Reporter: Aviva Lev-Ari, PhD, RN
Cause for Increased Cardiovascular Risk: proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO).
Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk
W.H. Wilson Tang, M.D., Zeneng Wang, Ph.D., Bruce S. Levison, Ph.D., Robert A. Koeth, B.S., Earl B. Britt, M.D., Xiaoming Fu, M.S., Yuping Wu, Ph.D., and Stanley L. Hazen, M.D., Ph.D.
N Engl J Med 2013; 368:1575-1584April 25, 2013DOI: 10.1056/NEJMoa1109400
BACKGROUND
Recent studies in animals have shown a mechanistic link between intestinal microbial metabolism of the choline moiety in dietary phosphatidylcholine (lecithin) and coronary artery disease through the production of a proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO). We investigated the relationship among intestinal microbiota-dependent metabolism of dietary phosphatidylcholine, TMAO levels, and adverse cardiovascular events in humans.
METHODS
We quantified plasma and urinary levels of TMAO and plasma choline and betaine levels by means of liquid chromatography and online tandem mass spectrometry after a phosphatidylcholine challenge (ingestion of two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine) in healthy participants before and after the suppression of intestinal microbiota with oral broad-spectrum antibiotics. We further examined the relationship between fasting plasma levels of TMAO and incident major adverse cardiovascular events (death, myocardial infarction, or stroke) during 3 years of follow-up in 4007 patients undergoing elective coronary angiography.
RESULTS
Time-dependent increases in levels of both TMAO and its d9 isotopologue, as well as other choline metabolites, were detected after the phosphatidylcholine challenge. Plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after withdrawal of antibiotics. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (hazard ratio for highest vs. lowest TMAO quartile, 2.54; 95% confidence interval, 1.96 to 3.28; P<0.001). An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P<0.001), as well as in lower-risk subgroups.
CONCLUSIONS
The production of TMAO from dietary phosphatidylcholine is dependent on metabolism by the intestinal microbiota. Increased TMAO levels are associated with an increased risk of incident major adverse cardiovascular events. (Funded by the National Institutes of Health and others.)
Supported by grants from the National Institutes of Health and its Office of Dietary Supplements (R01HL103866 and 1P20HL113452). The clinical study GeneBank was supported by grants from the National Institutes of Health (P01HL098055, P01HL076491, R01HL103931, and R01DK080732) and a Cleveland Clinic/Case Western Reserve University Clinical and Translational Science Award (UL1TR000439). Dr. Hazen was supported by a gift from the Leonard Krieger Fund. Mass spectrometry instrumentation used was housed within the Cleveland Clinic Mass Spectrometry Facility with partial support through a Center of Innovation by AB SCIEX.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank Linda Kerchenski and Cindy Stevenson for their assistance in recruitment of study participants and Amber Gist and Naomi Bongorno for their assistance in the preparation of earlier versions of the figures and the manuscript.
SOURCE INFORMATION
From the Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland.
Address reprint requests to Dr. Hazen at the Cleveland Clinic, 9500 Euclid Ave. NC-10, Cleveland, OH 44195, or at hazens@ccf.org.
http://www.nejm.org/doi/full/10.1056/NEJMoa1109400?query=genetics
EDITORIAL
Gut Microbiota, the Genome, and Diet in Atherogenesis
Joseph Loscalzo, M.D., Ph.D.
N Engl J Med 2013; 368:1647-1649April 25, 2013DOI: 10.1056/NEJMe1302154
The Galtonian distinction between the influence of genetics and environment on phenotype is now widely recognized as an overly simplistic dichotomy. Genes and environmental factors interact in myriad ways to modulate and modify the biology of all living organisms, challenging the notion that these two principal determinants of phenotype can ever truly act independently of each other. Environmental exposures and experiences can have a direct influence on the expression of genes through epigenetic processes or on the function of gene products through post-translational modification. Likewise, genetic factors influence the consequences of environmental exposures or stresses on the organism.
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Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette