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BACKGROUND. L-Carnitine, an abundant nutrient in red meat, accelerates atherosclerosis in mice via gut microbiota- dependent formation of trimethylamine (TMA) and trimethylamine N-oxide (TMAO) via a multistep pathway involving an atherogenic intermediate, [gamma]-butyrobetaine ([gamma]BB). The contribution of [gamma]BB in gut microbiota- dependent L-carnitine metabolism in humans is unknown.METHODS. Omnivores and vegans/vegetarians ingested deuterium-labeled L-carnitine ([d.sub.3]-L-carnitine) or [gamma]BB ([d.sub.9]-[gamma]BB), and both plasma metabolites and fecal polymicrobial transformations were examined at baseline, following oral antibiotics, or following chronic ([greater than or equal to] 2 months) L-carnitine supplementation. Human fecal commensals capable of performing each step of the L-carnitine [right arrow] [gamma]BB [right arrow] TMA transformation were identified.RESULTS. Studies with oral [d.sub.3]-L-carnitine or [d.sub.9]-[gamma]BB before versus after antibiotic exposure revealed gut microbiota contribution to the initial 2 steps in a metaorganismal L-carnitine [right arrow] [gamma]BB [right arrow] TMA [right arrow] TMAO pathway in subjects. Moreover, a striking increase in [d.sub.3]-TMAO generation was observed in omnivores over vegans/vegetarians (>20-fold; P = 0.001) following oral [d.sub.3]-L-carnitine ingestion, whereas fasting endogenous plasma L-carnitine and [gamma]BB levels were similar in vegans/ vegetarians (n = 32) versus omnivores (n = 40). Fecal metabolic transformation studies, and oral isotope tracer studies before versus after chronic L-carnitine supplementation, revealed that omnivores and vegans/vegetarians alike rapidly converted carnitine to [gamma]BB, whereas the second gut microbial transformation, [gamma]BB [right arrow] TMA, was diet inducible (L-carnitine, omnivorous). Extensive anaerobic subculturing of human feces identified no single commensal capable of L-carnitine [right arrow] TMA transformation, multiple community members that converted L-carnitine to [gamma]BB, and only 1 Clostridiales bacterium, Emergencia timonensis, that converted [gamma]BB to TMA. In coculture, E. timonensis promoted the complete L-carnitine [right arrow] TMA transformation.CONCLUSION. In humans, dietary L-carnitine is converted into the atherosclerosis- and thrombosis-promoting metabolite TMAO via 2 sequential gut microbiota-dependent transformations: (a) initial rapid generation of the atherogenic intermediate [gamma]BB, followed by (b) transformation into TMA via low-abundance microbiota in omnivores, and to a markedly lower extent, in vegans/vegetarians. Gut microbiota [gamma]BB [right arrow] TMA/TMAO transformation is induced by omnivorous dietary patterns and chronic L-carnitine exposure.TRIAL REGISTRATION. ClinicalTrials.gov NCT01731236.FUNDING. NIH and Office of Dietary Supplements grants HL103866, HL126827, and DK106000, and the Leducq Foundation., IntroductionRecent studies identify a mechanistic link between a Western diet, gut microbiota-dependent metabolism, and development of both cardiovascular disease (CVD) and metabolic diseases (1-3). For example, the ingestion of trimethylamine-containing [...]

SCN5A encodes the voltage-gated [Na.sup.+] channel [Na.sub.v]1.5 that is responsible for depolarization of the cardiac action potential and rapid intercellular conduction. Mutations disrupting the SCN5A coding sequence cause inherited arrhythmias and cardiomyopathy, and single-nucleotide polymorphisms (SNPs) linked to SCN5A splicing, localization, and function associate with heart failure-related sudden cardiac death. However, the clinical relevance of SNPs that modulate SCN5A expression levels remains understudied. We recently generated a transcriptome-wide map of microRNA (miR) binding sites in human heart, evaluated their overlap with common SNPs, and identified a synonymous SNP (rs1805126) adjacent to a miR-24 site within the SCN5A coding sequence. This SNP was previously shown to reproducibly associate with cardiac electrophysiological parameters, but was not considered to be causal. Here, we show that miR-24 potently suppresses SCN5A expression and that rs1805126 modulates this regulation. We found that the rs1805126 minor allele associates with decreased cardiac SCN5A expression and that heart failure subjects homozygous for the minor allele have decreased ejection fraction and increased mortality, but not increased ventricular tachyarrhythmias. In mice, we identified a potential basis for this in discovering that decreased 5cn5a expression leads to accumulation of myocardial reactive oxygen species. Together, these data reiterate the importance of considering the mechanistic significance of synonymous SNPs as they relate to miRs and disease, and highlight a surprising link between SCN5A expression and nonarrhythmic death in heart failure., Introduction The onset and clinical course of heart failure is shaped by a complex interplay of environmental and genetic factors that influence a host of biological processes, including gene regulatory [...]

