Structural or functional abnormalities within the heart’s left atrium may increase a person’s risk of developing dementia later in life by 35%

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Structural or functional abnormalities within the heart’s left atrium, with or without symptoms, may increase a person’s risk of developing dementia later in life by 35%, according to new research published today in the Journal of the American Heart Association.

Dementia risk increased even among those who did not experience atrial fibrillation or stroke, two conditions known to be associated with dementia.

The left atrium is one of four chambers of the heart and is responsible for receiving blood from the lungs and pumping it into the left ventricle, which then pumps the blood to the rest of the body. An abnormality in the structure or functioning of the left atrium, known as atrial cardiopathy, can often serve as a biomarker, or predictor, of a person’s cardiac risk.

Atrial cardiopathy is associated with an increased risk of stroke and atrial fibrillation, which are both linked to an enhanced risk of dementia.

In a study led by Michelle C. Johansen, M.D., Ph.D., an assistant professor of neurology at The Johns Hopkins University School of Medicine in Baltimore, the research team aimed to determine the relationship between atrial cardiopathy and dementia, and if so, whether it is independent of atrial fibrillation and stroke.

The study results highlight the need to get a better understanding of the relationship and mechanisms between a state of atrial dysfunction, that may be subclinical (not presenting symptoms) and the newly uncovered association with dementia, the researchers noted.

Participants in the current analysis were part of a larger study group of more than 15,000 people originally recruited for the ongoing Atherosclerosis Risk in Communities (ARIC) study, which began in 1987 to research heart health in people living within four diverse communities throughout the U.S. ARIC study participants were ages 45–65 years at the start of the study and from rural areas in the U.S. (Forsyth County, North Carolina, and Washington County, Maryland) and urban areas: Minneapolis and Jackson, Mississippi. All ARIC participants attended clinical visits every three years, and the resulting research and data – including hospital record abstraction, ECG tracings, and physician and coroner questionnaires, as well as death certificate data – have led to discoveries and guidelines surrounding atherosclerosis, heart disease, kidney disease, diabetes, stroke and cognitive decline.

This analysis uses data and assessments gathered during participants’ fifth ARIC clinical visit, between 2011 and 2013 as a baseline, and follows the participants through their sixth visit, between 2016 and 2017, and their seventh visit, between 2018 and 2019.

The current analysis included 5,078 of the 5,952 participants who returned for their fifth clinical visit; 59% were female, and 41% were male. The group of 5,078 were an average age of 75 years old, and 21% self-identified as Black adults. During their fifth, sixth and seventh clinical visit, the ARIC participants were evaluated for cognitive decline indicating dementia.

Researchers evaluated cognitive decline in all participants with a comprehensive neuropsychological test battery from the Uniform Data Set of the Alzheimer’s Disease Centers program of the National Institute on Aging, as well an informant interview in a subset of participants. Informant interviews are a screening test of questions, such as the Eight-Item Informant Interview to Differentiate Between Aging and Dementia, given to a spouse, adult child or close friend of the adult being evaluated for cognitive decline.

The neuropsychological test battery consists of brief measures of processing speed, episodic memory, language, attention and executive function. A diagnosis of dementia was generated based on testing results by a computer diagnostic algorithm and then decided upon by an expert based on the Diagnostic and Statistical Manual of Mental Disorders and the criteria outlined by the National Institutes of Health and the National Institutes of Health.

Hospital discharge codes – obtained as part of the ARIC study either directly from hospital discharge indices or from an indexing service or from an indexing service – and death certificate data, obtained as part of the ARIC study from the Automated Classification of Medical Entities system, were also included to assess participants’ cognitive status.

Additionally, cardiac evaluation, including echocardiography, electrocardiography (EKG/ECG) and blood work, was conducted to assess the size and function of the left atrium of the heart to check for signs of atrial cardiopathy.

The analysis of the collective health data found that throughout the more than 30 years of follow-up, 763 people developed dementia, and 1,709 had atrial cardiopathy. The participants with atrial cardiopathy appeared to be 35% more likely to develop dementia. When the researchers adjusted for participants who experienced atrial fibrillation and stroke, even after accounting for other vascular risks, they still observed a respective 31% and 28% increase in dementia risk in patients with atrial cardiopathy. The researchers suggested that a state of atrial cardiopathy leading to dementia s is not a result of atrial fibrillation or stroke alone.

While the researchers note the results do not imply causality, they emphasize the importance of lowering vascular and heart disease risks. Among the study’s limitations was the possibility that asymptomatic atrial fibrillation or silent strokes may have been missed in some study participants. Additionally, dementia develops slowly, therefore, some participants with milder symptoms may have been missed, and some patients in the study may have died before dementia was observed and documented. The study may also not be generalizable among populations with different demographics than the four communities in Forsyth County, North Carolina; Washington County, Maryland; Minneapolis; and Jackson, Mississippi that comprise ARIC.

