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Eur Cardiol. Author manuscript; available in PMC 2016 August 17. Published in final edited form as: Eur Cardiol. 2016 ; 11(1): 49–53. doi:10.15420/ecr.2016:13:2.
Atrial Fibrillation, Cognitive Decline And Dementia Alvaro Alonso, MD, PhD1 and Antonio P. Arenas de Larriva, MD2,3 1Department
of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA,
USA 2Division
of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA
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3Lipid
and Atherosclerosis Unit, IMIBIC/Hospital Universitario Reina Sofía/Universidad de Córdoba, Córdoba, Spain and CIBER Fisiopatología Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
Abstract
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Atrial fibrillation (AF) is a common cardiac arrhythmia. Growing evidence supports a role for AF as a risk factor for cognitive decline and dementia. In this review, we summarize epidemiologic observations linking AF with cognitive outcomes, describe potential mechanisms, and explore the impact of AF treatments on cognitive decline and dementia. Community-based, observational studies show a consistent higher rate of cognitive decline and risk of dementia in persons with AF. These associations are partly due to the increased risk of clinical stroke in AF, but other mechanisms, including incidence of silent cerebral infarcts, microbleeds, and cerebral hypoperfusion, are likely additional contributors. Adequate oral anticoagulation and improved management of the overall cardiovascular risk profile in persons with AF offer the promise of reducing the impact of AF on cognitive decline and dementia.
Keywords Atrial fibrillation; dementia; cognitive decline; cognitive impairment; epidemiology
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Atrial fibrillation (AF) is the most common clinically significant arrhythmia in the world.1 It is estimated that, in the United States alone, the number of people who suffer AF is approximately 2.5 million, being 1.5 times more often in men than in women.2 Despite the decline in morbidity and mortality from cardiovascular disease in general due to advances in prevention and treatment, AF has not followed a similar trend. Over the coming years, the incidence of AF is expected to increase.3 AF is a well-established risk factors for other cardiovascular diseases, including ischemic stroke and heart failure.4 However, growing evidence indicates that AF can have other
Corresponding author: Alvaro Alonso, MD, PhD. Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Rd, Room 3051, Atlanta, GA 30322, USA. Phone: +1 404 727 8714. [email protected]. DISCLOSURES None
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deleterious effects beyond an increased risk of cardiovascular diseases. Specifically, many recent studies have explored the impact of AF on cognition and dementia risk. With the aging of the population, the burden of dementia is expected to increase globally. More than 20% of people aged >70 years have mild cognitive impairment.5 Approximately 800,000 individuals develop mild cognitive impairment and >500,000 develop dementia annually in the United States.6 The total number of new cases of dementia worldwide is about 7.7 million, which means a new case every four seconds. It is estimated that worldwide, 35.6 million people were living with dementia in 2010, and this figure is expected to double every 20 years, 65.7 million in 2030 and 115.4 million in 2050.7 A better understanding of the association of AF with dementia and cognitive impairment, the predictors of cognitive impairment among those with AF, and the potential mechanisms explaining such associations, would inform strategies for the management of AF and the prevention of adverse cognitive outcomes among these patients. We conducted a review of the literature to examine the current evidence supporting an association of AF with cognitive function, dementia and mild cognitive impairment (MCI), describe the predictors of cognitive outcomes in persons with AF, summarize the potential pathophysiologic mechanisms, discuss the preventive interventions specific for AF, and explore the potential impact of current AF treatments on cognitive decline. To inform this review, we searched PubMed for publications through June 1, 2016, using the search query [atrial fibrillation AND (dementia OR cognitive impairment OR cognitive decline)], which considered the previous terms in any field as well as occurring as MeSH terms. We considered publications mostly from the past 5 years (November 1, 2010 and more recent), though we did not exclude frequently referenced older publications, and selected those considered relevant.
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ATRIAL FIBRILLATION AND COGNITIVE FUNCTION
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The most basic evidence supporting an association of AF with worse cognitive function comes from cross-sectional studies comparing cognition in individuals with and without AF. A major limitation of these studies, however, is the difficulty to discern the temporality of the association. In a study in Germany including 122 stroke-free individuals with AF and 564 individuals without AF undergoing a detailed cognitive assessment, those with AF performed significantly worse in tasks of learning, memory, and executive function.8 Similarly, prevalence of AF has been associated with amnestic MCI and with global cognitive function in other cross-sectional studies in Europe and the United States (US).9, 10 Interestingly, a recent analysis of the US-based Atherosclerosis Risk in Communities (ARIC) Study, including 325 individuals who underwent detailed cognitive assessment and heart rhythm monitoring during a maximum of 14 days, found that persistent but not paroxysmal AF was associated with lower cognitive function.11 These findings suggest that AF burden, in addition to its presence, may influence cognitive function.
ATRIAL FIBRILLATION AND COGNITIVE DECLINE Cross-sectional studies have methodological problems that limit the interpretation of their results. Longitudinal studies with repeated assessment of cognitive function provide a more
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rigorous assessment of the association of AF with cognition. Table 1 presents summary characteristics of selected prospective studies. An analysis of 31,506 participants in the multi-national ONTARGET and TRASCEND trials followed up by a median of 5 years found that those who had AF at baseline or developed it during the study had a 13% increased risk of cognitive decline, defined as a decrease of 3 or more points in the MiniMental State Examination (MMSE) test.12 Similar findings were reported in the Cardiovascular Health Study, a community-based study in the US, in which development of AF was associated with faster decline measured by a modified MMSE score during a mean follow-up of 7 years.13 More recently, we found that, among 935 stroke-free participants in the ARIC Study, incident AF was associated with faster decline in measures of executive function and verbal fluency. Of interest, this association was only present among individuals with subclinical cerebral infarcts, suggesting that vascular disease may mediate the link between AF and cognitive decline.14
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ATRIAL FIBRILLATION AND PREVALENCE OF DEMENTIA AND MCI
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In addition to exploring how AF affects cognitive trajectories over time, other relevant question is to determine the association of incident AF with the onset of dementia and MCI. Particularly, assessing whether such association is independent from clinical stroke is of interest since it would point to additional pathways linking AF and neurodegeneration. A few cross-sectional studies have explored differences in the prevalence of dementia/MCI by AF status. Investigators from the Rotterdam study, a community-based prospective cohort in Ommord, a suburb of Rotterdam, the Netherlands, were one of the first to report an association between AF and dementia / cognitive impairment. Among 6584 participants age 55 and older, those with AF had more than double the prevalence of dementia compared to those without AF. The association was stronger in women and younger (600,000 individuals, showing a 42% increased risk of dementia in those with AF versus those without AF.22 A recent systematic review and meta-analysis pooling some of these previous studies and others reported a hazard ratio (95% confidence interval) of dementia of 1.42 (1.17–1.72) comparing individuals with AF to those without AF.23
ATRIAL FIBRILLATION AND BRAIN ABNORMALITIES
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Evaluating the impact of AF on the prevalence and development of brain abnormalities can contribute to advance our understanding of the mechanisms linking AF with cognitive decline and dementia. Several reports emphasize the presence of signs of cerebrovascular disease in brains of patients with AF. Overall, AF patients have higher burden of silent cerebral infarcts and white matter disease, and may have increased prevalence of cerebral microbleeds.24 These lesions may explain the fastest cognitive decline and elevated dementia risk among AF patients.14 The presence of these abnormalities may also impact the management of AF patients, for example influencing decisions about prescribing oral anticoagulation or not.25 Other recent studies have explored the impact of AF on other brain-relate phenotypes. In 4251 participants of the Icelandic population-based Age, Gene/Environment SusceptibilityReykjavik Study, AF was associated with lower brain volume and grey matter.26 Similar findings have been recently reported in a cross-sectional study in individuals from a community-based study in southeastern Minnesota, US.27 An autopsy study in 134 individuals with and 194 without AF found that the prevalence of Alzheimer’s disease neuropathologic changes (neuritic plaques, neurofibrillatory tangles) was higher in individuals with permanent AF than in those without AF.28
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PREDICTORS OF COGNITIVE IMPAIRMENT AND DEMENTIA IN PERSONS WITH ATRIAL FIBRILLATION If patients with AF are at higher risk of developing dementia, then understanding the determinants of dementia among AF patients may inform interventions to prevent cognitive complications of the arrhythmia. Some studies have found that higher CHADS2 and CHA2DS2-VASc scores, stratification schemes commonly used to inform anticoagulant treatment in persons with AF, predict dementia in these patients.22, 29 This association is not surprising, given that age, possibly the strongest predictor of dementia, is part of the scores. Dementia-specific risk models are likely to provide more accurate predictions.
