April 23, 2025 | Over the past few years, a multidisciplinary team of experts has been spreading the news that an abnormality of the heart’s left atrium (LA), known as LA myopathy, can be a marker of elevated risk of stroke and dementia—even in the absence of atrial fibrillation (AFib). The current “gap in the field” is that there is no established way to characterize the condition, according to Lin Yee Chen, M.D., professor at the University of Minnesota Medical School, a cardiac electrophysiologist with M Health Fairview, and director of the Lillehei Heart Institute.
But as he and his colleagues have just shown, the best biomarker of them all when it comes to predicting stroke and dementia risk is “left atrial reservoir strain,” a measure of the left atrium’s ability to stretch. Findings emerged from a side-by-side comparison of the P wave abnormalities from a 12-lead electrocardiogram (ECG), NT-proBNP (N-terminal pro-B-type natriuretic peptide), and LA volume and strain parameters from the echocardiogram (Stroke, DOI: 10.1161/STROKEAHA.124.047747).
Study results could “transform the field” because clinical trials using anticoagulants, or blood thinners, for preventing repeat strokes in people with LA myopathy have to date failed, says Chen. “We argue that’s because researchers in the past have not used the optimal marker to enroll people.”
Based on that premise, his research group is now laying plans for a multi-center clinical trial that will identify people who have LA myopathy using LA reservoir strain to determine whether blood thinners can prevent stroke and dementia in individuals who have previously had an embolic stroke of undetermined source, he reports. They will, to that end, be submitting a grant application this fall to the Patient-Centered Outcomes Research Institute (PCORI), Chen says.
Study participants will be enrolled based on abnormal LA reservoir strain, randomized to receive an anticoagulant or aspirin, he adds, with follow-up for the development of recurrent stroke and dementia. The two diseases are strongly correlated and by themselves significant killers.
PCORI would be a “natural fit” for these outcomes, which are of great concern to patients, says Chen. The organization is interested in supporting pragmatic trials that significantly benefit patients in ways that are meaningful to them.
For the last four decades, it has been widely believed that AFib is a risk factor for stroke, Chen says. But over the last 10 years or so, research has emerged showing stroke can happen in the absence of AFib in people with an abnormal LA. Work thus began using ECG changes as a reflection of that abnormality, leading to the discovery that the LA myopathy—as indicated by abnormal ECG changes—is associated higher risk of stroke as well as dementia, independent of atrial fibrillation.
Chen therefore reasoned that “atrial fibrillation may not be the primary driver, but rather the underlying left atrial myopathy,” he says. “We prescribe blood thinners to prevent stroke in people with atrial fibrillation, but I think the risk may actually be driven by the underlying abnormal left atrium, so it could redirect our efforts toward chasing the correct target.”
AFib is the most common sustained heart abnormality in humans, he says, and there are two distinct types. Common AFib, which is a disease of aging, strikes about 10% of individuals over 80 years old. It tends to be due to underlying LA myopathy because cardiovascular risk factors—high blood pressure, diabetes, and obesity—can cause changes in the left atrium over time.
The second type of AFib, which typically affects younger people, is not due to underlying LA myopathy. It is “purely an electrical disease” and may have a genetic basis and familial component, says Chen.
These individuals often respond well to catheter ablation; once the procedure is done, they never have AFib again. If catheter ablation is done in an older person with AFib; however, it may reduce the burden of the arrhythmia, but patients will still be prescribed a blood thinner because of the underlying LA myopathy that sets them up for high risk of stroke, he explains.
Only in recent years has a body of evidence emerged in high-impact journals, including The Journal of the American Medical Association and Annals of Internal Medicine, showing the presence of LA myopathy “upstream and in the absence of atrial fibrillation, and in and of itself is associated with higher risk of stroke and dementia,” says Chen. The latest study in Stroke is a follow-up investigation on this clinical entity.
Like all impactful science, Chen says, the comparison study on LA myopathy biomarkers was a collaborative endeavor that has included investigators in the ongoing ARIC (Atherosclerosis Risk in Communities) study that has been funded by the National Institutes of Health (NIH) since 1987. Chen is principal investigator of the NIH grant that funded the measurement of LA reservoir strain. Other study authors provided expertise in cardiology, echocardiographic imaging, biostatistics, and statistical analysis.
NT-proBNP, the blood marker used in the study, is used clinically for the diagnosis of heart failure, where the heart can no longer pump effectively to meet the metabolic needs of the body, he continues. Affected patients typically experience fluid buildup in their feet, legs, or lungs, and have elevated NT-proBNP levels.
“Fundamentally, NT-proBNP becomes elevated in the blood when there is excessive stretch in the heart muscles,” says Chen. The protein is secreted by heart cells in response to stress in the wall of the heart.
“However,” he quickly adds, “a lot of things can influence the level of this protein.” Heart failure is one important cause, but NT-proBNP levels can also be influenced by age, AFib, and obesity. “So even though it is associated with stroke and dementia... NT-proBNP is not very specific.”
Now that Chen and his collaborators have identified a marker to capture LA myopathy, researchers elsewhere might want to explore the risk factors that can be targeted to prevent development of the condition, says Chen. “If we want to try and prevent something, we first have to be able to define it,” in this case based on LA reservoir strain below a specific cutoff.
It would also be possible to resurrect negative trials of anticoagulants from the past where echocardiography was used to detect LA myopathy, he notes. Echocardiographic images could be re-read based on LA reservoir strain to classify individuals as either having or not having the condition and then perform a post-hoc secondary analysis.
LA reservoir strain holds “powerful prognostic relevance” in the clinic, says Chen, since it has been shown to be a strong marker of not only stroke and dementia but also an independent predictive marker of cardiovascular diseases ranging from AFib and heart failure to chronic kidney disease. Unfortunately, echo labs typically ignore the function of the left atrium “because it is new knowledge.”
ECG reports are still largely limited to measurements of the size and dimensions of the different chambers of the heart and the function of the left ventricle, he says. The research team has made it part of their mission to get LA reservoir strain reported as a standard metric.
Raising “recognition and awareness” that LA reservoir strain is an important measure is the first order of business, says Chen. Longer term, the methodology used to measure the marker also needs to be standardized.