Co-authors are Wendy Wang, M.P.H.; Michael Zhang, M.D., Ph.D.; David S. Knopman, M.D.; Chiadi Ndumele, M.D., Ph.D.; Thomas H. Mosley Ph.D.; Elizabeth Selvin, M.P.H., Ph.D.; Amil M. Shah, M.D., M.P.H.; Scott D. Solomon M.D.; Rebecca F. Gottesman, M.D., Ph.D.; and Lin Yee Chen, M.D., M.S.


Atrial fibrillation (AF) represents the most frequent sustained cardiac arrhythmia in adults [1], with an estimated prevalence of 59.7 million patients worldwide [2]. Alarming epidemiological predictions foresee a further increase of this condition during the next few decades [3].

At the same time, Alzheimer’s disease and other dementias, characterized by memory impairment with at least one additional cognitive dysfunction, constitute an important burden for worldwide health, with an estimated prevalence of 51.6 million patients [4]. It is predicted that this number will increase by 4.6 million new cases every year, doubling in 20 years [5].

Dementia represents a substantial financial burden, comparable to heart disease and cancer. As an example, it was estimated that in the United States the total monetary cost related to dementia in 2010 was approximately $200 billion [6].

Increasing scientific evidence indicates that AF and cognitive decline/dementia are frequently associated. These two conditions share many risk factors, such as hypertension, heart failure, diabetes and age. However, a causal relationship between AF (cause) and dementia (effect) has also been claimed [7].

In addition to the potential contribution of AF-related clinical cerebrovascular accidents (CVAs), there are several additional mechanistic hypotheses sustaining a causal association, which holds true also in the absence of CVAs: hemodynamic mechanisms (e.g., reduced mean cerebral blood flow, beat-to-beat alterations resulting in distal hypoperfusion and/or hypertensive events), subclinical microembolic cerebral infarctions, subclinical cerebral microbleeds (favored by oral anticoagulation treatment), and impaired cerebrovascular reactivity [8,9,10,11,12,13,14].

The present study provides an overview of AF and dementia burden, reporting the most recent data regarding incidence, prevalence, mortality, and morbidity of these two associated conditions, intended to grow in the upcoming decades. In addition, based on the epidemiological estimates derived from the Global Burden of Disease (GBD) study 2019, a potential correlation of the epidemiological trends of the two examined diseases was investigated.

Discussion
The present study reports atrial fibrillation and dementia epidemiological data derived from the GBD Study 2019 and investigates the historical trend of these conditions (from 1990 to 2019). The main findings are:

In the last 30 years, the crude incidence and prevalence rate of AF and dementia increased by 41% and 71%, respectively. The consequent mortality and morbidity burden also doubled in the same timeframe, highlighting a progressively greater burden of these diseases.

Age-standardized metrics, which take into account the progressive aging of the global population in the previous decades, show substantial stability in terms of incidence and prevalence of both conditions, as well as in mortality and morbidity; if, on the one hand, these data suggest that the inflation of the crude estimates are driven mainly by population aging, on the other hand they highlight that further efforts are needed to prevent these conditions through stricter risk factor control.

Stratification by SDI suggests that these two conditions are clearly more frequently encountered in high SDI countries, not only due to longer life expectancy but also due to higher risk factors burden (as suggested by the fact that also age-standardized estimates, which intrinsically eliminate the confounding effect of the age-population structure, are greater for high compared to lower SDI countries). In particular, AF and dementia represent a higher relative share on total mortality and morbidity in high SDI countries.

Finally, the explorative analysis using the Granger test on the historical trends of the incidence rate of the two conditions confirms a correlation between the two diseases. Although this analysis cannot prove a causal relationship, it suggests that a close relationship between these two conditions exists, highlighting that any future increase in AF incidence would easily be followed by a similar increase in dementia.

A cross-sectional analysis of a subgroup of patients from the Rotterdam Study, published more than 20 years ago, showed for the first time an independent association between AF and dementia. In this seminal study, the risk of dementia/cognitive impairment was nearly twice in AF patients compared to non-AF individuals [18].

In fact, the potential correlation of the two diseases can be explained by several mechanisms. Since AF is one of the main causes of ischemic stroke, a vascular type of cognitive impairment/dementia may surely candidate for a central role in this association.

Similarly, advanced interatrial block (A-IAB), defined at ECG as p-wave duration ≥120 ms with biphasic morphology in inferior leads, is a marker of severe atrial disease. Indeed, A-IAB, as well as AF, is a manifestation of atrial cardiomyopathy [19,20], and stroke and microembolic events may be, at least partially, caused by the atrial disease and not only by the rhythm alteration. In fact, A-IAB has been found to be independently associated with onset of AF, stroke and, more specifically, cognitive decline [21,22,23].