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Oral anticoagulation is a mainstay of the treatment of patients with AF. The influence of anticoagulation control in AF patients on the risk of dementia has been the objective of at least two separate publications. Both studies, using data from the Intermountain Healthcare Clinical Pharmacist Anticoagulation Service, in Utah, US, reported that low percent of time in the therapeutic range among users of vitamin K antagonists were at higher risk of dementia due to under- or overcoagulation.30, 31 Though informative, these studies are limited in that they cannot determine whether baseline cognitive function confounds the association between suboptimal oral anticoagulation and the future risk of dementia. For example, individuals with worse cognitive function at the time of initiation of oral
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anticoagulation may have more problems following an adequate therapeutic regime and would be at higher risk of being diagnosed with dementia later on. Additional observational studies with adequate characterization of baseline cognition or, even better, randomized trials aimed to improve anticoagulation quality are needed to answer this question.
MECHANISMS LINKING ATRIAL FIBRILLATION, COGNITIVE DECLINE, AND DEMENTIA RISK
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The published evidence is consistent in supporting an association between AF and cognitive outcomes. The mechanisms underlying this association, however, still need clarification. An obvious pathway linking AF with cognitive decline or dementia is the elevated risk of stroke among AF patients. AF is associated with at least a doubling of stroke risk,32 and the effects of stroke on cognitive function are well established.18 However, elevated stroke risk does not completely mediate the increased risk of dementia and cognitive decline associated with AF.33 Other mechanisms such as silent cerebral infarcts, microbleeds associated with oral anticoagulation, and cerebral hypoperfusion are likely to play a role (Figure 1).
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AF more than doubles the risk of silent cerebral infarcts independently of stroke,34 and presence of silent cerebral infarcts is a risk factor for dementia.35 At least one study has specifically addressed the role of subclinical cerebrovascular disease as a mediator of the association between AF and cognitive impairment. In a subset of stroke-free participants of the ARIC study who had repeated brain MRIs approximately 12 years apart, we showed that AF was associated with cognitive decline only among individuals who developed incident silent cerebral infarcts.14 The hypercoagulable state resulting from AF is certain to play a role in this mechanism and, consequently, anticoagulation may be effective to prevent adverse cognitive outcomes in patients with AF.36 Similarly, AF could increase dementia risk through its impact on cardiac function. Patients with AF have been found to have reduced cerebral perfusion,37 and restoration of sinus rhythm in AF patients through cardioversion or ablation leads to improvements in cerebral blood flow.38, 39 Reduced diastolic function and low cardiac index, both potential consequences of AF, have been associated with incident dementia in prospective studies.40, 41 Moreover, AF is an established risk factors for heart failure,42 which in turn can worsen cerebral hypoperfusion.43
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Microbleeds may also explain part of the association of AF with cognitive impairment. These brain lesions are relatively frequent and have been linked with an increased risk of cerebral hemorrhage, lacunar infarcts, and degenerative changes of the brain matter.44 Oral anticoagulation in persons with AF can increase the risk of the development of microbleeds or worsen the impact of existing ones on cognitive function. In the community-based Rotterdam study, individuals using coumarin anticoagulants had a higher prevalence and incidence of microbleeds. This risk was particularly higher among individuals with greater variability in anticoagulation control.45 Of recent interest is the potential role that left atrial cardiopathy, as a precursor of AF, can play in cerebrovascular disease and, consequently, the development of cognitive decline and
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dementia. Analysis of several community-based studies have demonstrated that presence of electrocardiographic left atrial abnormality, a marker of atrial cardiopathy, is associated with increased risk of ischemic stroke, mostly non-lacunar, and vascular brain injury even in the absence of AF.46, 47 The impact of left atrial cardiopathy on dementia risk independently of AF needs to be explored.
PREVENTION OF COGNITIVE IMPAIRMENT IN PERSONS WITH ATRIAL FIBRILLATION
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Understanding the mechanisms responsible for the increased rates of cognitive decline and dementia in persons with AF can inform preventive strategies. Current guidelines recommend oral anticoagulation for stroke prevention in most individuals with AF.48, 49 Decreased stroke risk in patients receiving adequate anticoagulation should consequently lead to reduced risk of adverse cognitive outcomes. Improved anticoagulation control could be particularly effective in high-risk individuals, for example those who already have some cognitive impairment. A recent clinical trial including 973 elderly patients with AF found that patients randomized to warfarin had less cognitive decline than those randomized to aspirin after 33 months of follow-up, though the differences were not statistically significant.50 A recent analysis comparing risk of dementia in patients with AF using warfarin or non-vitamin K oral anticoagulants (NOACs) reported lower risk of dementia among NOAC than warfarin users.51 Unfortunately, additional evidence on the effect of oral anticoagulation on cognitive function is not available since larger randomized trials of oral anticoagulation, either traditional vitamin K antagonists or the more recent direct oral anticoagulants, have not considered cognitive endpoints. The long-term cognitive effects of other treatments for AF, such as catheter ablation, are unknown. Future studies that collect prospective information on cognitive outcomes should address this gap. A promising novel area in the management of AF, which could eventually translate into prevention of cognitive complications, is the role of lifestyle changes leading to weight loss and improvement in the overall cardiometabolic risk profile. A randomized trial of weight loss and risk factor management in 150 AF patients led to clinically significant reductions in AF burden and symptoms, and improved cardiac function.52 Similar findings were obtained in 355 AF patients participating in a weight loss intervention, where those who experience sustained weight loss had reductions in AF burden and were more likely to remain in sinus rhythm.53 The impact of these lifestyle interventions on cognitive outcomes in persons with AF has not been assessed to date. Given the role of cardiovascular risk factors in cognition and dementia risk,54 this area can be a fruitful avenue for future research.
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Finally, primary prevention of AF should be the ultimate goal to reduce the burden of AFrelated complications. Unfortunately, we currently lack effective interventions that have consistently demonstrated effectiveness in reducing AF risk in the general population. Though promising, some preventive interventions such as ω-3 fatty acid supplementation, statins, or inhibition of the renin-angiotensin-aldosterone system have failed to reduce AF risk.55, 56 Recent studies indicate that dietary intervention and improved blood pressure
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control can prevent AF.57, 58 Whether these interventions in turn could lead to reduced risk of dementia and cognitive decline remains undetermined.
CONCLUSION A growing and consistent body of literature supports a role for AF as a risk factor for cognitive decline and dementia. The mechanisms responsible for this association are diverse and go beyond the well-established increased stroke risk in persons with AF. Future research needs to deepen the understanding of those mechanisms and, more importantly, develop interventions that reduce the burden of adverse cognitive outcomes associated with AF.
