Left Atrial Dysfunction Linked to Future Dementia Risk

March 27, 2022

A new study has suggested that left atrial dysfunction could be a risk factor for the future development of dementia, raising the possibility of a new approach to dementia prevention.

In this exploratory analysis of a US community-based cohort, several echocardiographic measures of lower left atrial function were significantly associated with an increased risk of subsequent dementia.

"To the best of our knowledge this is the first study that has looked at the link between echocardiogram-defined left atrial function and dementia," lead author Wendy Wang, MPH, University of Minnesota, Minneapolis, told theheart.org | Medscape Cardiology. "Our results suggest that atrial myopathy could signal an increased risk of developing dementia and treating this condition could be a potentially new approach to preventing dementia."

Their results "improve our understanding of the relationship between the heart and dementia, and strengthens the link between cardiac dysfunction and dementia," she said.  

Senior author, Lin Yee Chen, MD, professor of medicine at the University of Minnesota Medical School, Minneapolis, added, "This study is important in highlighting the role of atrial myopathy as an independent risk factor for dementia."

But Wang noted that these findings should be regarded as preliminary and need to be confirmed in further studies. The study was published online in JAMA on March 22.

The researchers note that atrial myopathy — characterized by alterations in left atrial function and size — is associated with adverse cardiovascular events. Because lower left atrial reservoir function has been associated with presence of silent brain infarcts and white matter hyperintensities, it is possible that atrial myopathy is also associated with dementia.

Prior research has found electrocardiographic (ECG) markers of atrial myopathy to be associated with greater cognitive decline and dementia. But whether abnormal left atrial function and size, as assessed by echocardiography, are linked to increased dementia risk is unknown.

The current study was conducted to assess the association of echocardiographic measures of left atrial function and size with incident dementia in the Atherosclerosis Risk in Communities (ARIC) study, a large community-based cohort.

For the study, various measures of left atrial function and size were evaluated on the 2-dimensional echocardiograms taken as part of the ARIC study in 2011-2013. The measures were quantified by speckle tracking and volumetric analysis. Subsequent dementia cases over a median 6-year follow-up were identified using in-person and phone cognitive assessments, hospitalization codes, and death certificates, also as part of the ARIC study.  

The study involved 4096 participants (mean age, 75 years; 60% women; 22% Black individuals), and 531 dementia cases were ascertained over the follow-up period.

Results showed that, after adjustment, there were statistically significant associations between measures of left atrial function and dementia. Individuals with the lowest quintiles of various measures of left atrial function had a 43%-98% greater risk of developing dementia than those in the highest quintiles of the same measures.

The hazard ratios for the lowest vs highest quintile for reservoir strain were 1.98; conduit strain 1.50; contractile strain 1.57; emptying fraction 1.87; and for active emptying fraction 1.43, all values being statistically significant. Left atrial passive emptying fraction was not significantly associated with dementia.

There were two to three more dementia cases per 100 person-years in individuals in the lowest quintile of left atrial function measures than those in the highest quintile.

Measures of left atrial size were not significantly associated with dementia risk.

The researchers point out that because atrial myopathy is a well-established risk factor for atrial fibrillation (AF), and the latter is in turn associated with dementia, the contribution of AF needs to be accounted for when assessing the association between atrial myopathy and dementia.

Results from mediation analyses suggested that diagnosed AF accounted for less than 2% of the association between left atrial dysfunction and dementia.

Furthermore, in a sensitivity analysis that excluded participants with incident AF and stroke, lower left atrial function was associated with an elevated risk of dementia, similar to results from the primary analysis.

But the authors caution that ascertainment of AF may have been incomplete, and the results of these analyses need to be interpreted with that in mind.

The researchers also attempted to identify a binary cut-off value for atrial dysfunction that could be used clinically.

"We identified a left atrial reservoir strain measure of less than 27% as being a possible binary cut off," Wang noted. "This is just an initial observation, but left atrial reservoir strain showed a nonlinear relationship with dementia and we tried to identify the point at which there was sharp increase in the slope of this relationship. Other measures were more linear and therefore more difficult to identify a cut-off value."

She added, "If this can be confirmed in other studies, then a threshold could be defined, and individuals below this threshold could be enrolled in studies to investigate whether various treatments for atrial myopathy could reduce the future risk of dementia."   

New Ways to Identify Dementia Risk Factors

In an accompanying editorial, Shyam Prabhakaran, MD, University of Chicago, Illinois, and Philip Greenland, MD, Northwestern University, Chicago, Illinois, explain that atrial myopathy broadly describes a range of abnormalities associated with disease of the left atrium with or without AF.

They say that the current study by Wang et al "has raised important new considerations in the search for novel causes of dementia," adding that, "This report offers the hope for new ways to identify risk factors for dementia that are potentially treatable before dementia occurs."

The editorialists suggest several mechanisms that may explain the association of atrial myopathy and dementia risk. These include an effect mediated through ischemic stroke, subclinical embolism, altered cardiac output causing a reduction in cerebral perfusion, a role of inflammatory markers, and shared risk factors between atrial myopathy and dementia.

They suggest that future studies using cardiac magnetic resonance imaging (MRI) to evaluate the atrial myopathy more completely may identify more precisely which aspects of the diseased atrium are most important for development of dementia as well as stroke and AF.

They stress that, given the exploratory nature of the study findings, prospective validation in other cohorts is necessary.

Noting that randomized clinical trials testing treatments in patients with atrial myopathy could further establish a causal effect on dementia, Prabhakaran and Greenland point out that one such study — the ARCADIA trial — is already underway, investigating the embolic potential of a diseased left atrium, and comparing apixaban vs aspirin to reduce recurrent stroke risk in patients with recent embolic ischemic stroke but without AF.

A substudy of this trial aims to evaluate whether anticoagulation reduces cognitive decline and the incidence of subclinical brain infarcts after stroke in patients with atrial myopathy.    

Other therapeutic targets include MRI-guided atrial fibrosis ablation and could be evaluated in future trials, they suggest.

The ARIC study was funded by grants from the US National Institutes of Health. Wang reports no disclosures.

JAMA. Published online March 22. Full text. Editorial.  

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