Curr Cardiol Rep (2014) 16:519 DOI 10.1007/s11886-014-0519-y
INVASIVE ELECTROPHYSIOLOGY AND PACING (EK HEIST, SECTION EDITOR)
The Impact of Atrial Fibrillation and Its Treatment on Dementia Arun Kanmanthareddy & Ajay Vallakati & Arun Sridhar & Madhu Reddy & Hari Priya Sanjani & Jayasree Pillarisetti & Donita Atkins & Sudharani Bommana & Misty Jaeger & Loren Berenbom & Dhanunjaya Lakkireddy
Published online: 29 June 2014 # Springer Science+Business Media New York 2014
Abstract Atrial fibrillation (AF) is a very common tachyarrhythmia and is becoming increasingly prevalent, while dementia is a neurological condition manifested as loss of memory and cognitive ability. Both these conditions share several common risk factors. It is becoming increasingly evident that AF increases the risk of dementia. There are several pathophysiological mechanisms by which AF can cause dementia. AF increases the stroke risk and strokes are strongly associated with dementia. Besides stroke, altered cerebral blood flow in AF and cerebral microbleeds from anticoagulation may enhance the risk of dementia. Maintaining sinus rhythm may therefore decrease this risk. Catheter ablation is emerging as an effective alternative to maintain patients in sinus rhythm. This procedure has also shown promise in decreasing the risk of all types of dementia. Besides maintaining sinus rhythm and oral anticoagulation, aggressive risk factor modification may reduce the likelihood or delay the onset of dementia. Keywords Atrial fibrillation . Dementia . Cognitive impairment . Stroke and dementia . Catheter ablation and dementia This article is part of the Topical Collection on Invasive Electrophysiology and Pacing A. Kanmanthareddy : A. Vallakati : A. Sridhar : M. Reddy : H. P. Sanjani : J. Pillarisetti : D. Atkins : S. Bommana : M. Jaeger : L. Berenbom : D. Lakkireddy (*) Cardiovascular Research Institute, Bloch Heart Rhythm Center, University of Kansas Hospital, Kansas City, KS, USA e-mail: [email protected] D. Lakkireddy Center for Excellence in Atrial Fibrillation & Electrophysiology Research Bloch Heart Rhythm Center – Mid America Cardiology, Kansas City, KS, USA D. Lakkireddy KU Cardiovascular Research Institute- University of Kansas Hospital & Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
Introduction Atrial fibrillation (AF) is the most common tachyarrhythmia observed in the United States with more than 3 million people [1] estimated to have the disease and one in four men and women over the age of 40 are estimated to develop it during their lives [2]. This has almost reached an epidemic status worldwide causing a significant burden on health care delivery systems. The most feared complication of AF is stroke. Other neurological illnesses such as mild cognitive dysfunction (MCD), dementia and silent cerebral infarcts are increasingly being reported in patients with AF [3]. Many studies have shown an association between cognitive impairment and AF [4, 5]. Loss of memory and impaired functioning of at least one other cognitive domain characterize dementia. The prevalence of dementia is projected to increase from 24 million in 2001 to 81 million in 2040 [6]. Dementia is commonly seen in the elderly with an estimated prevalence of 14 % in the age group >70 years [7]. There are several subtypes of dementia based on etiology namely, Alzheimer’s dementia (AD), vascular dementia, Lewy body dementia, frontotemporal dementia, and prion associated dementia, among others [8]. AD is the most common subtype of dementia and in 2010, the estimated number of patients suffering with this disease was 4.7 million in individuals aged 65 and above and by 2050, approximately 14 million people are expected to suffer from AD [9, 10].
Atrial Fibrillation and Dementia Multiple studies have demonstrated an increasing association between AF and dementia. Ott and colleagues first described the risk of dementia in the Rotterdam study [11]. In their study the odds ratio (OR) of dementia in patients with AF was estimated to be 2.3 (95 % CI, 1.2 - 3.4). Subsequently, several studies have tried to better define this association. The relative risk of dementia in AF patients varied from 1.3 to 4.6 in
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different studies [12–15] (Table 1). Interestingly, the connection between AF and dementia was not as evident in a few studies [16–19]. These mixed results could be due to significant differences in the study design, varied population demographics, comorbidities, stroke status, duration and methods of follow up across different studies. However, pooled metaanalysis of these studies has shown that AF is associated with increased risk of dementia [20••, 21, 22]. Most recently Bunch et al. in their retrospective study of 37,000 patients reported that dementia of all subtypes were strongly associated with AF (hazard ratio (HR) of vascular, senile and Alzheimer’s dementia was 1.38, 1.41, and 1.45 respectively) [23••]. The risk of dementia strongly correlates with increasing age, however, this study shows that AF patients younger than 70 years were at the greatest risk of premature dementia [23••]. Further there is also increasing evidence to suggest the association of cognitive dysfunction in patients with AF. Initial evidence of this association was first observed in the Rotterdam study [11]. Cognitive dysfunction defined as a score of less than 26 on the Mini Mental Score was highly prevalent in subjects with AF compared to those without AF [11]. The age and sex adjusted OR of cognitive impairment in AF patients was 1.7 (95 % CI, 1.2-2.5). Interestingly the association was stronger in the Alzheimer’s type than vascular type of dementia [11]. Furthermore, they observed that younger elderly patients with AF were at higher risk of cognitive dysfunction and dementia [11]. Subsequently several studies have reported similar observations of increased cognitive impairment in AF [13, 24-27 (Table 2). Marzona et al. did a post-hoc analysis of two randomized clinical trials involving about 32,000 patients. In their study, AF increased the risk of cognitive impairment by 14 % [13]. Other studies have estimated this risk to be 2-8 times higher in AF patients [27, 25, 24]. Tilvis et al. in a 10-year follow up study observed that the risk of cognitive impairment was 2.8 times higher in patients with AF [25]. Contrary to the above findings, association between cognitive impairment and AF was not observed in a few studies [17, 28, 29].
