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High TMAO level predicts CV events in patients with ACS
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Patients presenting with ACS with elevated levels of trimethylamine N-oxide have increased risk for incident CV events, according to new data.
A high level of trimethylamine N-oxide (TMAO), a metabolite linked to atherogenesis and thrombosis produced from gut microbiota metabolism of choline, a nutrient found in meat and eggs, is known to predict incident CV event risk in stable patients, but its effect on patients with ACS was unknown, Stanley L. Hazen, MD, PhD, chair of the department of cellular and molecular medicine in the Lerner Research Institute and head of preventive cardiology and rehabilitation in the Miller Family Heart & Vascular Institute at Cleveland Clinic, told Cardiology Today.
“All our thinking on this pathway had been for a chronic situation, for the development of atherosclerosis or adverse events from atherosclerosis, but in a patient who is essentially stable,” Hazen, a member of the Cardiology Today Editorial Board, said in an interview. “But it might have clinical relevance for people who present to the ED with chest pain if you know who is at risk for enhanced thrombosis” via elevated TMAO.
Hazen and colleagues analyzed 530 sequential patients (mean age, 62 years; 58% men) presenting to the ED at Cleveland Clinic with chest pain of suspected cardiac origin to determine the relationship between TMAO levels and 30-day and 6-month major adverse cardiac events, defined as MI, stroke, revascularization or death.
In that cohort, elevated plasma TMAO levels were independently associated with elevated risk for major adverse cardiac events at 30 days (adjusted OR for fourth quartile = 6.3; 95% CI, 1.8-21) and at 6 months (adjusted OR for fourth quartile = 5.65; 95% CI, 1.91-16.7), according to the researchers.
Elevated plasma TMAO levels also predicted mortality at 7 years (adjusted HR for fourth quartile = 1.81; 95% CI, 1.04-3.15), Hazen and colleagues found.
High TMAO predicted incident major adverse cardiac events even in patients with persistemtly negative troponin T levels (< 0.1 ng/mL) during initial presentation at 30 days (adjusted OR for fourth quartile = 5.83; 95% CI, 1.79-19.03) and 6 months (adjusted OR for fourth quartile = 5.51; 95% CI, 1.9-16.01), the researchers wrote.
“Once we saw these results at Cleveland, we wanted to replicate them in an independent cohort,” Hazen told Cardiology Today. “We contacted Thomas F. Lüscher, MD, FRCP ... who had a four-site study in Switzerland specifically looking at ACS patients. We essentially saw comparable results: A high TMAO predicted future CV events in this multicenter ACS cohort.”
In the cohort of 1,683 patients with ACS (mean age, 64 years; 78% men) who underwent coronary angiography organized by Lüscher, professor and chairman of cardiology at University Heart Center, University Hospital, Zurich, director of the Center for Molecular Cardiology at the University of Zurich and editor in chief of the European Heart Journal, and colleagues, elevated TMAO levels predicted increased risk for major adverse cardiac events at 1 year (adjusted HR for fourth quartile = 1.57; 95% CI, 1.03-2.41).
A study concurrently published in Clinical Chemistry showed similar results, Hazen said. Those researchers “saw that addition of TMAO in patients who present with acute MI provides added prognostic value in terms of predicting adverse events. Interestingly, they looked at it a different way, finding that a low TMAO helps identify people who are not at near-term risk,” he said.
In that cohort of 1,079 patients, TMAO was an independent predictor of death or MI at 2 years (HR = 1.21; 95% CI, 1.03-1.43). Although TMAO was not an independent predictor of death or MI at 6 months (P = .119), it improved risk stratification for death or MI at 6 months by downclassifying patients with GRACE score > 119 and plasma TMAO concentration 3.7 µmol/L.
A test for TMAO levels exists. It “is available as a routine send-out test, like for cholesterol,” Hazen told Cardiology Today. “You wouldn’t routinely look at cholesterol to predict risk in the ED, and TMAO we have previously thought of like cholesterol: It helps identify people who are stable and at long-term risk. Clinically, it is able to be used in a less-urgent setting and helps identify who is at increased risk that otherwise wouldn’t be identified.”
Hazen said results from studies such as these highlight a need for the development a rapid test for TMAO that can be used in the ED to help triage patients and predict short-term CV risk in individuals presenting with possible ACS symptoms.
Another clinical use is that “if your TMAO is high, it means, whatever your diet is, you need to cut back on animal products,” Hazen said. “Maybe you should start trying to eat less red meat and egg yolk, or certainly not take supplements like lecithin, choline or carnitine.”
The findings also have implications for drug development, he said.
“I think of it like this: A statin blocks cholesterol synthesis in homo sapien cells. We need to develop drugs that block microbe-mediated synthesis of TMAO,” he said. “Based on all the studies, this looks like a very new and exciting approach for helping to treat CV and metabolic diseases.” – by Erik Swain
Disclosure: Hazen and a colleague are named as co-inventors on patents held by Cleveland Clinic related to CV diagnostics and therapeutics. Hazen also reports consulting for Esperion and Proctor & Gamble; receiving research funds from Pfizer, Proctor & Gamble, Roche Diagnostics and Takeda; and being eligible to receive royalties for inventions or discoveries related to products owned by Cleveland Heart Lab, Esperion, Frantz Biomarkers and Siemens. Lüscher reports receiving grants from AstraZeneca, Biotronik, Boston Scientific, Eli Lilly and St. Jude Medical. The other researchers report no relevant financial disclosures.
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