Research News

A team of researchers led by Robert Koeth, MD, PhD, have discovered how the gut microbial pathway trimethylamine N-oxide (TMAO), a compound produced by the gut microbiome from nutrients found in a western diet, is associated with atrial fibrillation (AFib).

While previous research in the field established a connection between the two, Cleveland Clinic researchers’ article, published in the Journal of Clinical Investigation, uses electrophysiology to pinpoint the reason TMAO may increase the potential for an individual to develop this common type of arrhythmia. The answer, Dr. Koeth believes, may be interference with receptors involved in the body’s “fight-or-flight” response.

This latest research is part of a multiyear study into AFib funded by the National Institutes of Health.

A known connection to heart health

Cleveland Clinic researchers have already identified links between TMAO and a higher risk for heart failure and other cardiovascular diseases. There was no clear answer about its role in AFib, an irregular heart rhythm condition that affects the function of the heart’s electrical system.

Dr. Koeth leads a lab in Cleveland Clinic Research and is a staff physician in the Cardiac Electrophysiology and Pacing section of Cleveland Clinic’s Heart, Vascular & Thoracic Institute. He decided to approach this gap in research through his specialty: analyzing the heart’s electrical signals, the branch of cardiology known as electrophysiology.

Electrophysiology testing in the lab

Dr. Koeth and his team designed and performed preclinical experiments to determine if the presence of TMAO creates conditions where the heart can more easily go off rhythm. To answer these questions, researchers measured the following using electrocardiogram monitoring, electrophysiology testing and optical mapping:

• How easily AFib could be triggered
• How quickly AFib developed on its own
• How fast electrical signals travel
• How quickly the heart cells reset after firing

The results suggested that exposure to TMAO does increase the risk for AFib to be triggered and develop on its own.

“We discovered through our electrophysiology testing that TMAO makes the heart’s electrical system more unstable,” Dr. Koeth says. “One effect is a shortened recovery time after each electrical signal the heart sends out. This is problematic because cells firing again too soon increases the chance for abnormal signals characteristic of AFib.”

Tissues that are too excitable

The researchers also calculated cardiac wavelength, which measures how much physical space an electrical signal occupies as it moves through the heart. TMAO shortened this wavelength, which results in tissues becoming more excitable — a characteristic of AFib.

This is also where the body’s fight-or-flight response comes in. That stress response is part of the autonomic nervous system, which controls many body functions automatically. The autonomic nervous system has two, normally balanced branches: the sympathetic nervous system (the fight-or-flight response) and the parasympathetic nervous system (a more regulated, calming type of response).

When those branches are imbalanced and the sympathetic nervous system is more active, the heart can become more electrically unstable. The researchers’ findings suggest that TMAO may contribute to this imbalance, creating conditions that make AFib more likely to develop.

Implications for the future

A better understanding of the heart’s electrical system could help identify people who are at greater risk of developing AFib. Dr. Koeth also believes that it may also help physicians determine stroke risk for people who already have AFib.

“Our study is the first that puts the connection between TMAO and AFib together from a bench-to-bedside approach, and we fulfilled our goal to establish a clear, probable mechanism,” Dr. Koeth says. “Further study will help refine an effective therapeutic approach, but our results from this electrophysiology testing add important insight about a too-common cardiac condition.”