Table 1 Risk of dementia in atrial fibrillation Study name
Year
Dementia risk (95 % CI)
Ott et al. [11] Forti et al. [15] Marengoni et al. [16] Peters et al. [17] Bunch et al. [23••] Dublin et al. [14] Li et al. [18] Marzona et al. [13] Rastas et al. [19]
1997 2007 2011 2009 2010 2011 2011 2012 2007
OR 2.3 (1.2 - 3.4) HR 4.6 (1.7-12.5) HR 0.8 (0.5-1.7) HR 1.03 (0.62-1.72) OR 1.56 (1.4-1.74) HR 1.38 (1.10-1.73) HR 1.09 (0.54-2.2) HR 1.3 (1.14-1.49) HR 0.86 (0.50-1.47)
Table 2 Risk of cognitive decline in atrial fibrillation Study name
Year
Risk of cognitive decline (95 % CI)
Ott et al. [11] Cacciatore et al. [28] Tilvis et al. [25] Elias et al. [24] Jozwiak et al. [26] Debette et al. [27] Bilato et al. [29] Peters et al. [17] Marzona et al. [13]
1997 1998 2004 2006 2006 2007 2009 2009 2012
OR 1.7 (1.1-2.6) OR 1.1 (0.5-2.2) RR 2.88 (1.26-6.06) OR 4.1 (1.84-8.74) OR 1.56 (1.27-1.92) OR 8.1 (1.9-34.6) OR 1.14 (0.73-1.8) HR 1.08 (0.80-1.46) HR 1.14 (1.03-1.26)
Etiology & Pathogenesis of Dementia in Atrial Fibrillation Etiology of dementia varies by the subtype of dementia; however, there are several established risk factors for dementia such as age, sex, education, hypertension, diabetes, hyperlipidemia, sleep apnea, and stroke. However, longitudinal studies that controlled for these comorbidities also showed increased risk of cognitive decline suggesting that there may be other factors in play [13, 24]. AF also shares several of these common risk factors such as age, hypertension, and diabetes. Stroke is an obvious complication of AF in high-risk groups. In addition to the above common risk factors, the triple insult of stroke, cerebral microbleeds from anticoagulation, and non-uniform cerebral blood flow during AF increase the risk of dementia tremendously in this group. Figure 1 illustrates the pathogenesis of dementia in AF patients and the pathological mechanisms specific to AF are discussed below.
Stroke Stroke risk is increased fivefold in patients with AF and approximately 20 % of all strokes are caused due to systemic thromboembolism from AF [30]. Depending on the other comorbidities, stroke risk varies among AF patients. Stroke risk in AF varies from 1-18 % per year based on additional risk factors [31, 32] (Table 3). The CHADS2 and CHADS2Vasc are simple but very practical risk assessment systems that help to identify the individual’s stroke risk. Stroke has been associated with both cognitive impairment as well as dementia [33]. Elderly patients are more vulnerable to dementia from stroke due to lower cortical volumes in these patients [33]. The size, severity, and the location of the stroke also influence the onset and severity of dementia [34] (Fig. 2). Loss of cortical matter from strokes is likely to result in impairment of memory and cognitive abilities, especially in the elderly as seen in Fig. 2. Recurrent strokes may further compromise these abilities if AF progression continues.
