Cleveland Clinic researchers discover new link between heart disease and red meat

(Press-News.org) EMBARGOED UNTIL 1 P.M. EDT, APRIL 7, 2013, Cleveland: A compound abundant in red meat and added as a supplement to popular energy drinks has been found to promote atherosclerosis – or the hardening or clogging of the arteries – according to Cleveland Clinic research published online this week in the journal Nature Medicine.

The study shows that bacteria living in the human digestive tract metabolize the compound carnitine, turning it into trimethylamine-N-oxide (TMAO), a metabolite the researchers previously linked in a 2011 study to the promotion of atherosclerosis in humans. Further, the research finds that a diet high in carnitine promotes the growth of the bacteria that metabolize carnitine, compounding the problem by producing even more of the artery-clogging TMAO.

The research team was led by Stanley Hazen, M.D., Ph.D., Vice Chair of Translational Research for the Lerner Research Institute and section head of Preventive Cardiology & Rehabilitation in the Miller Family Heart and Vascular Institute at Cleveland Clinic, and Robert Koeth, a medical student at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

The study tested the carnitine and TMAO levels of omnivores, vegans and vegetarians, and examined the clinical data of 2,595 patients undergoing elective cardiac evaluations. They also examined the cardiac effects of a carnitine-enhanced diet in normal mice compared to mice with suppressed levels of gut microbes, and discovered that TMAO alters cholesterol metabolism at multiple levels, explaining how it enhances atherosclerosis.

The researchers found that increased carnitine levels in patients predicted increased risks for cardiovascular disease and major cardiac events like heart attack, stroke and death, but only in subjects with concurrently high TMAO levels. Additionally, they found specific gut microbe types in subjects associated with both plasma TMAO levels and dietary patterns, and that baseline TMAO levels were significantly lower among vegans and vegetarians than omnivores. Remarkably, vegans and vegetarians, even after consuming a large amount of carnitine, did not produce significant levels of the microbe product TMAO, whereas omnivores consuming the same amount of carnitine did.

"The bacteria living in our digestive tracts are dictated by our long-term dietary patterns," Hazen said. "A diet high in carnitine actually shifts our gut microbe composition to those that like carnitine, making meat eaters even more susceptible to forming TMAO and its artery-clogging effects. Meanwhile, vegans and vegetarians have a significantly reduced capacity to synthesize TMAO from carnitine, which may explain the cardiovascular health benefits of these diets."

Prior research has shown that a diet with frequent red meat consumption is associated with increased cardiovascular disease risk, but that the cholesterol and saturated fat content in red meat does not appear to be enough to explain the increased cardiovascular risks. This discrepancy has been attributed to genetic differences, a high salt diet that is often associated with red meat consumption, and even possibly the cooking process, among other explanations. But Hazen says this new research suggests a new connection between red meat and cardiovascular disease.

"This process is different in everyone, depending on the gut microbe metabolism of the individual," he says. "Carnitine metabolism suggests a new way to help explain why a diet rich in red meat promotes atherosclerosis."

While carnitine is naturally occurring in red meats, including beef, venison, lamb, mutton, duck, and pork, it's also a dietary supplement available in pill form and a common ingredient in energy drinks. With this new research in mind, Hazen cautions that more research needs to be done to examine the safety of chronic carnitine supplementation.

"Carnitine is not an essential nutrient; our body naturally produces all we need," he says. "We need to examine the safety of chronically consuming carnitine supplements as we've shown that, under some conditions, it can foster the growth of bacteria that produce TMAO and potentially clog arteries."

This study is the latest in a line of research by Hazen and his colleagues exploring how gut microbes can contribute to atherosclerosis, uncovering new and unexpected pathways involved in heart disease. In a 2011 Nature study, they first discovered that people are not predisposed to cardiovascular disease solely because of their genetic make-up, but also based on how the micro-organisms in their digestive tracts metabolize lecithin, a compound with a structure similar to carnitine.

### This research was supported by the National Institutes of Health (grants R01 HL103866, P20 HL113452, PO1 HL30568, PO1 H28481, R00 HL096166, UH3-DK083981, 1RC1DK086472).

About Cleveland Clinic Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S.News & World Report consistently names Cleveland Clinic as one of the nation's best hospitals in its annual "America's Best Hospitals" survey. More than 3,000 full-time salaried physicians and researchers and 11,000 nurses represent 120 medical specialties and subspecialties. The Cleveland Clinic health system includes a main campus near downtown Cleveland, more than 75 Northern Ohio outpatient locations, including 16 full-service Family Health Centers, Cleveland Clinic Florida, the Lou Ruvo Center for Brain Health in Las Vegas, Cleveland Clinic Canada, and, currently under construction, Cleveland Clinic Abu Dhabi. In 2012, there were 5.1 million outpatient visits throughout the Cleveland Clinic health system and 157,000 hospital admissions. Patients came for treatment from every state and from more than 130 countries. Visit us at http://www.clevelandclinic.org. Follow us at http://www.twitter.com/ClevelandClinic.

About the Lerner Research Institute The Lerner Research Institute (LRI) is home to laboratory, translational and clinical research at Cleveland Clinic. Its three-part mission is: to promote human health by investigating the causes of disease and discovering new approaches to prevention and treatments, to train the next generation of biomedical researchers and to foster collaborations with clinical care providers. LRI's total annual research expenditure was $255 million in 2012 (nearly $110 million in federal funding). With more than 700,000 square feet of lab, office, and core services space, LRI is home to more than 2,000 people working in disease-focused research programs. In 2012, LRI researchers published over 600 articles in high-impact biomedical journals (top 10 percent) and generated 83 invention disclosures, 10 new licenses and 35 patents. LRI faculty oversee curriculum and teach courses in the Cleveland Clinic Lerner College of Medicine (CCLCM) of Case Western Reserve University and participate in doctoral programs, including the Molecular Medicine PhD Program, supported in part by the Howard Hughes Medical Institute.

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Contact: Wyatt DuBois, 216.445.9946, duboisw@ccf.org Laura Ambro, 216.636.5876, ambrol@ccr.org Tora Vinci, 216.444.2412, vinciv@ccf.org