Acknowledgments FUNDING
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Dr. Alonso was supported by grants U01-HL096902 and R01-HL122200 from the National Heart, Lung, and Blood Institute, and by grant 16EIA26410001 from the American Heart Association.
References
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1. Chugh SS, Havmoeller R, Narayana K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014; 129:837–847. [PubMed: 24345399] 2. 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. 2001; 285:2370–2375. [PubMed: 11343485] 3. 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. 2006; 114:119–125. [PubMed: 16818816] 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. [PubMed: 22042927] 5. Plassman BL, Langa KM, Fisher GG, et al. Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med. 2008; 148:427–434. [PubMed: 18347351] 6. Plassman BL, Langa KM, McCammon RJ, et al. Incidence of dementia and cognitive impairment, not dementia in the United States. Ann Neurol. 2011; 70:418–426. [PubMed: 21425187] 7. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013; 9:63–75. [PubMed: 23305823] 8. Knecht S, Oelschläger C, Duning T, et al. Atrial fibrillation in stroke-free patients is associated with memory impairment and hippocampal atrophy. Eur Heart J. 2008; 29:2125–2132. [PubMed: 18667399] 9. Casado Naranjo I, Portilla Cuenca JC, Duque de San Juan B, et al. Association of vascular factors and amnestic mild cognitive impairment: a comprehensive approach. J Alzheimers Dis. 2015; 44:695–704. [PubMed: 25362037] 10. Alosco ML, Spitznagel MB, Sweet LH, Josephson R, Hughes J, Gunstad J. Atrial fibrillation exacerbates cognitive dysfunction and cerebral perfusion in heart failure. Pacing Clin Electrophysiol. 2015; 38:178–186. [PubMed: 25492027] 11. Chen LY, Agarwal SK, Norby FL, et al. Persistent but not paroxysmal atrial fibrillation is independently associated with lower cognitive function: the Atherosclerosis Risk in Communities (ARIC) Study. J Am Coll Cardiol. 2016; 67:1379–1380. [PubMed: 26988962] 12. Marzona I, O’Donnell M, Teo K, et al. Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies. CMAJ. 2012; 184:E329–E336. [PubMed: 22371515] 13. Thacker EL, McKnight B, Psaty BM, et al. Atrial fibrillation and cognitive decline: a longitudinal cohort study. Neurology. 2013; 81:119–125. [PubMed: 23739229] Eur Cardiol. Author manuscript; available in PMC 2016 August 17.
Alonso and Arenas de Larriva
Page 8
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
14. Chen LY, Lopez FL, Gottesman RF, et al. Atrial fibrillation and cognitive decline–the role of subclinical cerebral infarcts: the Atherosclerosis Risk in Communities Study. Stroke. 2014; 45:2568–2574. [PubMed: 25052319] 15. Ott A, Breteler MMB, de Bruyne MC, van Harskamp F, Grobbee DE, Hofman A. Atrial fibrillation and dementia in a population-based study: the Rotterdam Study. Stroke. 1997; 28:316–321. [PubMed: 9040682] 16. Di Nisio M, Prisciandaro M, Rutjes AWS, Russi I, Maiorini L, Porreca E. Dementia in patients with atrial fibrillation and the value of the Hachinski ischemic score. Geriatr Gerontol Int. 2015; 15:770–777. [PubMed: 25311856] 17. Habeych ME, Castilla-Puentes R. Comorbid medical conditions in vascular dementia: a matched case-control study. J Nerv Ment Dis. 2015; 203:604–608. [PubMed: 26230648] 18. Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association / American Stroke Association. Stroke. 2011; 42:2672–2713. [PubMed: 21778438] 19. Dublin S, Anderson ML, Haneuse SJ, et al. Atrial fibrillation and risk of dementia: a prospective cohort study. J Am Geriatr Soc. 2011; 59:1369–1375. [PubMed: 21806558] 20. Rusanen M, Kivipelto M, Levalahti E, et al. Heart disease and long-term risk of dementia and Alzheimer’s disease: a population-based CAIDE study. J Alzheimers Dis. 2014; 42:183–191. [PubMed: 24825565] 21. de Bruijn RFAG, Heeringa J, Wolters FJ, et al. Association between atrial fibrillation and dementia in the general population. JAMA neurology. 2015; 72:1288–1294. [PubMed: 26389654] 22. Liao JN, Chao TF, Liu CJ, et al. Risk and prediction of dementia in patients with atrial fibrillation– a nationwide population-based cohort study. Int J Cardiol. 2015; 199:25–30. [PubMed: 26173170] 23. Santangeli P, Di Biase L, Bai R, et al. Atrial fibrillation and the risk of incident dementia: A metaanalysis. Heart Rhythm. 2012; 9:1761–1768.e1762. [PubMed: 22863685] 24. Gaita F, Corsinovi L, Anselmino M, et al. Prevalence of silent cerebral ischemia in paroxysmal and persistent atrial fibrillation and correlation with cognitive function. J Am Coll Cardiol. 2013; 62:1990–1997. [PubMed: 23850917] 25. Haeusler KG, Wilson D, Fiebach JB, Kirchof P, Werring DJ. Brain MRI to personalise atrial fibrillation therapy: current evidence and perspectives. Heart. 2014; 100:1408–1413. [PubMed: 24951485] 26. Stefansdottir H, Arnar DO, Aspelund T, et al. Atrial fibrillation is associated with reduced brain volume and cognitive function independent of cerebral infarcts. Stroke. 2013; 44:1020–1025. [PubMed: 23444303] 27. Graff-Radford J, Madhavan M, Vemuri P, et al. Atrial fibrillation, cognitive impairment, and neuroimaging. Alzheimers Dement. 2016; 12:391–398. [PubMed: 26607820] 28. Dublin S, Anderson ML, Heckbert SR, et al. Neuropathologic changes associated with atrial fibrillation in a population-based autopsy cohort. J Gerontol A Biol Sci Med Sci. 2014; 69:609– 615. [PubMed: 24077599] 29. Ball J, Carrington MJ, Stewart S, on behalf of the SAFETY investigators. Mild cognitive impairment in high-risk patients with chronic atrial fibrillation: a forgotten component of clinical management? Heart. 2013; 99:542–547. [PubMed: 23315607] 30. Jacobs V, Woller SC, Stevens S, et al. Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk of dementia. Heart Rhythm. 2014; 11:2206–2213. [PubMed: 25111326] 31. Jacobs V, Woller SC, Stevens SM, et al. Percent time with a supratherapeutic INR in atrial fibrillation patients also using an antiplatelet agent is associated with long-term risk of dementia. J Cardiovasc Electrophysiol. 2015; 26:1180–1186. 32. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991; 22:983–988. [PubMed: 1866765] 33. Kalantarian S, Stern TA, Mansour M, Ruskin JN. Cognitive impairment associated with atrial fibrillation: a meta-analysis. Ann Intern Med. 2013; 158:338–346. [PubMed: 23460057]
Eur Cardiol. Author manuscript; available in PMC 2016 August 17.