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Fig. 1 Mechanisms of pathogenesis of dementia in atrial fibrillation
There is increasing evidence to show that dementia and its subtypes may be related to AF even without clinical strokes and it is much more common in women than in men [11]. Cha et al. estimated the burden of silent strokes in AF using MRI. In their study, silent strokes in AF were present in 28.3 % compared to 6.6 % for patients with sinus rhythm [35]. A few
Table 3 Risk of stroke according to CHADS2 and CHA2DS2-Vasc risk stratification systems [31, 32] CHADS2 score§
Stroke%/year
CHA2DS2-Vasc¶
Stroke%/year
0 1 2 3 4 5 6
1.9 2.8 4.0 5.9 8.5 12.5 18.2
0 1 2 3 4 5 6 7 8 9
0 1.3 2.2 3.2 4.0 6.7 9.8 9.6 6.7 15.2
CHADS2 = C- congestive heart failure (1), H – Hypertension (1), A – Age ≥75 (1), D- Diabetes (1), S- Stroke (2) §
¶ CHA2DS2-Vasc = C- Congestive heart failure (1), H – Hypertension (1), A –Age 65-74 (1) and ≥ 75 (2), D- Diabetes (1), S- Sex- female (1) and Stroke (2), V – Vascular disease (1)
other studies have also estimated a higher risk of non-clinical strokes in patients with AF [36, 37]. Kalantarian et al., in a meta-analysis of all studies examining the relationship of AF and cognitive impairment, conclude that patients with AF have a relative risk of 1.4 (95 % CI, 1.191.64) when compared to those without AF [20••]. Further, subgroup analysis revealed that following stroke, patients with AF had a 2.7 fold rise in their risk of cognitive impairment. Pooled analysis of studies that excluded patients with stroke revealed that their relative risk of developing cognitive impairment was 1.37, which was similar to the overall risk. Therefore, in addition to clinically detected stroke, micro-emboli causing silent infarctions are postulated to be associated with cognitive impairment. Silent infarcts are estimated to double the risk of dementia; thalamic infarcts were associated with memory loss and non-thalamic infarcts were associated with loss of psychomotor speed [38]. These silent infarcts independently increase the risk of developing dementia [38–40]. Cerebral Microbleeds These are hypo-intense small round lesions seen on T2 weighted magnetic resonance imaging of the brain and are a marker of hemosiderin deposits from prior hemorrhages [41] (Fig. 3). These microbleeds are a result of microangiopathy and are a predictor of future intracerebral hemorrhage [42].
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Fig. 2 Concept of the cumulative effects of stroke, neurodegeneration, and subcortical disconnection (white matter lesion). In normal ageing, cognitive decline and psychomotor impairment remain moderate; white matter lesion load is subtle (green line). In neurodegeneration, the slope is similar during the preclinical time; thereafter, rapid dementia and psychomotor disturbances occur along with significant white matter lesion
load (blue line). Stroke in a preclinical neurodegenerative period shortens the preclinical period of neurodegeneration by cumulation (red line). Asterisks indicate stroke. MRI scans are from the LADIS (leukoaraiosis and disability) study. (Reprinted from Hennerici M. et al., What are the mechanisms for post-stroke dementia? The Lancet Neurology 8(11): 973975. Copyright (2009), with permission from Elsevier [70]
Various studies have estimated the occurrence of cerebral microbleeds in the range of 3.1 - 23.5 % [43–47]. In a population based cohort study, the prevalence of cerebral microbleeds varied with age [48]. The overall prevalence was 15.3 %, while in the age group 45 - 50 years it was 6.5 % and in the subjects >80 years it was 35.7 % [48]. These cerebral microbleeds were strongly associated with lacunar infarcts (OR 2.37, 95 % CI 1.70–3.30) and subsequent degenerative changes of the brain matter [48]. With increasing age the cerebral capillaries become increasingly susceptible to microbleeds due to the structural changes they undergo when exposed to antiplatelet and anticoagulants while in AF. Even though the risk of gross embolic stroke is significantly decreased, the risk of microbleeds could significantly increase in this group of patients. In the Rotterdam study, clopidogrel use was associated with cerebral microbleeds (OR 1.55, 95 % CI 1.01 - 2.37) [49]. There has been an increasing trend of association of these cerebral microbleeds with oral anticoagulant drugs [50]. Additionally patients on oral anticoagulants and microbleeds are at increased risk of intracerebral hemorrhage. Cerebral microbleeds are also associated with increased risk of mortality and this risk increases with the increase in the number of cerebral microbleeds [51]. The presence of cerebral microbleeds and increased number of these were associated with cognitive dysfunction
[52–54]. The risk of cognitive dysfunction, defined as >1.5 standard deviations below the mean score for particular age on MMSE was increased fivefold in subjects with a cerebral microbleed [54, 53]. A recent meta-analysis by Lei et al. also supports these findings [55]. In a prospective cohort study, cerebral microbleeds were associated with increased risk of dementia (OR 1.57; 95 % CI, 1.002-2.45) after adjustment for age, sex, and education [52]. This risk was significant only for vascular dementia and not for Alzheimer’s dementia [52]. AF patients typically require long-term oral anticoagulation and although these drugs do not appear to be causative of these microbleeds, these agents may worsen the pre-existing microbleeds and may therefore increase dementia risk. Brain Perfusion Issues in AF Perfusion in AF is non-uniform because of the irregular ventricular contractions and blood flow changes in the intracranial circulation have been extensively investigated. On transcranial Doppler evaluation, the blood flow in the intracranial arteries decreased during the AF episodes [56] (Fig. 4). The mean flow velocity decreased significantly in the middle cerebral artery in patients during AF [56]. The flow velocity drop was not significant in the basilar artery and in the internal carotid artery [56]. It is also important to note that AF patients have further decrease in blood flow in the intracranial circulation
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during acute stroke. Porebska et al. studied the hemodynamic changes in the cerebral blood flow in patients having stroke during AF and sinus rhythm [56]. They noted that patients in AF during the acute phase of stroke have decreased mean blood flow in the middle cerebral artery of both intact and stroke hemispheres [56]. This decrease in blood flow in patients with AF may further worsen the hypoxemia in the ischemic penumbra of the stroke region and may therefore result in worse outcomes. In contrast one study observed that blood flow velocity was not different in patients with and without AF [57]. However, the blood flow velocity improved in AF patients after cardioversion [57]. This improvement in cerebral blood flow appears to be sustained even after 30 days if the patients remain in sinus rhythm [58]. With progressive increase in age, this decrease in cerebral blood flow with AF is less pronounced [59]. Lavy et al. estimated that younger patients with AF had nearly 18 % drop in blood flow compared to age matched controls [59]. Non-uniform blood flow in the cerebral circulation during AF may accentuate dementia risk in younger individuals.
