Cardiovascular disease (CVD) represents the major source of morbidity and mortality. Despite maximal therapeutic intervention, significant risks remain. There is a critical need for discovery of pathways linked to CVD pathogenesis. The proposed studies combine unbiased metabolomics approaches, with more quantitative targeted analyses, and mechanistic animal models and human studies, to define novel analytes and pathways linked to CVD pathogenesis.
In aim 1, we propose new mechanistic studies in animal models of disease, and in humans, centered around a new and unpublished pathway discovered recently during performance of our initial unbiased metabolomics studies. We have accrued substantial preliminary data in both mouse models and human clinical investigations showing a dietary nutrient abundant in red meat is metabolized by gut flora and is linked to atherosclerosis. Unpublished targeted metabolomics studies, isotope tracer studies in germ free mice and humans ? antibiotic suppression, and additional mechanistic animal model studies, collectively indicate at least three distinct metabolites produced by gut flora may possess direct biological activity impacting upon atherosclerosis susceptibility and cholesterol metabolism.
In aim 2 we propose to substantially extend upon our initial unbiased metabolomics investigations using two distinct and well defined clinical cohorts. Studies in subjects undergoing elective cardiac evaluations and for whom long term follow-up is available will enable us to discover new analytes and pathways associated with development of atherosclerotic heart disease and its adverse complications heart attack, heart failure and death. While metabolomics studies in another, a clinical trial monitored by sequential coronary intravascular ultrasound [IVUS]), will allow us to define analytes and pathways associated with response to therapy for high potency statins. Successful completion of our proposed research program will provide opportunities for development of both novel diagnostic tests and therapeutic approaches for the treatment and prevention of atherosclerotic heart disease and its major complications. It will also further establish gut flora-dependent metabolism of an abundant nutrient in red meat as a new pathway for cardiovascular disease pathogenesis discovered through unbiased metabolomics.

Public Health Relevance

Despite the identification of numerous genetic and clinical risk factors for cardiovascular disease, we can still only explain in a small fraction of patients why that individual develops the disease, and many novel pathways contributing to disease still remain unexplored. The present studies will help identify novel pathways of clinical relevance with mechanistic links to cardiovascular disease pathogenesis and adverse sequelae such as myocardial infarction and heart failure, with the hope to better diagnose and treat or prevent disease progression. (End of Abstract)

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (F2))
Program Officer
Srinivas, Pothur R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Tang, W H Wilson; Wang, Zeneng; Shrestha, Kevin et al. (2015) Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J Card Fail 21:91-6
Grodin, Justin L; Hammadah, Muhammad; Fan, Yiying et al. (2015) Prognostic value of estimating functional capacity with the use of the duke activity status index in stable patients with chronic heart failure. J Card Fail 21:44-50
Grodin, Justin L; Neale, Sarah; Wu, Yuping et al. (2015) Prognostic comparison of different sensitivity cardiac troponin assays in stable heart failure. Am J Med 128:276-82
Hazen, Stanley L; Brown, J Mark (2014) Eggs as a dietary source for gut microbial production of trimethylamine-N-oxide. Am J Clin Nutr 100:741-3
Campbell, Caitlin; Grapov, Dmitry; Fiehn, Oliver et al. (2014) Improved metabolic health alters host metabolism in parallel with changes in systemic xeno-metabolites of gut origin. PLoS One 9:e84260
Cajka, Tomas; Fiehn, Oliver (2014) Comprehensive analysis of lipids in biological systems by liquid chromatography-mass spectrometry. Trends Analyt Chem 61:192-206
Shao, Zhili; Zhang, Renliang; Shrestha, Kevin et al. (2014) Usefulness of elevated urine neopterin levels in assessing cardiac dysfunction and exercise ventilation inefficiency in patients with chronic systolic heart failure. Am J Cardiol 113:1839-43
Brown, J Mark; Hazen, Stanley L (2014) Metaorganismal nutrient metabolism as a basis of cardiovascular disease. Curr Opin Lipidol 25:48-53
Brown, J Mark; Hazen, Stanley L (2014) Seeking a unique lipid signature predicting cardiovascular disease risk. Circulation 129:1799-803
Hammadah, Muhammad; Fan, Yiying; Wu, Yuping et al. (2014) Prognostic value of elevated serum ceruloplasmin levels in patients with heart failure. J Card Fail 20:946-52

Showing the most recent 10 out of 45 publications