Alonso and Arenas de Larriva
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34. Kalantarian S, Ay H, Gollub RL, et al. Association between atrial fibrillation and silent cerebral infarctions: a systematic review and meta-analysis. Ann Intern Med. 2014; 161:650–658. [PubMed: 25364886] 35. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003; 348:1215–1222. [PubMed: 12660385] 36. Kalantarian S, Ruskin JN. Atrial fibrillation and cognitive decline: phenomenon or epiphenomenon? Cardiol Clin. 2016; 34:279–285. [PubMed: 27150176] 37. Gomez CR, McLaughlin JR, Njemanze PC, Nashed A. Effect of cardiac dysfunction upon diastolic cerebral blood flow. Angiology. 1992; 43:625–630. [PubMed: 1632564] 38. Porebska A, Nowacki P, Safranow K, Drechsler H. Nonembolic, hemodynanic blood flow disturbances in the middle cerebral arteries in patients with paroxysmal atrial fibrillation without significant carotid stenosis. Clin Neurol Neurosurg. 2007; 109:753–757. [PubMed: 17658680] 39. Efimova I, Efimova N, Chernov V, Popov S, Lishmanov Y. Ablation and pacing: improving brain perfusion and cognitive function in patients with atrial fibrillation and uncontrolled ventricular rates. Pacing Clin Electrophysiol. 2012; 35:320–326. [PubMed: 22126258] 40. de Bruijn RF, Portegies ML, Leening MJ, et al. Subclinical cardiac dysfunction increases the risk of stroke and dementia: the Rotterdam Study. Neurology. 2015; 84:833–840. [PubMed: 25632093] 41. Jefferson AL, Beiser AS, Himali JJ, et al. Low cardiac index is associated with incident dementia and Alzheimer disease: the Framingham Heart Study. Circulation. 2015; 131:1333–1339. [PubMed: 25700178] 42. Magnani JW, Norby FL, Agarwal SK, et al. Racial differences in atrial fibrillation-related cardiovascular disease and mortality: the Atherosclerosis Risk in Communities (ARIC) Study. JAMA Cardiol. 2016 in press. 43. Kim MS, Kim JJ. Heart and brain interconnection – clinical implications of changes in brain function during heart failure. Circ J. 2015; 79:942–947. [PubMed: 25891994] 44. Poels MM, Vernooij MW, Ikram MA, et al. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke. 2010; 41:S103–S106. [PubMed: 20876479] 45. Akoudad S, Darweesh SK, Leening MJ, et al. Use of coumarin anticoagulants and cerebral microbleeds in the general population. Stroke. 2014; 45:3436–3439. [PubMed: 25316276] 46. Kamel H, O’Neal WT, Okin PM, Loehr LR, Alonso A, Soliman EZ. Electrocardiographic left atrial abnormality and stroke subtype in the Atherosclerosis Risk in Communities study. Ann Neurol. 2015; 78:670–678. [PubMed: 26179566] 47. Kamel H, Bartz TM, Longstreth WT Jr, et al. Association between left atrial abnormality on ECG and vascular brain injury on MRI in the Cardiovascular Health Study. Stroke. 2015; 46:711–716. [PubMed: 25677594] 48. 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. Circulation. 2014; 130:e199–e267. [PubMed: 24682347] 49. Camm AJ, Kirchhof P, Lip GYH, et al. Guidelines for the management of atrial fibrillation. Eur Heart J. 2010; 31:2369–2429. [PubMed: 20802247] 50. Mavaddat N, Roalfe A, Fletcher K, et al. Warfarin versus aspirin for prevention of cognitive decline in atrial fibrillation: randomized controlled tiral (Birmingham Atrial Fibrillation Treatment of the Aged Study). Stroke. 2014; 45:1381–1386. [PubMed: 24692475] 51. Jacobs V, May HT, Bair TL, et al. Long-term population-based cerebral ischemic event and cognitive outcomes of direct oral anticoagulants compared with warfarin among long-term anticoagulated patients for atrial fibrillation. Am J Cardiol. 2016 May 5. (epub ahead of print). doi: 10.1016/j.amjcard.2016.1004.1039 52. Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: A randomized clinical trial. JAMA. 2013; 310:2050–2060. [PubMed: 24240932]
Eur Cardiol. Author manuscript; available in PMC 2016 August 17.
Alonso and Arenas de Larriva
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53. Pathak RK, Middeldorp ME, Meredith M, et al. Long-term Effect of Goal directed weight management in an Atrial fibrillation Cohort: a long-term follow-up studY (LEGACY Study). J Am Coll Cardiol. 2015; 65:2159–2169. [PubMed: 25792361] 54. Alonso A, Mosley TH, Gottesman R, Catellier D, Sharrett AR, Coresh J. Risk of dementia hospitalization associated with cardiovascular risk factors in midlife and older age: the Atherosclerosis Risk in Communities (ARIC) Study. J Neurol Neurosurg Psychiatry. 2009; 80:1194–1201. [PubMed: 19692426] 55. Savelieva I, Kakourps N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part I: primary prevention. Europace. 2011; 13:308–328. [PubMed: 21345926] 56. Woods CE, Olgin J. Atrial fibrillation therapy now and in the future: drugs, biologicals, and ablation. Circ Res. 2014; 114:1532–1546. [PubMed: 24763469] 57. Martinez-Gonzalez MA, Toledo E, Arós F, et al. Extra-virgin olive oil consumption reduces risk of atrial fibrillation: the PREDIMED trial. Circulation. 2014; 130:18–26. [PubMed: 24787471] 58. Chen LY, Bigger JT, Hickey KT, et al. Effect of intensive blood pressure lowering on incident atrial fibrillation and p-wave indices in the ACCORD Blood Pressure Trial. American Journal of Hypertension. 2015 Oct 16. (epub ahead of print).
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Figure 1.
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Potential mechanisms linking atrial fibrillation with cognitive decline and dementia. Atrial fibrillation increases the risk of stroke and subclinical cerebral infarcts and can lead to brain hypoperfusion. Oral anticoagulation in patients with atrial fibrillation can lead to new or worsening cerebral microbleeds. In turn, these conditions lead to cognitive decline and increased risk of mild cognitive impairment (MCI) and dementia. Independently, left atrial cardiopathy increases the risk of atrial fibrillation and is associated with stroke risk independently of atrial fibrillation.
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Thacker et al, 201313
Chen et al, 201414 935 men and women (62% women, mean age 62)
5,150 men and women (59% women, mean age 73)
31,506 men and women (30% women, mean age 67)
Study population
Median 10.6 years
Mean 7 years
Mean 4.7 years
Follow-up length
DWR, DSS, WF tests
100-point modified MMSE
Repeated MMSE
Cognitive assessment
Incident AF associated with faster decline in DSS and WF tests
Faster decline in individuals with incident AF, with stronger impact at older age
AF associated with increased risk of cognitive decline (HR 1.14, 95%CI 1.03–1.26)
Main findings
CI: Confidence interval; DSS: Digit Symbol Substitution; DWR: Delayed Word Recall; HR: Hazard ratio; MMSE: Mini-Mental State Examination; WF: Word Fluency
Marzona et al,
Multi-country
Setting
201212
Reference
Selected prospective studies reporting the association of atrial fibrillation with cognitive decline
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Table 1 Alonso and Arenas de Larriva Page 12
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Liao et al, 201522 665,330 men and women (44% women, mean age 70)
6,196 men and women without prevalent AF (59% women, mean age 68)
1,510 men and women (62% women, mean age 65)
31,506 men and women (30% men, mean age 67)
3,045 men and women (60% women, median age 74)
Study population
CI: Confidence Interval; HR: Hazard Ratio; MMSE: Mini-Mental State Examination
Rotterdam, the Netherlands
De Bruijn et al, 201521
Multi-country
Marzona et al, 201212 Eastern Finland
Seattle area, United States
Dublin et al, 201119
Rusanen et al, 201420
Setting
Reference
Mean 4.9 years
Mean 12.8 years
Mean 7.8 years
Mean 4.7 years
Mean 6.8 years
Follow-up length
Diagnosis codes from medical claims
Cognitive screening followed by detailed examination, plus review of medical records
Cognitive screening followed by detailed neuropsychological and clinical assessment
“New diagnosis of dementia, reported severe cognitive impairment, MMSE
Eur Cardiol. Author manuscript; available in PMC 2016 August 17. Published in final edited form as: Eur Cardiol. 2016 ; 11(1): 49–53. doi:10.15420/ecr.2016:13:2.