Fig. 3 Example of 3 T MRIs of two patients with vascular dementia based on extensive small vessel disease and multiple microbleeds. Axial slices of the brain are shown. The Fluid-Attenuated Inversion Recovery (FLAIR) images on the left allow visualization of white matter hyperintensities and lacunes. The right panels show the T2*-weighted images which allow appreciation of the microbleeds. The patient in the upper panel (A) has severe white matter hyperintensities (left panel) and multiple microbleeds with a deep location (right panel: see arrows for examples). Patient B in the lower panel has white matter hyperintensities and multiple lacunes (left panel: arrows) and microbleeds with a lobar location (right panel: arrows for examples). (Reprinted from Van der Flier W. et al., Microbleeds in vascular dementia: Clinical aspects. Experimental Gerontology 47(11):853-857, Copyright (2012), with permission from Elsevier) [71]
Fig. 4 Waveforms depicting blood flow in the left MCA in a patient in atrial fibrillation (left), waveform in the same patient after cardioversion (right). (Reprinted from Porebska A. et al., Nonembolic, hemodynamic blood flow disturbances in the middle cerebral arteries in patients with
Others Besides the above factors, AF is a pro-inflammatory state that may be associated with development of dementia. Elevated levels of C reactive protein (CRP), an inflammatory marker was found in patients with AF and on multivariate analysis, CRP was found to be an independent risk factor for development of AF [60, 61]. In a systematic review of population based studies, high concentrations of CRP was predictive of cognitive decline and dementia as well [62]. Other inflammatory markers such as tumor necrosis factor-α, Interleukins (2, 6, 8) are elevated in AF patients [63]. In dementia syndromes,
paroxysmal atrial fibrillation without significant carotid stenosis. Clinical Neurology and Neurosurgery 109(9):753-757, Copyright (2007), with permission from Elsevier) [57]
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Interleukin-6 levels were also found to be elevated [64]. The elevated inflammatory markers in both AF and dementia suggest the role of inflammatory pathways in the mediation of both these diseases. The inflammatory mediators may accentuate vasculopathy and neuronal degeneration and thereby increase the risk of dementia. It is however not known if inflammation is a cause or effect of AF.
Impact of AF Treatment on Dementia As AF is associated with cognitive impairment, it would be logical to think that early rhythm control may attenuate the risk of developing dementia. The AFFIRM study failed to show a difference in the rates of cognitive impairment associated with pharmacologic treatment of AF using antiarrhythmic agents in addition to lack of difference in mortality and stroke [65]. However, the AFFIRM trial is limited by short duration of follow up of only 3.5 years and brain changes take a much longer time to result in quantifiable effects. Therefore, long term studies examining the impact of antiarrhythmic agents and development of MCD in patients with AF need to be undertaken. Oral anticoagulation is a key part of management in AF and warfarin for long has been the oral anticoagulant available until the advent of newer oral anticoagulants. The main problem with warfarin was its inability to maintain a steady therapeutic anticoagulation range. Increased cognitive dysfunction has been seen with decreased time in the therapeutic anticoagulation range [66]. It is well known that extreme fluctuations in the systemic anticoagulation levels can lead to increased risk of systemic bleeding including brain. As it is clearly known that a low overall time in therapeutic range (TTR) increases the risk of embolization and the extreme fluctuations could increase the risk of micro and gross bleeds. It remains to be seen if the improved TTRs and mitigation of fluctuations in anticoagulation levels with the new generation oral anticoagulants can play a role in reducing the risk of cognitive impairment and dementia. The challenges that still need to be sorted out are to what extent the cerebral embolization or microbleeds play a major role in the progression of cerebral degeneration, and by aggressive systemic anticoagulation are we still causing enough microbleeds to be concerned about. This dilemma opens up a new question if therapeutic approaches that decrease cerebral embolization by mechanically excluding the left atrial appendage obviating the need for long term oral anticoagulation. There is emerging data on the clinical efficacy and safety of exclusion devices (off anticoagulation) in decreasing the risk of stroke in patients with AF compared to oral anticoagulation [67••]. These devices could decrease both embolization and the risk of microbleeds may be conferring better protection against neurodegenerative changes of brain in patients with AF.
