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Elevated levels of the gut microbiome trimethylamine N-oxide (TMAO) pathway led to a higher risk of heart failure independent of other risk factors, Cleveland Clinic and Tufts University researchers found during a study of two large National Institutes of Health cohorts.

TMAO is a metabolite that forms when gut bacteria digest certain nutrients abundant in red meat and other animal products. Over the past decade, a Cleveland Clinic research team led by Stanley Hazen, MD, PhD, has published numerous studies linking high levels of TMAO to increased risk of developing both cardiovascular disease, including adverse events like heart attack and stroke, and chronic kidney disease. The most recent study further investigated this association by following nearly 12,000 participants who were healthy at the time of enrollment, examining the effects of elevated TMAO over time.

The study was recently published in the journal Circulation: Heart Failure. Researchers measured serial blood level samples over almost 16 years, resulting in over 20,000 evaluations of TMAO levels. The participants totaled 11,757, after excluding individuals with prevalent heart failure at baseline. Overall, 2,102 cases of heart failure occurred. Within this group, they found that TMAO served as a remarkably strong biomarker for identifying subjects at risk for incident development of heart failure, after adjustment for a range of cardiovascular disease risk factors, sociodemographic, lifestyle, medical and biochemical markers. The findings were generally consistent across cardiovascular disease risk factors including age, race/ethnicity, BMI and baseline renal function.

“The present studies show that even amongst apparently healthy subjects at time of enrollment, serial blood TMAO levels predicted incident risk for heart failure development during long term follow up,” Dr. Hazen says. “They add to the growing body of research linking the gut microbial TMAO pathway to cardiovascular and metabolic diseases, and identifying it as a potential target for therapeutics.”

The study is part of a long-standing collaboration between a Cleveland Clinic research team led by Dr. Hazen, senior author and chair of the Department of Cardiovascular & Metabolic Sciences, and Dariush Mozaffarian, MD, DrPH, from the Food is Medicine Institute at the Friedman School of Nutrition Science and Policy at Tufts University. W. H. Wilson Tang, MD, a cardiologist with expertise in heart failure and transplantation at the Cleveland Clinic was a lead author of the study.

TMAO is primarily generated in humans through diet, largely through eating animal products. The gut microbiome processes these protein sources. Dr. Hazen’s team has been developing treatment options that target the TMAO pathway to prevent and treat diseases like cardiovascular disease and chronic kidney disease. His team has found success in the lab and in preclinical models of disease in halting TMAO production as a novel pharmaceutical approach.

“Heart failure is one of the leading causes of death worldwide. Our identification of a novel physiological risk pathway is significant for the field,” Dr. Hazen explains. “These results open a new avenue for potential treatment and prevention. Since subjects with elevated TMAO levels are at increased risk for development of heart failure, we’ve seen interventions designed to lower TMAO may help prevent heart failure from ever developing. I’m hopeful we will someday have medications that target the TMAO pathway and prevent its negative effects from occurring.”

During the current study, investigators also observed that elevated concentrations of two other TMAO pathway-related metabolites—crotonobetaine and choline—were associated with an increased risk of incident heart failure. This finding will likely prompt new avenues of study to further mechanistically link these metabolites to heart failure.

Disclosures: Dr. Hazen is named as co-inventor on pending and issued patents held by Cleveland Clinic in relation to cardiovascular diagnostics and therapeutics.