CLEVELAND, Ohio—Most people are aware that their risk forcardiovascular disease (CVD) can be measured by family history, cholesterollevels or weight, but a new finding linking CVD risk to a gut flora metaboliteknown as trimethylamine N-oxide (TMAO) may hold promise for the development ofdiagnostic tests to more definitively predict a person's likelihood ofdeveloping heart disease.
The groundbreaking discovery, described in an April 2011 Naturearticle authored by Cleveland Clinicresearcher Dr. Stanley Hazen, demonstrated the impact of gut flora on thedevelopment of CVD in both animal models and humans. In-vitro diagnostic company LipoScience Inc. has entered intoan exclusive, worldwide licensing agreement with the Cleveland Clinic todevelop and commercialize a diagnostic test for CVD risk based on TMAO levels.
Hazen is a molecular medicine professor at the ClevelandClinic Lerner College of Medicine at Case Western Reserve University, as wellas vice chair of translational research at the Lerner Research Institute. Hehas published more than 200 peer-reviewed articles, invited reviews and bookchapters in the fields of atherosclerosis, oxidation and inflammation chemistryand CVD. He holds many patents for his work in identifying patients who are atincreased risk for CVD, diagnosing asthma and treating inflammation andassociated complications.
In his study, "Gut flora metabolism of phosphatidylcholinepromotes cardiovascular disease," Hazen used a metabolomics approach togenerate unbiased small-molecule metabolic profiles in plasma that predict riskfor CVD. Three metabolites of the dietary lipid phosphatidylcholine—choline,trimethylamine N-oxide (TMAO) and betaine—were identified and then shown topredict risk for CVD in an independent large clinical cohort. Dietarysupplementation of mice with choline, TMAO or betaine promoted upregulation ofmultiple macrophage scavenger receptors linked to atherosclerosis, andsupplementation with choline or TMAO promoted atherosclerosis. Studies usinggerm-free mice confirmed a critical role for dietary choline and gut flora inTMAO production, augmented macrophage cholesterol accumulation and foam cellformation. Suppression of intestinal microflora in atherosclerosis-prone miceinhibited dietary-choline-enhanced atherosclerosis. Genetic variationscontrolling expression of flavin monooxygenases, an enzymatic source of TMAO, segregatedwith atherosclerosis in hyperlipidemic mice.
"Discovery of a relationship between gut-flora-dependentmetabolism of dietary phosphatidylcholine and CVD pathogenesis providesopportunities for the development of new diagnostic tests and therapeuticapproaches for atherosclerotic heart disease," Hazen and his colleaguesconcluded.
Now, Hazen—who is a member of LipoScience's advisorycommittee and is entitled to receive royalty payments for inventions ordiscoveries commercialized by the company—has entered into a licensingagreement that aims to translate the discovery that gut flora can be abiomarker for CVD into a test to help patients assess their risk for CVD.
"Right now, other than looking at a person's family history,triglyceride levels or weight, we don't know if they are at risk forcardiovascular disease or not. The idea is to try to commercialize this testfor predicting cardiovascular risk and then monitor the patient in a moreobjective matter to assess whether a person's diet is adequate for them."
Hazen notes that to date, all research on TMAO has beenconducted using mass spectrometry for detection, which can be a tedious andtime-consuming method. However, the properties of TMAO make it well-suited formeasurement by magnetic resonance. According to Richard O. Brajer, CEO ofLipoScience, this makes the company "the ideal collaborator to develop aclinically viable assay."
Raleigh, N.C.-based LipoScience is an in-vitro diagnostic company committed to advancing patientcare in cardiovascular, metabolic and other diseases using an innovative andproprietary technology platform based on nuclear magnetic resonance (NMR)technology. The company's first diagnostic test, the NMR LipoProfile
test, measures the number of low-density lipoproteinparticles (LDL-P) in a blood sample and provides physicians and their patientswith actionable information to personalize management of risk for CVD. To date,more than 7 million NMR LipoProfile tests have been ordered.
"We look forward to working closely with the ClevelandClinic team to make this new and important diagnostic assay available to ourcustomers," Brajer said in a statement announcing the licensing deal.
Financial terms of the agreement were not released.LipoScience did not respond to requests for interviews.
From a scientific standpoint, the collaborators need todevelop a valid, robust, reproducible high-throughput assay, but everythingabout LipoScience's platform indicates that this is "imminently achievable,"says Hazen.
"In addition, identifying the role that gut flora can playin this pathway suggests a whole new way to find therapies that block TMAO," hesays.
Hazen's research was funded by the U.S. National Institutesof Health.