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Catheter ablation has evolved to become a frontline treatment for AF. Results from several studies suggest that catheter ablation may be superior to medical management. However these studies have not evaluated the benefit of catheter ablation on dementia outcomes. More recently, results from a prospective registry suggest that the risk of dementia is attenuated in AF patients following catheter ablation [23••]. This study reported the results on 4200 patients with AF who underwent catheter ablation. These patients were followed up for a mean duration of 3.1±2.4 years. AD was less common in patients undergoing catheter ablation (0.2 % vs. 0.9 %, p < 0.001) [23••]. Dementia of all other types was also decreased in the catheter ablation group (0.4 % vs. 1.9 %, p
INVASIVE ELECTROPHYSIOLOGY AND PACING (EK HEIST, SECTION EDITOR)
The Impact of Atrial Fibrillation and Its Treatment on Dementia Arun Kanmanthareddy & Ajay Vallakati & Arun Sridhar & Madhu Reddy & Hari Priya Sanjani & Jayasree Pillarisetti & Donita Atkins & Sudharani Bommana & Misty Jaeger & Loren Berenbom & Dhanunjaya Lakkireddy
Published online: 29 June 2014 # Springer Science+Business Media New York 2014
Abstract Atrial fibrillation (AF) is a very common tachyarrhythmia and is becoming increasingly prevalent, while dementia is a neurological condition manifested as loss of memory and cognitive ability. Both these conditions share several common risk factors. It is becoming increasingly evident that AF increases the risk of dementia. There are several pathophysiological mechanisms by which AF can cause dementia. AF increases the stroke risk and strokes are strongly associated with dementia. Besides stroke, altered cerebral blood flow in AF and cerebral microbleeds from anticoagulation may enhance the risk of dementia. Maintaining sinus rhythm may therefore decrease this risk. Catheter ablation is emerging as an effective alternative to maintain patients in sinus rhythm. This procedure has also shown promise in decreasing the risk of all types of dementia. Besides maintaining sinus rhythm and oral anticoagulation, aggressive risk factor modification may reduce the likelihood or delay the onset of dementia. Keywords Atrial fibrillation . Dementia . Cognitive impairment . Stroke and dementia . Catheter ablation and dementia This article is part of the Topical Collection on Invasive Electrophysiology and Pacing A. Kanmanthareddy : A. Vallakati : A. Sridhar : M. Reddy : H. P. Sanjani : J. Pillarisetti : D. Atkins : S. Bommana : M. Jaeger : L. Berenbom : D. Lakkireddy (*) Cardiovascular Research Institute, Bloch Heart Rhythm Center, University of Kansas Hospital, Kansas City, KS, USA e-mail: [email protected] D. Lakkireddy Center for Excellence in Atrial Fibrillation & Electrophysiology Research Bloch Heart Rhythm Center – Mid America Cardiology, Kansas City, KS, USA D. Lakkireddy KU Cardiovascular Research Institute- University of Kansas Hospital & Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
Introduction Atrial fibrillation (AF) is the most common tachyarrhythmia observed in the United States with more than 3 million people [1] estimated to have the disease and one in four men and women over the age of 40 are estimated to develop it during their lives [2]. This has almost reached an epidemic status worldwide causing a significant burden on health care delivery systems. The most feared complication of AF is stroke. Other neurological illnesses such as mild cognitive dysfunction (MCD), dementia and silent cerebral infarcts are increasingly being reported in patients with AF [3]. Many studies have shown an association between cognitive impairment and AF [4, 5]. Loss of memory and impaired functioning of at least one other cognitive domain characterize dementia. The prevalence of dementia is projected to increase from 24 million in 2001 to 81 million in 2040 [6]. Dementia is commonly seen in the elderly with an estimated prevalence of 14 % in the age group >70 years [7]. There are several subtypes of dementia based on etiology namely, Alzheimer’s dementia (AD), vascular dementia, Lewy body dementia, frontotemporal dementia, and prion associated dementia, among others [8]. AD is the most common subtype of dementia and in 2010, the estimated number of patients suffering with this disease was 4.7 million in individuals aged 65 and above and by 2050, approximately 14 million people are expected to suffer from AD [9, 10].
Atrial Fibrillation and Dementia Multiple studies have demonstrated an increasing association between AF and dementia. Ott and colleagues first described the risk of dementia in the Rotterdam study [11]. In their study the odds ratio (OR) of dementia in patients with AF was estimated to be 2.3 (95 % CI, 1.2 - 3.4). Subsequently, several studies have tried to better define this association. The relative risk of dementia in AF patients varied from 1.3 to 4.6 in
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different studies [12–15] (Table 1). Interestingly, the connection between AF and dementia was not as evident in a few studies [16–19]. These mixed results could be due to significant differences in the study design, varied population demographics, comorbidities, stroke status, duration and methods of follow up across different studies. However, pooled metaanalysis of these studies has shown that AF is associated with increased risk of dementia [20••, 21, 22]. Most recently Bunch et al. in their retrospective study of 37,000 patients reported that dementia of all subtypes were strongly associated with AF (hazard ratio (HR) of vascular, senile and Alzheimer’s dementia was 1.38, 1.41, and 1.45 respectively) [23••]. The risk of dementia strongly correlates with increasing age, however, this study shows that AF patients younger than 70 years were at the greatest risk of premature dementia [23••]. Further there is also increasing evidence to suggest the association of cognitive dysfunction in patients with AF. Initial evidence of this association was first observed in the Rotterdam study [11]. Cognitive dysfunction defined as a score of less than 26 on the Mini Mental Score was highly prevalent in subjects with AF compared to those without AF [11]. The age and sex adjusted OR of cognitive impairment in AF patients was 1.7 (95 % CI, 1.2-2.5). Interestingly the association was stronger in the Alzheimer’s type than vascular type of dementia [11]. Furthermore, they observed that younger elderly patients with AF were at higher risk of cognitive dysfunction and dementia [11]. Subsequently several studies have reported similar observations of increased cognitive impairment in AF [13, 24-27 (Table 2). Marzona et al. did a post-hoc analysis of two randomized clinical trials involving about 32,000 patients. In their study, AF increased the risk of cognitive impairment by 14 % [13]. Other studies have estimated this risk to be 2-8 times higher in AF patients [27, 25, 24]. Tilvis et al. in a 10-year follow up study observed that the risk of cognitive impairment was 2.8 times higher in patients with AF [25]. Contrary to the above findings, association between cognitive impairment and AF was not observed in a few studies [17, 28, 29].