Atrial Fibrillation, Cognitive Decline And Dementia Alvaro Alonso, MD, PhD1 and Antonio P. Arenas de Larriva, MD2,3 1Department
of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA,
USA 2Division
of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA
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3Lipid
and Atherosclerosis Unit, IMIBIC/Hospital Universitario Reina Sofía/Universidad de Córdoba, Córdoba, Spain and CIBER Fisiopatología Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
Abstract
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Atrial fibrillation (AF) is a common cardiac arrhythmia. Growing evidence supports a role for AF as a risk factor for cognitive decline and dementia. In this review, we summarize epidemiologic observations linking AF with cognitive outcomes, describe potential mechanisms, and explore the impact of AF treatments on cognitive decline and dementia. Community-based, observational studies show a consistent higher rate of cognitive decline and risk of dementia in persons with AF. These associations are partly due to the increased risk of clinical stroke in AF, but other mechanisms, including incidence of silent cerebral infarcts, microbleeds, and cerebral hypoperfusion, are likely additional contributors. Adequate oral anticoagulation and improved management of the overall cardiovascular risk profile in persons with AF offer the promise of reducing the impact of AF on cognitive decline and dementia.
Keywords Atrial fibrillation; dementia; cognitive decline; cognitive impairment; epidemiology
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Atrial fibrillation (AF) is the most common clinically significant arrhythmia in the world.1 It is estimated that, in the United States alone, the number of people who suffer AF is approximately 2.5 million, being 1.5 times more often in men than in women.2 Despite the decline in morbidity and mortality from cardiovascular disease in general due to advances in prevention and treatment, AF has not followed a similar trend. Over the coming years, the incidence of AF is expected to increase.3 AF is a well-established risk factors for other cardiovascular diseases, including ischemic stroke and heart failure.4 However, growing evidence indicates that AF can have other
Corresponding author: Alvaro Alonso, MD, PhD. Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Rd, Room 3051, Atlanta, GA 30322, USA. Phone: +1 404 727 8714. [email protected]. DISCLOSURES None
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deleterious effects beyond an increased risk of cardiovascular diseases. Specifically, many recent studies have explored the impact of AF on cognition and dementia risk. With the aging of the population, the burden of dementia is expected to increase globally. More than 20% of people aged >70 years have mild cognitive impairment.5 Approximately 800,000 individuals develop mild cognitive impairment and >500,000 develop dementia annually in the United States.6 The total number of new cases of dementia worldwide is about 7.7 million, which means a new case every four seconds. It is estimated that worldwide, 35.6 million people were living with dementia in 2010, and this figure is expected to double every 20 years, 65.7 million in 2030 and 115.4 million in 2050.7 A better understanding of the association of AF with dementia and cognitive impairment, the predictors of cognitive impairment among those with AF, and the potential mechanisms explaining such associations, would inform strategies for the management of AF and the prevention of adverse cognitive outcomes among these patients. We conducted a review of the literature to examine the current evidence supporting an association of AF with cognitive function, dementia and mild cognitive impairment (MCI), describe the predictors of cognitive outcomes in persons with AF, summarize the potential pathophysiologic mechanisms, discuss the preventive interventions specific for AF, and explore the potential impact of current AF treatments on cognitive decline. To inform this review, we searched PubMed for publications through June 1, 2016, using the search query [atrial fibrillation AND (dementia OR cognitive impairment OR cognitive decline)], which considered the previous terms in any field as well as occurring as MeSH terms. We considered publications mostly from the past 5 years (November 1, 2010 and more recent), though we did not exclude frequently referenced older publications, and selected those considered relevant.
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ATRIAL FIBRILLATION AND COGNITIVE FUNCTION
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The most basic evidence supporting an association of AF with worse cognitive function comes from cross-sectional studies comparing cognition in individuals with and without AF. A major limitation of these studies, however, is the difficulty to discern the temporality of the association. In a study in Germany including 122 stroke-free individuals with AF and 564 individuals without AF undergoing a detailed cognitive assessment, those with AF performed significantly worse in tasks of learning, memory, and executive function.8 Similarly, prevalence of AF has been associated with amnestic MCI and with global cognitive function in other cross-sectional studies in Europe and the United States (US).9, 10 Interestingly, a recent analysis of the US-based Atherosclerosis Risk in Communities (ARIC) Study, including 325 individuals who underwent detailed cognitive assessment and heart rhythm monitoring during a maximum of 14 days, found that persistent but not paroxysmal AF was associated with lower cognitive function.11 These findings suggest that AF burden, in addition to its presence, may influence cognitive function.
ATRIAL FIBRILLATION AND COGNITIVE DECLINE Cross-sectional studies have methodological problems that limit the interpretation of their results. Longitudinal studies with repeated assessment of cognitive function provide a more
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rigorous assessment of the association of AF with cognition. Table 1 presents summary characteristics of selected prospective studies. An analysis of 31,506 participants in the multi-national ONTARGET and TRASCEND trials followed up by a median of 5 years found that those who had AF at baseline or developed it during the study had a 13% increased risk of cognitive decline, defined as a decrease of 3 or more points in the MiniMental State Examination (MMSE) test.12 Similar findings were reported in the Cardiovascular Health Study, a community-based study in the US, in which development of AF was associated with faster decline measured by a modified MMSE score during a mean follow-up of 7 years.13 More recently, we found that, among 935 stroke-free participants in the ARIC Study, incident AF was associated with faster decline in measures of executive function and verbal fluency. Of interest, this association was only present among individuals with subclinical cerebral infarcts, suggesting that vascular disease may mediate the link between AF and cognitive decline.14
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ATRIAL FIBRILLATION AND PREVALENCE OF DEMENTIA AND MCI
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In addition to exploring how AF affects cognitive trajectories over time, other relevant question is to determine the association of incident AF with the onset of dementia and MCI. Particularly, assessing whether such association is independent from clinical stroke is of interest since it would point to additional pathways linking AF and neurodegeneration. A few cross-sectional studies have explored differences in the prevalence of dementia/MCI by AF status. Investigators from the Rotterdam study, a community-based prospective cohort in Ommord, a suburb of Rotterdam, the Netherlands, were one of the first to report an association between AF and dementia / cognitive impairment. Among 6584 participants age 55 and older, those with AF had more than double the prevalence of dementia compared to those without AF. The association was stronger in women and younger (600,000 individuals, showing a 42% increased risk of dementia in those with AF versus those without AF.22 A recent systematic review and meta-analysis pooling some of these previous studies and others reported a hazard ratio (95% confidence interval) of dementia of 1.42 (1.17–1.72) comparing individuals with AF to those without AF.23
ATRIAL FIBRILLATION AND BRAIN ABNORMALITIES
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Evaluating the impact of AF on the prevalence and development of brain abnormalities can contribute to advance our understanding of the mechanisms linking AF with cognitive decline and dementia. Several reports emphasize the presence of signs of cerebrovascular disease in brains of patients with AF. Overall, AF patients have higher burden of silent cerebral infarcts and white matter disease, and may have increased prevalence of cerebral microbleeds.24 These lesions may explain the fastest cognitive decline and elevated dementia risk among AF patients.14 The presence of these abnormalities may also impact the management of AF patients, for example influencing decisions about prescribing oral anticoagulation or not.25 Other recent studies have explored the impact of AF on other brain-relate phenotypes. In 4251 participants of the Icelandic population-based Age, Gene/Environment SusceptibilityReykjavik Study, AF was associated with lower brain volume and grey matter.26 Similar findings have been recently reported in a cross-sectional study in individuals from a community-based study in southeastern Minnesota, US.27 An autopsy study in 134 individuals with and 194 without AF found that the prevalence of Alzheimer’s disease neuropathologic changes (neuritic plaques, neurofibrillatory tangles) was higher in individuals with permanent AF than in those without AF.28
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PREDICTORS OF COGNITIVE IMPAIRMENT AND DEMENTIA IN PERSONS WITH ATRIAL FIBRILLATION If patients with AF are at higher risk of developing dementia, then understanding the determinants of dementia among AF patients may inform interventions to prevent cognitive complications of the arrhythmia. Some studies have found that higher CHADS2 and CHA2DS2-VASc scores, stratification schemes commonly used to inform anticoagulant treatment in persons with AF, predict dementia in these patients.22, 29 This association is not surprising, given that age, possibly the strongest predictor of dementia, is part of the scores. Dementia-specific risk models are likely to provide more accurate predictions.
