACE) trial, there was no significant difference in the primary composite endpoint of cardiovascular mortality, heart failure, thromboembolic complications, bleeding, need for a pacemaker, and severe adverse AAD effects among the 522 patients who were randomized to rhythm or rate control strategy.⁵⁸