Table 1 Risk of dementia in atrial fibrillation Study name
Year
Dementia risk (95 % CI)
Ott et al. [11] Forti et al. [15] Marengoni et al. [16] Peters et al. [17] Bunch et al. [23••] Dublin et al. [14] Li et al. [18] Marzona et al. [13] Rastas et al. [19]
1997 2007 2011 2009 2010 2011 2011 2012 2007
OR 2.3 (1.2 - 3.4) HR 4.6 (1.7-12.5) HR 0.8 (0.5-1.7) HR 1.03 (0.62-1.72) OR 1.56 (1.4-1.74) HR 1.38 (1.10-1.73) HR 1.09 (0.54-2.2) HR 1.3 (1.14-1.49) HR 0.86 (0.50-1.47)
Table 2 Risk of cognitive decline in atrial fibrillation Study name
Year
Risk of cognitive decline (95 % CI)
Ott et al. [11] Cacciatore et al. [28] Tilvis et al. [25] Elias et al. [24] Jozwiak et al. [26] Debette et al. [27] Bilato et al. [29] Peters et al. [17] Marzona et al. [13]
1997 1998 2004 2006 2006 2007 2009 2009 2012
OR 1.7 (1.1-2.6) OR 1.1 (0.5-2.2) RR 2.88 (1.26-6.06) OR 4.1 (1.84-8.74) OR 1.56 (1.27-1.92) OR 8.1 (1.9-34.6) OR 1.14 (0.73-1.8) HR 1.08 (0.80-1.46) HR 1.14 (1.03-1.26)
Etiology & Pathogenesis of Dementia in Atrial Fibrillation Etiology of dementia varies by the subtype of dementia; however, there are several established risk factors for dementia such as age, sex, education, hypertension, diabetes, hyperlipidemia, sleep apnea, and stroke. However, longitudinal studies that controlled for these comorbidities also showed increased risk of cognitive decline suggesting that there may be other factors in play [13, 24]. AF also shares several of these common risk factors such as age, hypertension, and diabetes. Stroke is an obvious complication of AF in high-risk groups. In addition to the above common risk factors, the triple insult of stroke, cerebral microbleeds from anticoagulation, and non-uniform cerebral blood flow during AF increase the risk of dementia tremendously in this group. Figure 1 illustrates the pathogenesis of dementia in AF patients and the pathological mechanisms specific to AF are discussed below.
Stroke Stroke risk is increased fivefold in patients with AF and approximately 20 % of all strokes are caused due to systemic thromboembolism from AF [30]. Depending on the other comorbidities, stroke risk varies among AF patients. Stroke risk in AF varies from 1-18 % per year based on additional risk factors [31, 32] (Table 3). The CHADS2 and CHADS2Vasc are simple but very practical risk assessment systems that help to identify the individual’s stroke risk. Stroke has been associated with both cognitive impairment as well as dementia [33]. Elderly patients are more vulnerable to dementia from stroke due to lower cortical volumes in these patients [33]. The size, severity, and the location of the stroke also influence the onset and severity of dementia [34] (Fig. 2). Loss of cortical matter from strokes is likely to result in impairment of memory and cognitive abilities, especially in the elderly as seen in Fig. 2. Recurrent strokes may further compromise these abilities if AF progression continues.