Based on these data, further studies are necessary to evaluate whether the presence of A-IAB confers per se an increased risk of stroke or whether this association is mediated by the occurring of subclinical AF episodes. In the former case, A-IAB and AF could be considered as clinically equivalent, and randomized trials evaluating the role of oral anticoagulation for the prevention of stroke and dementia, whose indication should be driven by clinical factors, such as CHA2DS2-VASc score, and, possibly, by imaging data (e.g., left atrial fibrosis at MRI or left atrial strain at echocardiography) would be necessary. As a matter of fact, AF patients present a 30% increased risk of developing dementia regardless of clinical cerebrovascular events (transient ischemic attacks or strokes) [24]. Moreover, AF and dementia share several risk factors, including hypertension, diabetes, inflammatory diseases, altered lipid profile, physical inactivity, and ageing [25,26,27].

Therefore, other mechanisms can potentially further explain this relationship. The inflammatory states associated with AF have been advocated in the genesis of cognitive decline; inflammatory markers elevation is typical in AF patients, and relates to a prothrombotic state [28]. Moreover, inflammatory cytokines, released after cerebral vascular damage, can increase the production of amyloid precursor protein, whose misfolded oligomeric forms are toxic to the brain cells and are implicated in Alzheimer’s disease [29,30,31]. In addition, AF can lead to silent cerebral ischemias (SCI), which are twice as common in AF compared to sinus rhythm patients [12]. These lesions can be found at magnetic resonance imaging (MRI) and are directly associated with cognitive impairment [11,12].

AF can also cause microbleeds, possibly facilitated by anticoagulation treatment, whose presence and number are correlated to a reduced cognitive function [32,33]. Finally, the hemodynamic effects of AF on systemic and cerebral flow might play an active role; the loss of the atrial systole is responsible for a 20–30% reduction in cardiac output [34], particularly impacting in elderly subjects with impaired cerebral blood flow autoregulation [35], and AF-related cerebrovascular dysfunction [13]. Indeed, patients with AF present lower mean cerebral blood flow than in age-matched controls, particularly in cases of persistent AF [36,37].

In addition, a computational model simulating AF R-R interval variability has documented beat-to-beat effects resulting in transient cerebral hypoperfusion and hypertensive events in the deep cerebral circle [8,9]. The latter hypothesis was also recently validated in vivo using spatially resolved cerebral near infrared spectroscopy (SRS-NIRS). Elective electrical cardioversion restoration sinus rhythm in persistent AF patients, significantly reduced beat-to-beat hypoperfusion and hypertensive events in the cerebral microcirculation, assessed by inter-beat differences of tissue hemoglobin index, an indirect index of tissue perfusion [10].

Definitive evidence regarding the optimal strategy to prevent dementia in patients with AF is lacking. However, increasing scientific evidence suggests that a rhythm control strategy aiming at sinus rhythm maintenance, on top of a proper oral anticoagulation, may prevent (or at least delay) cognitive decline/dementia occurrence. Waiting for randomized clinical trials to shed light on this topic, several observational data are presently available, largely focusing on the role of catheter ablation (the most effective rhythm control approach) in preventing cognitive decline [38].

A retrospective analysis conducted on 194,928 patients registered in the Korean National Health Insurance Service database reported that, over a median follow-up of more than four years, catheter ablation was associated with lower rate of overall dementia compared to patients medically treated after censored for stroke (HR 0.76). This reduction was evident in case of ablation success, while ablation failure, with recurrence of the arrhythmia, was not associated with significant differences [39].

Another retrospective study reported, over nine years follow up, a lower incidence of new onset dementia in patients who had undergone catheter ablation compared to patients with AF who were not recommended for catheter ablation (HR 0.44), especially in those aged >65 years old (HR 0.46) [40]. The Montreal cognitive assessment score also reported improved cognitive performance within an AF catheter ablation group compared to patients treated medically. Interestingly, cognitive improvement was more evident in patients who presented pre-ablation cognitive impairment (OR 13.70, 95%CI 4.83–38.87) [41].

Eventually AF catheter ablation has shown to reduce the risk of stroke/TIA and dementia (HR 0.51, p = 0.04) [42], and to confer to the patient a post-ablation dementia risk similar to that of the general population free from AF [43]. All of this evidence is pointing toward a potential reduction of AF-related dementia incidence when sinus rhythm maintenance is pursued with effective treatment, lay the ground for dedicated, properly powered, randomized studies assessing whether catheter ablation-based rhythm control strategy might help in breaking the causal chain between AF and cognitive decline/dementia.

reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8955523/


More information: Risk of Dementia Associated With Atrial Cardiopathy: The ARIC Study, Journal of the American Heart Association (2022). DOI: 10.1161/JAHA.121.025646

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