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Oral anticoagulation is a mainstay of the treatment of patients with AF. The influence of anticoagulation control in AF patients on the risk of dementia has been the objective of at least two separate publications. Both studies, using data from the Intermountain Healthcare Clinical Pharmacist Anticoagulation Service, in Utah, US, reported that low percent of time in the therapeutic range among users of vitamin K antagonists were at higher risk of dementia due to under- or overcoagulation.30, 31 Though informative, these studies are limited in that they cannot determine whether baseline cognitive function confounds the association between suboptimal oral anticoagulation and the future risk of dementia. For example, individuals with worse cognitive function at the time of initiation of oral
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anticoagulation may have more problems following an adequate therapeutic regime and would be at higher risk of being diagnosed with dementia later on. Additional observational studies with adequate characterization of baseline cognition or, even better, randomized trials aimed to improve anticoagulation quality are needed to answer this question.
MECHANISMS LINKING ATRIAL FIBRILLATION, COGNITIVE DECLINE, AND DEMENTIA RISK
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The published evidence is consistent in supporting an association between AF and cognitive outcomes. The mechanisms underlying this association, however, still need clarification. An obvious pathway linking AF with cognitive decline or dementia is the elevated risk of stroke among AF patients. AF is associated with at least a doubling of stroke risk,32 and the effects of stroke on cognitive function are well established.18 However, elevated stroke risk does not completely mediate the increased risk of dementia and cognitive decline associated with AF.33 Other mechanisms such as silent cerebral infarcts, microbleeds associated with oral anticoagulation, and cerebral hypoperfusion are likely to play a role (Figure 1).
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AF more than doubles the risk of silent cerebral infarcts independently of stroke,34 and presence of silent cerebral infarcts is a risk factor for dementia.35 At least one study has specifically addressed the role of subclinical cerebrovascular disease as a mediator of the association between AF and cognitive impairment. In a subset of stroke-free participants of the ARIC study who had repeated brain MRIs approximately 12 years apart, we showed that AF was associated with cognitive decline only among individuals who developed incident silent cerebral infarcts.14 The hypercoagulable state resulting from AF is certain to play a role in this mechanism and, consequently, anticoagulation may be effective to prevent adverse cognitive outcomes in patients with AF.36 Similarly, AF could increase dementia risk through its impact on cardiac function. Patients with AF have been found to have reduced cerebral perfusion,37 and restoration of sinus rhythm in AF patients through cardioversion or ablation leads to improvements in cerebral blood flow.38, 39 Reduced diastolic function and low cardiac index, both potential consequences of AF, have been associated with incident dementia in prospective studies.40, 41 Moreover, AF is an established risk factors for heart failure,42 which in turn can worsen cerebral hypoperfusion.43
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Microbleeds may also explain part of the association of AF with cognitive impairment. These brain lesions are relatively frequent and have been linked with an increased risk of cerebral hemorrhage, lacunar infarcts, and degenerative changes of the brain matter.44 Oral anticoagulation in persons with AF can increase the risk of the development of microbleeds or worsen the impact of existing ones on cognitive function. In the community-based Rotterdam study, individuals using coumarin anticoagulants had a higher prevalence and incidence of microbleeds. This risk was particularly higher among individuals with greater variability in anticoagulation control.45 Of recent interest is the potential role that left atrial cardiopathy, as a precursor of AF, can play in cerebrovascular disease and, consequently, the development of cognitive decline and
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dementia. Analysis of several community-based studies have demonstrated that presence of electrocardiographic left atrial abnormality, a marker of atrial cardiopathy, is associated with increased risk of ischemic stroke, mostly non-lacunar, and vascular brain injury even in the absence of AF.46, 47 The impact of left atrial cardiopathy on dementia risk independently of AF needs to be explored.
PREVENTION OF COGNITIVE IMPAIRMENT IN PERSONS WITH ATRIAL FIBRILLATION
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Understanding the mechanisms responsible for the increased rates of cognitive decline and dementia in persons with AF can inform preventive strategies. Current guidelines recommend oral anticoagulation for stroke prevention in most individuals with AF.48, 49 Decreased stroke risk in patients receiving adequate anticoagulation should consequently lead to reduced risk of adverse cognitive outcomes. Improved anticoagulation control could be particularly effective in high-risk individuals, for example those who already have some cognitive impairment. A recent clinical trial including 973 elderly patients with AF found that patients randomized to warfarin had less cognitive decline than those randomized to aspirin after 33 months of follow-up, though the differences were not statistically significant.50 A recent analysis comparing risk of dementia in patients with AF using warfarin or non-vitamin K oral anticoagulants (NOACs) reported lower risk of dementia among NOAC than warfarin users.51 Unfortunately, additional evidence on the effect of oral anticoagulation on cognitive function is not available since larger randomized trials of oral anticoagulation, either traditional vitamin K antagonists or the more recent direct oral anticoagulants, have not considered cognitive endpoints. The long-term cognitive effects of other treatments for AF, such as catheter ablation, are unknown. Future studies that collect prospective information on cognitive outcomes should address this gap. A promising novel area in the management of AF, which could eventually translate into prevention of cognitive complications, is the role of lifestyle changes leading to weight loss and improvement in the overall cardiometabolic risk profile. A randomized trial of weight loss and risk factor management in 150 AF patients led to clinically significant reductions in AF burden and symptoms, and improved cardiac function.52 Similar findings were obtained in 355 AF patients participating in a weight loss intervention, where those who experience sustained weight loss had reductions in AF burden and were more likely to remain in sinus rhythm.53 The impact of these lifestyle interventions on cognitive outcomes in persons with AF has not been assessed to date. Given the role of cardiovascular risk factors in cognition and dementia risk,54 this area can be a fruitful avenue for future research.
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Finally, primary prevention of AF should be the ultimate goal to reduce the burden of AFrelated complications. Unfortunately, we currently lack effective interventions that have consistently demonstrated effectiveness in reducing AF risk in the general population. Though promising, some preventive interventions such as ω-3 fatty acid supplementation, statins, or inhibition of the renin-angiotensin-aldosterone system have failed to reduce AF risk.55, 56 Recent studies indicate that dietary intervention and improved blood pressure
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control can prevent AF.57, 58 Whether these interventions in turn could lead to reduced risk of dementia and cognitive decline remains undetermined.
CONCLUSION A growing and consistent body of literature supports a role for AF as a risk factor for cognitive decline and dementia. The mechanisms responsible for this association are diverse and go beyond the well-established increased stroke risk in persons with AF. Future research needs to deepen the understanding of those mechanisms and, more importantly, develop interventions that reduce the burden of adverse cognitive outcomes associated with AF.
Acknowledgments FUNDING
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Dr. Alonso was supported by grants U01-HL096902 and R01-HL122200 from the National Heart, Lung, and Blood Institute, and by grant 16EIA26410001 from the American Heart Association.