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Fig. 1 Mechanisms of pathogenesis of dementia in atrial fibrillation
There is increasing evidence to show that dementia and its subtypes may be related to AF even without clinical strokes and it is much more common in women than in men [11]. Cha et al. estimated the burden of silent strokes in AF using MRI. In their study, silent strokes in AF were present in 28.3 % compared to 6.6 % for patients with sinus rhythm [35]. A few
Table 3 Risk of stroke according to CHADS2 and CHA2DS2-Vasc risk stratification systems [31, 32] CHADS2 score§
Stroke%/year
CHA2DS2-Vasc¶
Stroke%/year
0 1 2 3 4 5 6
1.9 2.8 4.0 5.9 8.5 12.5 18.2
0 1 2 3 4 5 6 7 8 9
0 1.3 2.2 3.2 4.0 6.7 9.8 9.6 6.7 15.2
CHADS2 = C- congestive heart failure (1), H – Hypertension (1), A – Age ≥75 (1), D- Diabetes (1), S- Stroke (2) §
¶ CHA2DS2-Vasc = C- Congestive heart failure (1), H – Hypertension (1), A –Age 65-74 (1) and ≥ 75 (2), D- Diabetes (1), S- Sex- female (1) and Stroke (2), V – Vascular disease (1)
other studies have also estimated a higher risk of non-clinical strokes in patients with AF [36, 37]. Kalantarian et al., in a meta-analysis of all studies examining the relationship of AF and cognitive impairment, conclude that patients with AF have a relative risk of 1.4 (95 % CI, 1.191.64) when compared to those without AF [20••]. Further, subgroup analysis revealed that following stroke, patients with AF had a 2.7 fold rise in their risk of cognitive impairment. Pooled analysis of studies that excluded patients with stroke revealed that their relative risk of developing cognitive impairment was 1.37, which was similar to the overall risk. Therefore, in addition to clinically detected stroke, micro-emboli causing silent infarctions are postulated to be associated with cognitive impairment. Silent infarcts are estimated to double the risk of dementia; thalamic infarcts were associated with memory loss and non-thalamic infarcts were associated with loss of psychomotor speed [38]. These silent infarcts independently increase the risk of developing dementia [38–40]. Cerebral Microbleeds These are hypo-intense small round lesions seen on T2 weighted magnetic resonance imaging of the brain and are a marker of hemosiderin deposits from prior hemorrhages [41] (Fig. 3). These microbleeds are a result of microangiopathy and are a predictor of future intracerebral hemorrhage [42].
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Fig. 2 Concept of the cumulative effects of stroke, neurodegeneration, and subcortical disconnection (white matter lesion). In normal ageing, cognitive decline and psychomotor impairment remain moderate; white matter lesion load is subtle (green line). In neurodegeneration, the slope is similar during the preclinical time; thereafter, rapid dementia and psychomotor disturbances occur along with significant white matter lesion
load (blue line). Stroke in a preclinical neurodegenerative period shortens the preclinical period of neurodegeneration by cumulation (red line). Asterisks indicate stroke. MRI scans are from the LADIS (leukoaraiosis and disability) study. (Reprinted from Hennerici M. et al., What are the mechanisms for post-stroke dementia? The Lancet Neurology 8(11): 973975. Copyright (2009), with permission from Elsevier [70]
Various studies have estimated the occurrence of cerebral microbleeds in the range of 3.1 - 23.5 % [43–47]. In a population based cohort study, the prevalence of cerebral microbleeds varied with age [48]. The overall prevalence was 15.3 %, while in the age group 45 - 50 years it was 6.5 % and in the subjects >80 years it was 35.7 % [48]. These cerebral microbleeds were strongly associated with lacunar infarcts (OR 2.37, 95 % CI 1.70–3.30) and subsequent degenerative changes of the brain matter [48]. With increasing age the cerebral capillaries become increasingly susceptible to microbleeds due to the structural changes they undergo when exposed to antiplatelet and anticoagulants while in AF. Even though the risk of gross embolic stroke is significantly decreased, the risk of microbleeds could significantly increase in this group of patients. In the Rotterdam study, clopidogrel use was associated with cerebral microbleeds (OR 1.55, 95 % CI 1.01 - 2.37) [49]. There has been an increasing trend of association of these cerebral microbleeds with oral anticoagulant drugs [50]. Additionally patients on oral anticoagulants and microbleeds are at increased risk of intracerebral hemorrhage. Cerebral microbleeds are also associated with increased risk of mortality and this risk increases with the increase in the number of cerebral microbleeds [51]. The presence of cerebral microbleeds and increased number of these were associated with cognitive dysfunction
[52–54]. The risk of cognitive dysfunction, defined as >1.5 standard deviations below the mean score for particular age on MMSE was increased fivefold in subjects with a cerebral microbleed [54, 53]. A recent meta-analysis by Lei et al. also supports these findings [55]. In a prospective cohort study, cerebral microbleeds were associated with increased risk of dementia (OR 1.57; 95 % CI, 1.002-2.45) after adjustment for age, sex, and education [52]. This risk was significant only for vascular dementia and not for Alzheimer’s dementia [52]. AF patients typically require long-term oral anticoagulation and although these drugs do not appear to be causative of these microbleeds, these agents may worsen the pre-existing microbleeds and may therefore increase dementia risk. Brain Perfusion Issues in AF Perfusion in AF is non-uniform because of the irregular ventricular contractions and blood flow changes in the intracranial circulation have been extensively investigated. On transcranial Doppler evaluation, the blood flow in the intracranial arteries decreased during the AF episodes [56] (Fig. 4). The mean flow velocity decreased significantly in the middle cerebral artery in patients during AF [56]. The flow velocity drop was not significant in the basilar artery and in the internal carotid artery [56]. It is also important to note that AF patients have further decrease in blood flow in the intracranial circulation
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during acute stroke. Porebska et al. studied the hemodynamic changes in the cerebral blood flow in patients having stroke during AF and sinus rhythm [56]. They noted that patients in AF during the acute phase of stroke have decreased mean blood flow in the middle cerebral artery of both intact and stroke hemispheres [56]. This decrease in blood flow in patients with AF may further worsen the hypoxemia in the ischemic penumbra of the stroke region and may therefore result in worse outcomes. In contrast one study observed that blood flow velocity was not different in patients with and without AF [57]. However, the blood flow velocity improved in AF patients after cardioversion [57]. This improvement in cerebral blood flow appears to be sustained even after 30 days if the patients remain in sinus rhythm [58]. With progressive increase in age, this decrease in cerebral blood flow with AF is less pronounced [59]. Lavy et al. estimated that younger patients with AF had nearly 18 % drop in blood flow compared to age matched controls [59]. Non-uniform blood flow in the cerebral circulation during AF may accentuate dementia risk in younger individuals.
