Stanley Hazen Lab | Lerner Research Institute

Principal Investigator

Stanley Hazen, MD, PhD

Department Chair
The Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis
Director, Center for Cardiovascular Diagnostics & Prevention
Director, Center for Microbiome & Human Health
Email: hazens@ccf.org
Location: Cleveland Clinic Main Campus

Research

A long term goal of my laboratory is to understand the ways in which our immune system contributes to diseases like heart disease and asthma. I have several major areas of focus. One centers on the role of myeloperoxidase, a protein found in white blood cells that plays an important role in fighting infections, but which we have discovered also participates in development of heart diseases. A second area focuses on the role of microbes in our intestines (called gut flora) in heart disease. Another area focuses on the HDL particle (carrier of good cholesterol in the blood).

Biography

Stanley Hazen, MD, PhD, received clinical training in Internal Medicine and subspecialty training in Diabetes, Endocrinology and Metabolism from Barnes/Jewish Hospital, St. Louis, MO, and a PhD in Biophysical Chemistry and Molecular Biology from Washington University School of Medicine, St. Louis, MO. He holds multiple leadership positions at the Cleveland Clinic including chair, Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, co-Section head, Preventive Cardiology & Rehabilitation, Heart, Vascular & Thoracic Institute, and Director, Center for Microbiome & Human Health. Dr. Hazen sees patients within the Preventive Cardiology Clinic, specializing in preventive cardiovascular medicine care of patients including treatment of hyperlipidemia, hypertension, obesity and diabetes. He also sees patients within the Cardiovascular Rehabilitation program. His research interests include studies of mechanisms for the development of cardiovascular disease, with emphasis on understanding the role of the gut microbiome, inflammation and oxidant stress in the pathogenesis of atherosclerosis and other inflammatory diseases.

A renowned physician scientist, Dr. Hazen has made pioneering discoveries in new understandings of mechanisms contributing to cardiovascular and inflammatory disease research. He is credited with numerous seminal discoveries linking gut microbial pathways to cardiovascular disease pathogenesis, as well as enumerating the role of myeloperoxidase and other inflammatory and oxidative pathways in cardiovascular disease. Dr. Hazen is among the top 0.1% cited researchers in the world with over 140,000 citations. He has published over 475 peer-reviewed articles in top tier basic and clinical journals alike in the fields of atherosclerosis, lipoprotein metabolism, gut microbiome, inflammation, vascular biology, and other topics related to preventive cardiovascular medicine. His research in multiple areas has impacted clinical practice, and lays the foundation for FDA- and EU-cleared diagnostic tests for cardiovascular disease risk assessment in use worldwide. He is listed as inventor on over 100 patents, and his research has helped to spawn pharmaceutical development of cardiovascular disease drugs in clinical trials.

Dr. Hazen has received numerous awards including being the Inaugural recipient of the Top 10 Clinical Discovery of the Year (2011) Award, Clinical Research Forum; the American Heart Association/American Stroke Association “top 10 advance in heart disease and stroke science” award (2013); and the American Heart Association Distinguished Scientist Award (2017). Dr Hazen has been honored with election of membership into honorary societies in both science and clinical arenas alike, including the American Society for Clinical Investigation (ASCI) and the American Association of Physicians (AAP). Dr. Hazen is an elected fellow of the American Association for the Advancement of Science (AAAS). Dr. Hazen also is an elected member of the National Academy of Medicine, USA.

Education & Professional Highlights

Education & Fellowships

Fellowship - Barnes-Jewish Hospital
Endocrinology
St. Louis, MO USA
1996

Residency - Barnes-Jewish Hospital
Internal Medicine
St. Louis, MO USA
1994

Medical Education - Washington University School of Medicine
St. Louis, MO USA
1992

Medical Education - Washington University
St. Louis, MO USA
1992

Undergraduate - Washington University
St. Louis, MO USA
1985

Professional Highlights

Chair, Gordon Research Conference on Oxygen Radicals
Jeffrey M Hoeg Arteriosclerosis, Thrombosis and Vascular Biology Award for Basic Science and Clinical Research
Election, Association of American Physicians (AAP)
Election, Fellow of American Heart Association Scientific Council for Arteriosclerosis
Election, American Society for Clinical Investigation

Awards & Honors

Howard Hughes Medical Institute Research Fellowship for Physicians Award, 1995-1997
AAP, ASCI, and AFMR Certificate of Achievement Award, 1997
Marilyn Hansen American Thoracic Society Award, 1997
Junior Faculty Award, American Federation of Medical Research, 1999
Gill Heart Institute Physician Scientist Award, University of Kentucky, Lexington Ky., 2001
Election, American Society for Clinical Investigation, 2003
John J. Ferchill Award for Innovation, Cleveland Clinic, 2004
Nomination, Howard Hughes Medical Institute Investigator Award, 2004
Vice-Chair, Gordon Research Conference on Oxygen Radicals, 2006
Jeffrey M Hoeg Arteriosclerosis, Thrombosis and Vascular, 2007

Innovations & Patents

Patent Title: Diagnostic Methods for Asthma; U.S. Serial Number 09/253,380
Patent Title: Myeloperoxidase, a Risk Indicator for Cardiovascular Disease; U.S., Serial Number 10/039,753
Patent Title: Treating Inflammation and Associated Complications; Patent Reference Number 09531-030P01 (Pending)
Patent Title: Methods of Identifying Subjects at Increased Risk for Cardiovascular Disease; U.S. Serial Number 60/259,340 (Pending)
Patent Title: Monitoring Anti-inflammatory and Anti-oxidant Actions of Therapies; U.S. Serial Number (Pending)
Patent Title: Diagnostic Method for Identifying Subjects at Risk for Atherosclerosis and its Complications; U.S. Serial Number (Pending)

Memberships

American Society for Clinical Investigation
American Association for the Advancement of Science
American Heart Association Scientific Council for Arteriosclerosis
American Society for Investigative Pathology
American College of Cardiology

Research

Overview

A long term goal of my laboratory is to understand mechanisms through which inflammation contributes to diseases like atherosclerosis and asthma. Several major research programs are currently under investigation. One research program focuses on the role of myeloperoxidase, a leukocyte heme protein, in promoting oxidant stress in vivo, and its participation in cardiovascular diseases. A second area focuses on HDL structure and function. A final area of research interest focuses on the role of intestinal microbiota in cardiometabolic disease.

All research projects rely heavily on chemical and analytical methods to identify specific reactions/products, their mechanisms of formation, and their use as probes to elaborate pathways responsible for disease. Research efforts in each program span from bench-to-bedside, including basic/genetic, cellular, animal model, and human clinical investigations.

Experimental Data

Experimental data and computational models for downloading

1) The refined structure of nascent HDL reveals a key functional domain for particle maturation and dysfunction

Wu, Z.; Wagner, M. A.; Zheng, L.; Parks, J. S.; Shy II, J. M.; Smith, J. D.; Gogonea, V.; Hazen, S. L. Nat. Struct. Mol. Biol. 14, 861-8 (2007).

Computational model:

a) All-atom molecular model of the Solar Flares model of nascent HDL. Available at mi.caspur.it (accession code PM0074956).

2) The double super helix model of high density lipoprotein

Wu, Z.; Gogonea, V.; Lee, X.; Wagner, M. A.; Li, X.-M.; Huang, Y.; Arundhati, U.; May, R. P.; Haertlein, M.; Moulin, M.; Gutsche, I.; Zaccai, G.; DiDonato, J.; Hazen, S. L. J. Biol. Chem. 284, 36605-19 (2009).

Experimental data and computational models:

	a) Small angle neutron scattering intensities for the protein component of nascent HDL (12 % D2O, collected at the Institute Laue-Langevin, Grenoble, France).
	b) The solution low-resolution structure of the protein component of nascent HDL obtained by small angle neutron scattering with contrast variation (12 % D2O, ILL data).
	c) Small angle neutron scattering intensities for the lipid component of nascent HDL (42 % D2O, collected at the Institute Laue-Langevin, Grenoble, France).
	d) The solution low-resolution structure of the lipid component of nascent HDL obtained by small angle neutron scattering with contrast variation (42 % D2O, ILL data).
	e) The Double Super Helix model of nascent HDL. Available at www.rcsb.org (accession code 3K2S).