References
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1. Chugh SS, Havmoeller R, Narayana K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014; 129:837–847. [PubMed: 24345399] 2. 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. 2001; 285:2370–2375. [PubMed: 11343485] 3. 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. 2006; 114:119–125. [PubMed: 16818816] 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. [PubMed: 22042927] 5. Plassman BL, Langa KM, Fisher GG, et al. Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med. 2008; 148:427–434. [PubMed: 18347351] 6. Plassman BL, Langa KM, McCammon RJ, et al. Incidence of dementia and cognitive impairment, not dementia in the United States. Ann Neurol. 2011; 70:418–426. [PubMed: 21425187] 7. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013; 9:63–75. [PubMed: 23305823] 8. Knecht S, Oelschläger C, Duning T, et al. Atrial fibrillation in stroke-free patients is associated with memory impairment and hippocampal atrophy. Eur Heart J. 2008; 29:2125–2132. [PubMed: 18667399] 9. Casado Naranjo I, Portilla Cuenca JC, Duque de San Juan B, et al. Association of vascular factors and amnestic mild cognitive impairment: a comprehensive approach. J Alzheimers Dis. 2015; 44:695–704. [PubMed: 25362037] 10. Alosco ML, Spitznagel MB, Sweet LH, Josephson R, Hughes J, Gunstad J. Atrial fibrillation exacerbates cognitive dysfunction and cerebral perfusion in heart failure. Pacing Clin Electrophysiol. 2015; 38:178–186. [PubMed: 25492027] 11. Chen LY, Agarwal SK, Norby FL, et al. Persistent but not paroxysmal atrial fibrillation is independently associated with lower cognitive function: the Atherosclerosis Risk in Communities (ARIC) Study. J Am Coll Cardiol. 2016; 67:1379–1380. [PubMed: 26988962] 12. Marzona I, O’Donnell M, Teo K, et al. Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies. CMAJ. 2012; 184:E329–E336. [PubMed: 22371515] 13. Thacker EL, McKnight B, Psaty BM, et al. Atrial fibrillation and cognitive decline: a longitudinal cohort study. Neurology. 2013; 81:119–125. [PubMed: 23739229] Eur Cardiol. Author manuscript; available in PMC 2016 August 17.
Alonso and Arenas de Larriva
Page 8
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
14. Chen LY, Lopez FL, Gottesman RF, et al. Atrial fibrillation and cognitive decline–the role of subclinical cerebral infarcts: the Atherosclerosis Risk in Communities Study. Stroke. 2014; 45:2568–2574. [PubMed: 25052319] 15. Ott A, Breteler MMB, de Bruyne MC, van Harskamp F, Grobbee DE, Hofman A. Atrial fibrillation and dementia in a population-based study: the Rotterdam Study. Stroke. 1997; 28:316–321. [PubMed: 9040682] 16. Di Nisio M, Prisciandaro M, Rutjes AWS, Russi I, Maiorini L, Porreca E. Dementia in patients with atrial fibrillation and the value of the Hachinski ischemic score. Geriatr Gerontol Int. 2015; 15:770–777. [PubMed: 25311856] 17. Habeych ME, Castilla-Puentes R. Comorbid medical conditions in vascular dementia: a matched case-control study. J Nerv Ment Dis. 2015; 203:604–608. [PubMed: 26230648] 18. Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association / American Stroke Association. Stroke. 2011; 42:2672–2713. [PubMed: 21778438] 19. Dublin S, Anderson ML, Haneuse SJ, et al. Atrial fibrillation and risk of dementia: a prospective cohort study. J Am Geriatr Soc. 2011; 59:1369–1375. [PubMed: 21806558] 20. Rusanen M, Kivipelto M, Levalahti E, et al. Heart disease and long-term risk of dementia and Alzheimer’s disease: a population-based CAIDE study. J Alzheimers Dis. 2014; 42:183–191. [PubMed: 24825565] 21. de Bruijn RFAG, Heeringa J, Wolters FJ, et al. Association between atrial fibrillation and dementia in the general population. JAMA neurology. 2015; 72:1288–1294. [PubMed: 26389654] 22. Liao JN, Chao TF, Liu CJ, et al. Risk and prediction of dementia in patients with atrial fibrillation– a nationwide population-based cohort study. Int J Cardiol. 2015; 199:25–30. [PubMed: 26173170] 23. Santangeli P, Di Biase L, Bai R, et al. Atrial fibrillation and the risk of incident dementia: A metaanalysis. Heart Rhythm. 2012; 9:1761–1768.e1762. [PubMed: 22863685] 24. Gaita F, Corsinovi L, Anselmino M, et al. Prevalence of silent cerebral ischemia in paroxysmal and persistent atrial fibrillation and correlation with cognitive function. J Am Coll Cardiol. 2013; 62:1990–1997. [PubMed: 23850917] 25. Haeusler KG, Wilson D, Fiebach JB, Kirchof P, Werring DJ. Brain MRI to personalise atrial fibrillation therapy: current evidence and perspectives. Heart. 2014; 100:1408–1413. [PubMed: 24951485] 26. Stefansdottir H, Arnar DO, Aspelund T, et al. Atrial fibrillation is associated with reduced brain volume and cognitive function independent of cerebral infarcts. Stroke. 2013; 44:1020–1025. [PubMed: 23444303] 27. Graff-Radford J, Madhavan M, Vemuri P, et al. Atrial fibrillation, cognitive impairment, and neuroimaging. Alzheimers Dement. 2016; 12:391–398. [PubMed: 26607820] 28. Dublin S, Anderson ML, Heckbert SR, et al. Neuropathologic changes associated with atrial fibrillation in a population-based autopsy cohort. J Gerontol A Biol Sci Med Sci. 2014; 69:609– 615. [PubMed: 24077599] 29. Ball J, Carrington MJ, Stewart S, on behalf of the SAFETY investigators. Mild cognitive impairment in high-risk patients with chronic atrial fibrillation: a forgotten component of clinical management? Heart. 2013; 99:542–547. [PubMed: 23315607] 30. Jacobs V, Woller SC, Stevens S, et al. Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk of dementia. Heart Rhythm. 2014; 11:2206–2213. [PubMed: 25111326] 31. Jacobs V, Woller SC, Stevens SM, et al. Percent time with a supratherapeutic INR in atrial fibrillation patients also using an antiplatelet agent is associated with long-term risk of dementia. J Cardiovasc Electrophysiol. 2015; 26:1180–1186. 32. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991; 22:983–988. [PubMed: 1866765] 33. Kalantarian S, Stern TA, Mansour M, Ruskin JN. Cognitive impairment associated with atrial fibrillation: a meta-analysis. Ann Intern Med. 2013; 158:338–346. [PubMed: 23460057]
Eur Cardiol. Author manuscript; available in PMC 2016 August 17.
