Research News

Testing for elevated levels of the metabolite TMAO (trimethylamine N-oxide) in blood holds promise as a screening tool in the general population and a potential therapeutic target for abdominal aortic aneurysm (AAA), according to a new study co-led by Cleveland Clinic and Tufts University.

The results of the study, published in the European Heart Journal, advance more than a decade of research into the cardiovascular effects of TMAO.

A promising biomarker to predict AAA

AAA is a deadly disease caused by a bulge in the aorta, the largest blood vessel in the body. AAA typically shows no symptoms for years until a sudden rupture, which carries a risk of death greater than 50 percent. Currently, clinicians are limited to using imaging of the aorta to guide decisions around patient care. Screening is difficult because a single image does not indicate whether the AAA is stable or is rapidly expanding over time. No clear drug targets currently exist that prevent AAA from rupturing.

TMAO is the first clinical biomarker to ever predict aortic rupture, a devastating and usually fatal tear in the blood vessel wall, says Scott Cameron, MD, PhD, co-author and Cleveland Clinic’s section head of Vascular Medicine. Doctors can already measure TMAO, a compound produced by bacteria in the gut, through a readily available blood test.

Community-based study cohort reinforces potential for TMAO blood test

In the new study, investigators sought to determine whether TMAO blood levels predict AAA risks in a large group of apparently healthy subjects pulled from the general population.

The study team was co-led by two researchers with a longstanding collaboration on this topic: Cleveland Clinic’s Stanley Hazen, MD, PhD, Chair, Department of Heart, Blood & Kidney Research and co-section head of Preventive Cardiology; and Dariush Mozaffarian, MD, PhD, Director of the Food is Medicine Institute at Tufts University. A collaborative study from the two institutions published in 2022, which involved over 10,000 apparently healthy subjects, noted that higher TMAO levels are associated with animal-sourced foods, especially red meat.

For this study, Drs. Hazen and Mozaffarian drew data from the Cardiovascular Health Study, a national study that follows adults 65 and older to explore risk factors for cardiovascular disease. They analyzed TMAO levels in blood samples measured repeatedly over time in more than 4,400 participants who were followed for up to two decades. Results of the analysis showed that individuals with elevated TMAO levels were at higher risk for the following:

• Developing AAA
• Needing surgical intervention for AAA
• AAA rupture
• AAA-associated mortality 

Building on more than a decade of novel cardiovascular research

A Cleveland Clinic team led by Dr. Hazen, who holds the Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis, first established the connection between the diet, gut microbiome-generated TMAO and cardiovascular disease in 2011. Previous AAA-focused preclinical studies with this team—including a 2023 study in Circulation co-led with Phillip Owens, PhD, at the University of Cincinnati—showed that elevating TMAO levels drives AAA development and lowering TMAO can halt AAA expansion and rupture.

“We’re encouraged that our collaborative studies show TMAO can serve as a blood test to predict risk for AAA even among apparently healthy elderly individuals,” Dr. Hazen says. “The results add to a growing body of data pointing to the gut microbiome as a target for potential treatment strategies for AAA and other cardiometabolic diseases.”

“Altering TMAO concentration in the blood is a clinically actionable strategy both directly blocking its harmful effect at the blood vessel wall and indirectly preventing the ability of the gut microbiome to facilitate TMAO production,” Dr. Cameron says. “This is as close as the field has ever come to finding a non-surgical therapeutic agent for a high-quality clinical trial—one that Cleveland Clinic is well-positioned to lead.”