3) Congruency between biophysical data from multiple platforms and molecular dynamics simulation of the double super helix model of nascent high-density lipoprotein

Gogonea, V.; Wu, Z.; Lee, X.; Pipich, V.; Li, X.-M., Ioffe, I. A.; DiDonato, J.; Hazen, S. L. Biochemistry, 49, 7323-43 (2010).

Experimental and computational models, and data calculated from simulation trajectory:

	a) Small angle neutron scattering intensities for the protein component of nascent HDL (12 % D2O, collected at the Jülich Center for Neutron Science, Garching, Germany).
	b) The solution low-resolution structure of the protein component of nascent HDL obtained by small angle neutron scattering with contrast variation (12 % D2O, JCNS data).
	Mirror image of the solution low-resolution structure of the protein component of nascent HDL.
	c) Small angle neutron scattering intensities for the lipid component of nascent HDL (42 % D2O, collected at the Jülich Center for Neutron Science, Garching, Germany).
	d) The solution low-resolution structure of the lipid component of nascent HDL obtained by small angle neutron scattering with contrast variation (42 % D2O, JCNS data, PDB file)
	e) Molecular model of nascent HDL obtained after 60 ns molecular dynamics simulation of the Double Super Helix model.
	f) Hydrogen-deuterium exchange data (HD incorporation factors, residue unfolding constants, HD exchange rate constants) calculated from the molecular dynamics simulation trajectory of the Double Super Helix model (excel format).

4) The low resolution structure of ApoA1 in spherical high density lipoprotein revealed by small angle neutron scattering

Wu, Z.; Gogonea, V.; Lee, X.; May, R.P.; Pipich, V.; Wagner, M.A.; Undurti, A.; Tallant, T. C.; Baleanu-Gogonea, C.; Charlton, F.; Ioffe, I. A.; DiDonato, J.A.; Rye, K.-A.; Hazen, S. L. J. Biol. Chem., 286, 12495-508 (2011).

Low resolution structures:

	a) Small angle neutron scattering intensities for the protein component of spherical HDL (12 % D2O).
	b) The solution low-resolution structure of the protein component of spherical HDL obtained by small angle neutron scattering with contrast variation (12 % D2O).
	c) Small angle neutron scattering intensities for the lipid component of spherical HDL (42 % D2O).
	d) The solution low-resolution structure of the lipid component of spherical HDL obtained by small angle neutron scattering with contrast variation (42 % D2O).

5) The low resolution structure of nascent high density lipoprotein reconstituted with DMPC with and without cholesterol reveals a mechanism for particle expansion

Gogonea, V.; Gerstenecker, G. S.; Wu, Z.; Lee, X.; Topbas, C.; Wagner, M. A.; Tallant, T. C.; Smith J. D.; Callow, P.; Pipich, V.; Malet, H.; Schoehn, G.; DiDonato, J. A.; Hazen, S. L. J. Lipid Res., in print.

Low resolution structures and computational model:

	a) Small angle neutron scattering intensities for the protein component of nascent HDL/DMPC (12 % D2O).
	b) The solution low-resolution structure of the protein component of nascent HDL/DMPC obtained by small angle neutron scattering with contrast variation (12 % D2O).
	c) Small angle neutron scattering intensities for the lipid component of nascent HDL/DMPC (42 % D2O).
	d) The solution low-resolution structure of the lipid component of nascent HDL/DMPC obtained by small angle neutron scattering with contrast variation (42 % D2O).
	e) Molecular model of nascent HDL/DMPC obtained from the low resolution structures of the protein and lipid components of nascent HDL/DMPC (PDB file).
	f) Small angle neutron scattering intensities for the protein component of nascent HDL/DMPC+Chol (12 % D2O).
	g) The solution low-resolution structure of the protein component of nascent HDL/DMPC+Chol obtained by small angle neutron scattering with contrast variation (12 % D2O).
	h) Small angle neutron scattering intensities for the lipid component of nascent HDL/DMPC+Chol (42 % D2O).
	i) The solution low-resolution structure of the lipid component of nascent HDL/DMPC+Chol obtained by small angle neutron scattering with contrast variation (42 % D2O).