Alonso and Arenas de Larriva
Page 9
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
34. Kalantarian S, Ay H, Gollub RL, et al. Association between atrial fibrillation and silent cerebral infarctions: a systematic review and meta-analysis. Ann Intern Med. 2014; 161:650–658. [PubMed: 25364886] 35. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003; 348:1215–1222. [PubMed: 12660385] 36. Kalantarian S, Ruskin JN. Atrial fibrillation and cognitive decline: phenomenon or epiphenomenon? Cardiol Clin. 2016; 34:279–285. [PubMed: 27150176] 37. Gomez CR, McLaughlin JR, Njemanze PC, Nashed A. Effect of cardiac dysfunction upon diastolic cerebral blood flow. Angiology. 1992; 43:625–630. [PubMed: 1632564] 38. Porebska A, Nowacki P, Safranow K, Drechsler H. Nonembolic, hemodynanic blood flow disturbances in the middle cerebral arteries in patients with paroxysmal atrial fibrillation without significant carotid stenosis. Clin Neurol Neurosurg. 2007; 109:753–757. [PubMed: 17658680] 39. Efimova I, Efimova N, Chernov V, Popov S, Lishmanov Y. Ablation and pacing: improving brain perfusion and cognitive function in patients with atrial fibrillation and uncontrolled ventricular rates. Pacing Clin Electrophysiol. 2012; 35:320–326. [PubMed: 22126258] 40. de Bruijn RF, Portegies ML, Leening MJ, et al. Subclinical cardiac dysfunction increases the risk of stroke and dementia: the Rotterdam Study. Neurology. 2015; 84:833–840. [PubMed: 25632093] 41. Jefferson AL, Beiser AS, Himali JJ, et al. Low cardiac index is associated with incident dementia and Alzheimer disease: the Framingham Heart Study. Circulation. 2015; 131:1333–1339. [PubMed: 25700178] 42. Magnani JW, Norby FL, Agarwal SK, et al. Racial differences in atrial fibrillation-related cardiovascular disease and mortality: the Atherosclerosis Risk in Communities (ARIC) Study. JAMA Cardiol. 2016 in press. 43. Kim MS, Kim JJ. Heart and brain interconnection – clinical implications of changes in brain function during heart failure. Circ J. 2015; 79:942–947. [PubMed: 25891994] 44. Poels MM, Vernooij MW, Ikram MA, et al. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke. 2010; 41:S103–S106. [PubMed: 20876479] 45. Akoudad S, Darweesh SK, Leening MJ, et al. Use of coumarin anticoagulants and cerebral microbleeds in the general population. Stroke. 2014; 45:3436–3439. [PubMed: 25316276] 46. Kamel H, O’Neal WT, Okin PM, Loehr LR, Alonso A, Soliman EZ. Electrocardiographic left atrial abnormality and stroke subtype in the Atherosclerosis Risk in Communities study. Ann Neurol. 2015; 78:670–678. [PubMed: 26179566] 47. Kamel H, Bartz TM, Longstreth WT Jr, et al. Association between left atrial abnormality on ECG and vascular brain injury on MRI in the Cardiovascular Health Study. Stroke. 2015; 46:711–716. [PubMed: 25677594] 48. 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. Circulation. 2014; 130:e199–e267. [PubMed: 24682347] 49. Camm AJ, Kirchhof P, Lip GYH, et al. Guidelines for the management of atrial fibrillation. Eur Heart J. 2010; 31:2369–2429. [PubMed: 20802247] 50. Mavaddat N, Roalfe A, Fletcher K, et al. Warfarin versus aspirin for prevention of cognitive decline in atrial fibrillation: randomized controlled tiral (Birmingham Atrial Fibrillation Treatment of the Aged Study). Stroke. 2014; 45:1381–1386. [PubMed: 24692475] 51. Jacobs V, May HT, Bair TL, et al. Long-term population-based cerebral ischemic event and cognitive outcomes of direct oral anticoagulants compared with warfarin among long-term anticoagulated patients for atrial fibrillation. Am J Cardiol. 2016 May 5. (epub ahead of print). doi: 10.1016/j.amjcard.2016.1004.1039 52. Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: A randomized clinical trial. JAMA. 2013; 310:2050–2060. [PubMed: 24240932]
Eur Cardiol. Author manuscript; available in PMC 2016 August 17.
Alonso and Arenas de Larriva
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53. Pathak RK, Middeldorp ME, Meredith M, et al. Long-term Effect of Goal directed weight management in an Atrial fibrillation Cohort: a long-term follow-up studY (LEGACY Study). J Am Coll Cardiol. 2015; 65:2159–2169. [PubMed: 25792361] 54. Alonso A, Mosley TH, Gottesman R, Catellier D, Sharrett AR, Coresh J. Risk of dementia hospitalization associated with cardiovascular risk factors in midlife and older age: the Atherosclerosis Risk in Communities (ARIC) Study. J Neurol Neurosurg Psychiatry. 2009; 80:1194–1201. [PubMed: 19692426] 55. Savelieva I, Kakourps N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part I: primary prevention. Europace. 2011; 13:308–328. [PubMed: 21345926] 56. Woods CE, Olgin J. Atrial fibrillation therapy now and in the future: drugs, biologicals, and ablation. Circ Res. 2014; 114:1532–1546. [PubMed: 24763469] 57. Martinez-Gonzalez MA, Toledo E, Arós F, et al. Extra-virgin olive oil consumption reduces risk of atrial fibrillation: the PREDIMED trial. Circulation. 2014; 130:18–26. [PubMed: 24787471] 58. Chen LY, Bigger JT, Hickey KT, et al. Effect of intensive blood pressure lowering on incident atrial fibrillation and p-wave indices in the ACCORD Blood Pressure Trial. American Journal of Hypertension. 2015 Oct 16. (epub ahead of print).
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Figure 1.
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Potential mechanisms linking atrial fibrillation with cognitive decline and dementia. Atrial fibrillation increases the risk of stroke and subclinical cerebral infarcts and can lead to brain hypoperfusion. Oral anticoagulation in patients with atrial fibrillation can lead to new or worsening cerebral microbleeds. In turn, these conditions lead to cognitive decline and increased risk of mild cognitive impairment (MCI) and dementia. Independently, left atrial cardiopathy increases the risk of atrial fibrillation and is associated with stroke risk independently of atrial fibrillation.
Author Manuscript Eur Cardiol. Author manuscript; available in PMC 2016 August 17.
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Thacker et al, 201313
Chen et al, 201414 935 men and women (62% women, mean age 62)
5,150 men and women (59% women, mean age 73)
31,506 men and women (30% women, mean age 67)
Study population
Median 10.6 years
Mean 7 years
Mean 4.7 years
Follow-up length
DWR, DSS, WF tests
100-point modified MMSE
Repeated MMSE
Cognitive assessment
Incident AF associated with faster decline in DSS and WF tests
Faster decline in individuals with incident AF, with stronger impact at older age
AF associated with increased risk of cognitive decline (HR 1.14, 95%CI 1.03–1.26)
Main findings
CI: Confidence interval; DSS: Digit Symbol Substitution; DWR: Delayed Word Recall; HR: Hazard ratio; MMSE: Mini-Mental State Examination; WF: Word Fluency
Marzona et al,
Multi-country
Setting
201212
Reference
Selected prospective studies reporting the association of atrial fibrillation with cognitive decline
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Table 1 Alonso and Arenas de Larriva Page 12
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Author Manuscript Taiwan
Liao et al, 201522 665,330 men and women (44% women, mean age 70)
6,196 men and women without prevalent AF (59% women, mean age 68)
1,510 men and women (62% women, mean age 65)
31,506 men and women (30% men, mean age 67)
3,045 men and women (60% women, median age 74)
Study population
CI: Confidence Interval; HR: Hazard Ratio; MMSE: Mini-Mental State Examination
Rotterdam, the Netherlands
De Bruijn et al, 201521
Multi-country
Marzona et al, 201212 Eastern Finland
Seattle area, United States
Dublin et al, 201119
Rusanen et al, 201420
Setting
Reference
Mean 4.9 years
Mean 12.8 years
Mean 7.8 years
Mean 4.7 years
Mean 6.8 years
Follow-up length
Diagnosis codes from medical claims
Cognitive screening followed by detailed examination, plus review of medical records
Cognitive screening followed by detailed neuropsychological and clinical assessment
“New diagnosis of dementia, reported severe cognitive impairment, MMSE
