Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice and has grown significantly in both the number of patients affected as well as its impact on the healthcare system.^1-3 It is estimated that >1% of the adult population in the United States is affected, with a greater predilection among the elderly.¹ Current epidemiological projections estimate that by 2050, as many as 15.9 million Americans will have some form of AF whether it be paroxysmal (episodes spontaneously terminating within 7 days), persistent (episodes lasting for more than 7 days and requiring some type of intervention to terminate), or permanent (persistent AF where the decision has been made to not pursue further efforts toward restoring sinus rhythm).⁴ 

Over the years, we have developed a greater appreciation for the risk factors  associated with the development of AF (Table 1). Some of these factors are potentially modifiable (e.g., alcohol use, smoking, physical activity), but most are not. Hence, AF is a problem that will likely remain a significant part of our clinical practice.

While AF is associated with an increased risk of all-cause mortality, myocardial infarction and heart failure,⁵ its strongest link has been to an increased risk for ischemic stroke. In fact, individuals with AF (as a group) have a five-fold higher risk of stroke,⁵ and among those that do experience a stroke, the risk of serious disability and death is 50% and 60% higher, respectively, when AF is present.^6-8 Additionally, more recent studies have demonstrated that among patients with embolic stroke of uncertain source, AF is more likely to be present when compared to a group of patients without stroke.⁹ These observations highlight the tight link AF has with stroke, but do they necessarily point to a cause-and-effect relationship?

Observations Supporting a Cause-and-Effect Relationship

The biological mechanisms linking AF and stroke have long been based on the premise that fibrillatory activity within the atrium results in a loss of effective atrial contractility and blood transport. This allows for blood stasis within the atrium (in particular, the left atrial appendage [LAA]) and the development of emboli that can dislodge and travel to the cerebral and systemic circulation. In fact, echocardiographic imaging studies of patients with persistent AF have shown the presence of thromboemboli within the LAA thought to be secondary to reduced atrial contraction. These explanations would provide a potential cause-and-effect relationship between AF and stroke, and would also imply that the longer one is in AF, the higher the likelihood of developing emboli. In fact, two studies of patients with cardiac implantable electronic devices (CIEDs) capable of detecting episodes of mode switching (as a surrogate for AF) have shown that the amount of AF matters. The TRENDS observational study of patients with at least 1 stroke risk factor with a CIED continuously monitoring for AF found that an AF burden of >5.5 hours was associated with an unadjusted increase risk for thromboembolism, while AF burden of <5.5 hours had a risk of thromboembolism that was no different from those with an AF burden of 0.¹⁰ AF burden in this study was defined as the total amount of AF in a 24-hour period, and may have reflected the total amount of AF time from many different episodes and not just one. In another study, the ASSERT trial found that among patients with CIEDs who had episodes of high atrial arrhythmic events (presumably due to AF) that lasted for at least 6 minutes, the risk of a stroke was more than two-fold higher compared to those without.¹¹ When the investigators stratified the AF events based on duration, they found that AF statistically increased the risk of stroke only when the duration of AF exceeded 17.72 hours. Lastly, in two recent analyses of prior AF trials,^12,13 patients with persistent AF had a higher risk of thromboembolic events when compared to patients with paroxysmal AF, providing further evidence that perhaps that the amount of time spent in AF (among other reasons) matters.

Observations Supporting No Cause-and-Effect Relationship 

While these prior observations may support a cause-and-effect relationship between AF and stroke, there have been a number of observations that cast doubt on this assertion. First, AF rarely occurs alone and often is present in the setting of other atrial abnormalities that can promote thrombogenesis such as chamber dilatation, impaired myocyte behavior and endothelial cell dysfunction.^14,15 Second, studies focused on understanding the temporal link between AF events and subsequent strokes have failed to do so. If AF does cause stroke, then one would expect that strokes would occur soon thereafter, especially among patients with paroxysmal AF. Both in the ASSERT trial¹⁶ and the IMPACT trial,¹⁷thromboembolic events were not temporally associated with an AF event. Third, several observational studies have shown that other atrial arrhythmic events (in particular, premature atrial complexes) can also increase the risk of stroke.^18-20 In fact, one recent observational study found that patients with excessive premature atrial beats (PABs, >30 per hour) and no known AF had a significantly increased risk of stroke compared to those without frequent PABs.²¹ This association remained statistically significant even after treating AF as a censoring event or modeling AF as a time-varying exposure variable. Taken together, these observations have led to the notion that AF and stroke are independent manifestations of an overall heightened stroke risk state due to atrial “cardiopathy” rather than one where AF is a direct cause of strokes (Figure 1).²² 

Why It Matters 

The implications of better understanding this relationship are substantial, because they will directly impact the way in which we manage the use of anticoagulants in AF patients. If AF actually causes strokes, then one can argue that elimination of AF through pulmonary vein isolation or use of antiarrhythmic medications should reduce stroke risk enough so that anticoagulants can be stopped. But if AF and strokes are simply two manifestations of a thrombogenic atrial cardiopathy, then whether or not AF is treated successfully would be irrelevant, and long-term anticoagulation should be advocated. In fact, one could extend that argument to say that perhaps anyone with a high enough CHA₂DS₂-VASc score should be anticoagulated regardless of the presence or absence of AF. In other words, a 75-year-old female with hypertension (CHA₂DS₂-VASc of 4) could be prescribed anticoagulation simply because of who she is, and not whether or not she has AF! 