Our group recently discovered that certain dietary nutrients possessing a trimethylamine (TMA) moiety, namely choline/ phosphatidylcholine and L-carnitine, participate in the development of atherosclerotic heart disease. A meta-organismal pathway was elucidated involving gut microbiota-dependent formation of TMA and host hepatic flavin monooxygenase 3-dependent (FMO3-dependent) formation of TMA-W-oxide (TMAO), a metabolite shown to be both mechanistically linked to atherosclerosis and whose levels are strongly linked to cardiovascular disease (CVD) risks. Collectively, these studies reveal that nutrient precursors, gut microbiota, and host participants along the meta-organismal pathway elucidated may serve as new targets for the prevention and treatment of CVD., Introduction Cardiovascular disease (CVD) remains the leading cause of death in both the United States and industrialized societies, with growing incidence in developing countries (1). Factors contributing to CVD arise [...]

Myeloperoxidase (MPO) and paraoxonase 1 (PON1) are high-density lipoprotein--associated (HDL-associated) proteins mechanistically linked to inflammation, oxidant stress, and atherosclerosis. MPO is a source of ROS during inflammation and can oxidize [...]

Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine-choline, trimethylamine N-oxide (TMAO) and betaine-were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with cholineorTMAO promoted atherosclerosis. Studies using germ- free mice confirmedacritical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease., The pathogenesis of CVD includes genetic and environmental factors. A known environmental risk factor for the development of CVD is a diet rich in lipids. A relationship between blood cholesterol [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2008.10.016 Byline: W.H. Wilson Tang (a), Wilson Tong (b) Abstract: Measurement of impedance is becoming increasingly available in the clinical setting as a tool for assessing hemodynamics and volume status in patients with heart failure. The 2 major categories of impedance assessment are the band electrode method and the implanted device lead method. The exact sources of the impedance signal are complex and can be influenced by physiologic effects such as blood volume, fluid, and positioning. This article provides a critical review of our current understanding and promises of impedance measurements, the techniques that have evolved, as well as the evidence and limitations regarding their clinical applications in the setting of heart failure management. Author Affiliation: (a) Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH (b) University of Cincinnati School of Medicine, Cincinnati, OH Article History: Received 30 April 2008; Accepted 7 October 2008 Article Note: (footnote) Dr. Tang is supported in part by the National Institutes of Health, National Center for Research Resources, CTSA 1UL1RR024989, Cleveland, OH.

OBJECTIVE: To evaluate modern surgical outcomes in patients with stable heart failure undergoing elective major noncardiac surgery and to compare the experience of patients with heart failure who have reduced [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2007.07.039 Byline: Wilfried Mullens, W.H. Wilson Tang, Richard A. Grimm Abstract: Cardiac resynchronization therapy has become a therapeutic option for refractory heart failure. Several imaging techniques play an increasingly important role in patient selection during and after implantation. This manuscript reviews the current echocardiographic techniques available for guiding both patient selection and optimization of device programming following implantation. Author Affiliation: Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH Article History: Received 24 April 2007; Accepted 24 July 2007

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2007.07.039 Byline: Wilfried Mullens, W.H. Wilson Tang, Richard A. Grimm Abstract: Cardiac resynchronization therapy has become a therapeutic option for refractory heart failure. Several imaging techniques play an increasingly important role in patient selection during and after implantation. This manuscript reviews the current echocardiographic techniques available for guiding both patient selection and optimization of device programming following implantation. Author Affiliation: Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH Article History: Received 24 April 2007; Accepted 24 July 2007

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2004.07.026 Byline: Anoop C. Parameswaran (a), W.H. Wilson Tang (b), Gary S. Francis (b), Ritesh Gupta (c), James B. Young (a)(b) Abstract: The longitudinal pattern of [beta]-blocker use in a heart-failure practice setting has not been explored. Previous studies have not specifically addressed the use of [beta]-blockers over time to determine the rate of use and reasons for discontinuation. The long-term compliance rate for [beta]-blocker drugs outside the context of a clinical trial has not been established. Author Affiliation: (a) Department of Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (b) Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (c) Division of Cardiovascular Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Ala Article History: Received 20 April 2004; Accepted 30 July 2004 Article Note: (miscellaneous) This project did not receive any financial support. Drs Tang and Francis are consultants for GlaxoSmithKline Pharmaceuticals; Dr Young is a consultant for AstraZeneca Pharmaceuticals.