Fig. 3 Example of 3 T MRIs of two patients with vascular dementia based on extensive small vessel disease and multiple microbleeds. Axial slices of the brain are shown. The Fluid-Attenuated Inversion Recovery (FLAIR) images on the left allow visualization of white matter hyperintensities and lacunes. The right panels show the T2*-weighted images which allow appreciation of the microbleeds. The patient in the upper panel (A) has severe white matter hyperintensities (left panel) and multiple microbleeds with a deep location (right panel: see arrows for examples). Patient B in the lower panel has white matter hyperintensities and multiple lacunes (left panel: arrows) and microbleeds with a lobar location (right panel: arrows for examples). (Reprinted from Van der Flier W. et al., Microbleeds in vascular dementia: Clinical aspects. Experimental Gerontology 47(11):853-857, Copyright (2012), with permission from Elsevier) [71]
Fig. 4 Waveforms depicting blood flow in the left MCA in a patient in atrial fibrillation (left), waveform in the same patient after cardioversion (right). (Reprinted from Porebska A. et al., Nonembolic, hemodynamic blood flow disturbances in the middle cerebral arteries in patients with
Others Besides the above factors, AF is a pro-inflammatory state that may be associated with development of dementia. Elevated levels of C reactive protein (CRP), an inflammatory marker was found in patients with AF and on multivariate analysis, CRP was found to be an independent risk factor for development of AF [60, 61]. In a systematic review of population based studies, high concentrations of CRP was predictive of cognitive decline and dementia as well [62]. Other inflammatory markers such as tumor necrosis factor-α, Interleukins (2, 6, 8) are elevated in AF patients [63]. In dementia syndromes,
paroxysmal atrial fibrillation without significant carotid stenosis. Clinical Neurology and Neurosurgery 109(9):753-757, Copyright (2007), with permission from Elsevier) [57]
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Interleukin-6 levels were also found to be elevated [64]. The elevated inflammatory markers in both AF and dementia suggest the role of inflammatory pathways in the mediation of both these diseases. The inflammatory mediators may accentuate vasculopathy and neuronal degeneration and thereby increase the risk of dementia. It is however not known if inflammation is a cause or effect of AF.
Impact of AF Treatment on Dementia As AF is associated with cognitive impairment, it would be logical to think that early rhythm control may attenuate the risk of developing dementia. The AFFIRM study failed to show a difference in the rates of cognitive impairment associated with pharmacologic treatment of AF using antiarrhythmic agents in addition to lack of difference in mortality and stroke [65]. However, the AFFIRM trial is limited by short duration of follow up of only 3.5 years and brain changes take a much longer time to result in quantifiable effects. Therefore, long term studies examining the impact of antiarrhythmic agents and development of MCD in patients with AF need to be undertaken. Oral anticoagulation is a key part of management in AF and warfarin for long has been the oral anticoagulant available until the advent of newer oral anticoagulants. The main problem with warfarin was its inability to maintain a steady therapeutic anticoagulation range. Increased cognitive dysfunction has been seen with decreased time in the therapeutic anticoagulation range [66]. It is well known that extreme fluctuations in the systemic anticoagulation levels can lead to increased risk of systemic bleeding including brain. As it is clearly known that a low overall time in therapeutic range (TTR) increases the risk of embolization and the extreme fluctuations could increase the risk of micro and gross bleeds. It remains to be seen if the improved TTRs and mitigation of fluctuations in anticoagulation levels with the new generation oral anticoagulants can play a role in reducing the risk of cognitive impairment and dementia. The challenges that still need to be sorted out are to what extent the cerebral embolization or microbleeds play a major role in the progression of cerebral degeneration, and by aggressive systemic anticoagulation are we still causing enough microbleeds to be concerned about. This dilemma opens up a new question if therapeutic approaches that decrease cerebral embolization by mechanically excluding the left atrial appendage obviating the need for long term oral anticoagulation. There is emerging data on the clinical efficacy and safety of exclusion devices (off anticoagulation) in decreasing the risk of stroke in patients with AF compared to oral anticoagulation [67••]. These devices could decrease both embolization and the risk of microbleeds may be conferring better protection against neurodegenerative changes of brain in patients with AF.
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Catheter ablation has evolved to become a frontline treatment for AF. Results from several studies suggest that catheter ablation may be superior to medical management. However these studies have not evaluated the benefit of catheter ablation on dementia outcomes. More recently, results from a prospective registry suggest that the risk of dementia is attenuated in AF patients following catheter ablation [23••]. This study reported the results on 4200 patients with AF who underwent catheter ablation. These patients were followed up for a mean duration of 3.1±2.4 years. AD was less common in patients undergoing catheter ablation (0.2 % vs. 0.9 %, p < 0.001) [23••]. Dementia of all other types was also decreased in the catheter ablation group (0.4 % vs. 1.9 %, p