Our Team

Publications

Selected Publications

View publications for Stanley Hazen, MD, PhD
(Disclaimer: This search is powered by PubMed, a service of the U.S. National Library of Medicine. PubMed is a third-party website with no affiliation with Cleveland Clinic.)

Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WHW, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature.(2011) 472(7341):57-63. PMCID: PMC3086762
Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk. New England Journal of Medicine. (2013) 368(17):1575-84. PMCID: PMC3701945
Koeth RA, Wang Z, Levison BS, Buffa J, Org E, Sheehy B, Li H, Britt EB, Fu X, Wu Y, Smith JD, DiDonato JA, Chen J, Li H, Wu G, Lewis JD, Warrier M, Brown, JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, and Hazen SL. Intestinal microbiota metabolism of L-Carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine. (2013) 19(5): 576-85. PMCID: PMC36501111
Huang Y, Didonato JA, Levison BS, Schmitt D, Li L, Wu Y, Buffa J, Kim T, Gerstenecker GS, Gu X, Kadiyala CS, Wang Z, Culley MK, Hazen JE, Didonato AJ, Fu X, Berisha SZ, Peng D, Nguyen TT, Liang S, Chuang CC, Cho L, Plow EF, Fox PL, Gogonea V, Tang WH, Parks JS, Fisher EA, Smith JD, Hazen SL. An abundant dysfunctional apolipoprotein A1 form in human atheroma. Nature Medicine. (2014) 20(2):193-203. PMCID: PMC3923163
Gregory JC, Buffa JA, Org E, Wang Z, Levison BS, Zhu W, Wagner MA, Bennett BJ, Li L, DiDonato JA, Lusis AJ, Hazen SL. Transmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation. The Journal of Biological Chemistry. (2015) 290(9):5647-60 PMCID: PMC4342477
Tang WHW, Wang Z, Kennedy DJ, Wu Y, Buffa J, Agatisa-Boyle B, Li XS, Levison BS, Hazen SL. The Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease. Circulation Research. (2015) 116(3):448-55 PMCID: PMC4312512

Research News

Common artificial sweetener, erythritol, associated with higher rates of heart attack, stroke

The additive’s clinical association with cardiovascular risk, coupled with increased clotting in preclinical models, showcases the need for further safety studies.

Cleveland Clinic researchers identify key enzymes in gut microbiome that produce compound linked to heart disease

Two distinct gut microbial enzyme pathways could be targeted in therapeutic development.

Higher levels of common diet-associated microbe elevates heart failure risk

New study finds elevated levels of the metabolite phenylacetylglutamine are associated with increased risk of heart failure.

Not Just Cholesterol: Cleveland Clinic, Tufts Red Meat Study Elaborates on Gut Bacteria’s Role in Forecasting Heart Disease

Building on more than a decade of research from Dr. Stanley Hazen’s lab, researchers explored how elevated levels of trimethylamine N-Oxide (TMAO) could serve as a warning sign for heart disease

Researchers Probe Further Into Link between Red Meat and Cardiovascular Disease Risk

Dr. Hazen identified the gbu gene cluster as a potential therapeutic target for diet-associated cardiovascular disease, and showed that dietary modifications may also help reduce risk.

Study Links the Gut Microbiome and Aggressive Prostate Cancer

Dr. Sharifi and collaborators identified choline, betaine and phenylacetylglutamine as nutrients and gut microbiome metabolites associated with increased risk for lethal prostate cancer, suggesting dietary interventions may help reduce disease risk.

New Research Identifies Link Between Gut Microbes and Stroke

Drs. Hazen and Zhu found that elevated levels of blood TMAO are associated with larger infarct volume and poorer functionality following injury in preclinical stroke models, offering the first evidence that the gut microbiome directly modulates stroke severity.

New Diet-Associated Gut-Microbe Metabolite Linked to CVD

Dr. Hazen found that a metabolic byproduct of phenylalanine, called PAGln, increases risk for adverse cardiac events, and that part of beta blockers’ potent efficacy may be due to blocking the activity of this metabolite.