Atrial Fibrosis Link to ESUS Questions Stroke–AF Connection

May 11, 2020

What if atrial fibrillation (AF) turned out to be a marker of risk for cardioembolic stroke but not necessarily the direct cause of culprit thrombi?

Patients with embolic stroke of undetermined source (ESUS) showed about as much atrial fibrosis on MRI as a separate group who had AF, regardless of the latter's history of stroke, in a small prospective study.

In those with ESUS, moreover, a greater degree of atrial fibrosis — 12% or more of the atrium — was a significant predictor of risk for either recurrent stroke or a first-time diagnosis of AF.

The findings, based on about 200 patients with and without AF, including 51 with ESUS, supports an "alternative hypothesis" about the origins of cardioembolic thrombi, asserted Nazem Akoum, MD, at a media briefing conducted online May 8 as part of the Heart Rhythm Society 2020 Scientific Sessions virtual presentation.

The hypothesis, he said, is "that it's not really the arrhythmia that is the necessary component in putting these patients at risk for stroke, but rather fibrosis within the atrium that may be putting these patients at risk," said Akoum, University of Washington School of Medicine, Seattle.

The current findings, he said, suggest that atrial fibrosis may be a common cause of both AF and embolic stroke in patients with ESUS, and that such patients "with a higher burden of fibrosis are at a higher risk for a recurrent event or new atrial fibrillation."

If that turns out to be true, Akoum proposed, then measuring the degree of atrial fibrosis in a patient with ESUS might help guide oral anticoagulation (OAC) therapy to those who would be most likely to benefit, regardless of any future AF.

Indeed, "we should stop thinking about atrial fibrillation as something that we start treating the moment it occurs," offered Joris R. de Groot, MD, PhD, Amsterdam University Medical Center, at the same briefing.

"We should think about risk profiles, we should think about atrial cardiomyopathy, we should think about ways to look for risk in patients who did not have the arrhythmia yet. And maybe the arrhythmia is just a marker of risk rather than the cause," he said.

Although aspirin is the standard of care in ESUS, "there is a lot of enthusiasm about going ahead and anticoagulating these patients," given what is thought to be their high prevalence of AF, observed Christine M. Albert, MD, MPH, Cedars Sinai Medical Center, Los Angeles, as an invited discussant following Akoum's formal presentation.

However, both Albert and Akoum pointed out, a strategy of OAC, compared with aspirin, was found unhelpful in at least two major randomized trials.

They include the NAVIGATE ESUS comparison of rivaroxaban (Xarelto, Bayer AG) and the RE-SPECT ESUS trial of dabigatran (Pradaxa, Boehringer Ingelheim). In neither study did OAC lead to a reduction in recurrent stroke, compared with aspirin, but the risk of bleeding went up.

The current study, Albert said, is small but suggests that "atrial fibrosis might be useful in ESUS patients to help identify those who will go on to develop atrial fibrillation and cerebrovascular events," and therefore, potentially, which patients might most benefit from OAC.

But it remains unclear which patients with ESUS, whether or not they have substantial atrial fibrosis, would benefit from OAC, she said, adding that the question should be explored in randomized trials.

The new study enrolled 201 patients with ESUS in Germany and the United States. They comprised 101 without AF (35 healthy control subjects, 15 patients with lacunar strokes, and 51 with ESUS) and 100 with AF (50 with and 50 without previous stroke).

All patients underwent cardiac MRI with late-gadolinium enhancement for delineation of any atrial fibrosis, defined as a percentage of left-atrial wall volume, and then were followed for 30 months for new-onset AF and recurrent ischemic stroke.

"Patients with ESUS had significantly higher fibrosis compared to healthy controls and lacunar-stroke patients. ESUS patients, on the other hand, had an indistinguishable atrial fibrosis burden compared to atrial fibrillation patients, indicating that ESUS is associated with significant fibrosis independent of atrial fibrillation," Akoum said when formally presenting the results.

Degree of Atrial Fibrosis by Study Group, Patients With and Without AF
Population n Atrial Fibrosis, % P vs ESUS Group
Patients without AF
Healthy control subjects 35 8.1 <.001
Lacunar stroke 15 10.8 .02
ESUS 51 14.7  
Patients with AF
No previous stroke 50 16.6 .49
Previous stroke 50 17.9 .54

Of the 51 patients with ESUS, 9.8% developed recurrent stroke a median of 7 months from their first stroke; those five patients had an average of 15.5% atrial fibrosis.

Also, 9.8% of ESUS patients developed first-time AF at a median of 18.6 months; their mean fibrosis severity was 19.6%.

Two patients had diagnoses of AF and recurrent stroke at the same time; their atrial fibrosis averaged 17.5%.

Patients with ESUS with a fibrosis severity of at least 12% showed a 22.6% rate of the composite end point of recurrent stroke or new AF. The rate was 5.0% for those with fibrosis severity less than 12% (P = .045). Akoum and colleagues chose a cutoff threshold of 12% based on their earlier research, he said.

In adjusted analysis, atrial fibrosis of at least 12% showed a hazard ratio (HR) for recurrent ischemic stroke or new AF of 4.35 (95% CI, 0.98 - 12.66; = .068), short of significance but "clearly trending" in that direction, Akoum said.

Whether atrial fibrosis can serve as a marker of high risk for embolic stroke, and therefore predict who might benefit from OAC, can only be answered by randomized trials, Akoum agreed.

Meanwhile, given the current evidence, "I would say any patient with ESUS is a candidate to have their fibrosis assessed," he told | Medscape Cardiology.

If they have a high fibrosis burden, "at least they need to be screened very carefully and monitored for atrial fibrillation, because that is something that will change therapy," Akoum said. "In the future, hopefully we'll prove that prophylactically starting oral anticoagulation based on fibrosis will be the way to go."

Akoum and the other authors of the report had no disclosures. de Groot discloses serving as a consultant or speaker for Atricure, Bayer, Daiichi Sankyo, Johnson & Johnson, Medtronic, Novartis, and Servier; receiving research grants from Abbott, Atricure, Bayer, Boston Scientific, and Medtronic; and owning RhythmCARE. Albert discloses conducting research for Abbott, Roche Diagnostics, and St. Jude Medical; and receiving honoraria or fees for speaking or consulting from Roche Diagnostics.

Heart Rhythm Society (HRS) 2020 Scientific Sessions: Late Breaking Clinical Trials 1. Presented May 8, 2020.

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