While this issue remains unanswered, there are a number of ongoing studies (e.g., CABANA [NCT00911508], ARTESiA [NCT01938248]) that may shed more light on this issue in the future. Until then, AF remains as one of the most important factors associated with increased stroke risk, and in its presence, should raise the possibility for needing long-term anticoagulation regardless of its frequency or duration.²³

Disclosure: The author has no conflicts of interest to report regarding the content herein. Dr. Cheng has received honorarium from Boston Scientific, Medtronic, and St. Jude Medical for participation in fellows educational programs and advisory boards. 

References

1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29-e322.
2. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129:837-847.
3. Alonso A, Bengtson LG. A rising tide: the global epidemic of atrial fibrillation. Circulation. 2014;129:829-830.
4. Magnani JW, Rienstra M, Lin H, et al. Atrial fibrillation: current knowledge and future directions in epidemiology and genomics. Circulation. 2011;124:1982-1993.
5. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64:e1-76.
6. McManus DD, Rienstra M, Benjamin EJ. An update on the prognosis of patients with atrial fibrillation. Circulation. 2012;126:e143-146.
7. Subramanian G, Silva J, Silver FL, et al. Risk factors for posterior compared to anterior ischemic stroke: an observational study of the Registry of the Canadian Stroke Network. Neuroepidemiology. 2009;33:12-16.
8. Turhan N, Atalay A, Muderrisoglu H. Predictors of functional outcome in first-ever ischemic stroke: a special interest to ischemic subtypes, comorbidity and age. NeuroRehabilitation. 2009;24:321-326.
9. Sanna T, Diener HC, Passman RS, et al. Cyptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:2478-2486.
10. Glotzer TV, Daoud EG, Wyse DG, et al. The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk: the TRENDS study. Circ Arrhythm Electrophysiol. 2009;2:474-480.
11. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012;366:120-129.
12. Vanassche T, Lauw MN, Elkelboom JW, et al. Risk of ischaemic stroke according to pattern of atrial fibrillation: analysis of 6563 aspirin-treated patients in ACTIVE-A and AVERROES. Eur Heart J. 2015;36:281-287a.
13. Steinberg BA, Hellkamp AS, Lokhnygina Y, et al. Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial. Eur Heart J. 2015;36:288-296.
14. Cai H, Li Z, Goette A, et al. Downregulation of endocardial nitric oxide synthase expression and nitric oxide production in atrial fibrillation: potential mechanisms for atrial thrombosis and stroke. Circulation. 2002;106:2854-2858.
15. Mihm MJ, Yu F, Carnes CA, et al. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation. 2001;104:174-180.
16. Brambatti M, Connolly SJ, Gold MR, et al. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation. 2014;129:2094-2099.
17. Martin DT, Bersohn MM, Waldo AL, et al. Randomized trial of atrial arrhythmia monitoring to guide anticoagulation in patients with implanted defibrillator and cardiac resynchronization devices. Eur Heart J. 2015;36:1660-1668.
18. Todo K, Moriwaki H, Saito K, Naritomi H. Frequent premature atrial contractions in stroke of undetermined etiology. Eur Neurol. 2009;61:285-288.
19. Binici Z, Intzilakis T, Nielsen OW, Køber L, Sajadieh A. Excessive supraventricular ectopic activity and increased risk of atrial fibrillation and stroke. Circulation. 2010;121:1904-1911.
20. Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke. 2013;44:1550-1554.
21. Larsen BS, Kumarathurai P, Falkenberg J, Nielsen OW, Sajadieh A. Excessive atrial ectopy and short atrial runs increase the risk of stroke beyond incident atrial fibrillation. J Am Coll Cardiol. 2015;66:232-241.
22. Kamel H, Okin PM, Longstreth WT Jr, Elkind MS, Soliman EZ. Atrial cardiopathy: a broadened concept of left atrial thromboembolism beyond atrial fibrillation. Future Cardiol. 2015;11(3):323-331.
23. Lip GY, Lane DA. Stroke prevention in atrial fibrillation: a systematic review. JAMA. 2015;313:1950-1962.