# US 10,551,372 B2 · Trimethylamine compounds as risk predictors of cardiovascular disease

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- Number: US 10,551,372 B2
- Document ID: US10551372B2
- Status: Granted
- Kind: B2
- Application number: 15/234,050
- Filed: 2016-08-11
- Published: 2016-12-01
- Granted: 2020-02-04
- Earliest claimed: 2007-12-05
- Assignees: The Cleveland Clinic Foundation
- Applicants: The Cleveland Clinic Foundation
- Inventors: Stanley L. Hazen; Zeneng Wang; Bruce S. Levison
- Web page: https://patentgrep.com/patent/US10551372B2

## CPC

- G01N 33/49: Blood {(chemical methods for determining blood cell populations G01N33/5094; chemical analysis of blood groups or blood types G01N33/80)}
- G01N 33/493: urine
- G01N 33/6893: {related to diseases not provided for elsewhere}
- G01N 33/92: involving lipids, e.g. cholesterol {, lipoproteins, or their receptors (steroid hormones G01N33/743)}
- H01J 49/0036: {Step by step routines describing the handling of the data generated during a measurement}
- G01N 2800/32: Cardiovascular disorders
- G01N 2800/323: Arteriosclerosis, Stenosis
- G01N 2800/50: Determining the risk of developing a disease
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- G01N 2800/56: Staging of a disease; Further complications associated with the disease
- Y10T 436/174614: Tertiary amine
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- H01J: ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS (spark-gaps H01T; electric arc lamps H05B31/00; particle accelerators H05H)
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

Methods of characterizing a test subject's risk of having or developing cardiovascular disease are provided. The methods include using an analytic device to determine levels of choline-related trimethylamine-containing compounds such as trimethylamine N-oxide, choline, or betaine in a biological sample obtained from the subject and comparing the levels of the choline-related trimethylamine-containing compound in the subject's biological sample to a control value. The test subject's risk of having cardiovascular disease is then characterized as higher if the levels of the choline-related trimethylamine-containing compound are higher than the control value. Also provided are methods of identifying a subject at risk of experiencing a complication of atherosclerotic cardiovascular disease, and methods of evaluating the efficacy of a cardiovascular therapeutic agent in a subject with cardiovascular disease using levels of choline-related trimethylamine-containing compounds.

## Claims

### Claim 1

A method of detecting trimethylamine-n-oxide (TMANO) in a serum or plasma sample comprising:
a) obtaining a plasma or serum sample, wherein said plasma or serum sample is from a non-TMANO treated human subject;
b) introducing at least a portion of said plasma or serum sample into an analytical device under conditions such that the concentration of TMANO present in said plasma or serum sample is determined,
wherein said analytical device comprises: i) an NMR spectrometer, a UV/Vis spectrometer, or a mass spectrometer, and ii) equipment to provide physical separation of said TMANO prior to determining said concentration; and
c) graphically displaying said subject's risk of having cardiovascular disease as higher than normal based on determining said level of TMANO in said plasma or serum sample being higher than 4.1 μM.

### Claim 2

A method of detecting trimethylamine-n-oxide (TMANO) in a serum or plasma sample comprising:
a) obtaining a plasma or serum sample, wherein said plasma or serum sample is from a non-TMANO treated human subject;
b) introducing at least a portion of said plasma or serum sample into an analytical device under conditions such that the concentration of TMANO present in said plasma or serum sample is determined,
wherein said analytical device comprises: i) an NMR spectrometer, a UV/Vis spectrometer, or a mass spectrometer, and ii) equipment to provide physical separation of said TMANO prior to determining said concentration; and
c) graphically displaying said subject's risk of having cardiovascular disease as higher than normal based on determining said level of TMANO in said plasma or serum sample being higher than 7.0 μM.

### Claim 3

A method of detecting trimethylamine-n-oxide (TMANO) in a serum or plasma sample comprising:
a) obtaining a plasma or serum sample, wherein said plasma or serum sample is from a non-TMANO treated human subject;
b) introducing at least a portion of said plasma or serum sample into an analytical device under conditions such that the concentration of TMANO present in said plasma or serum sample is determined,
wherein said analytical device comprises: i) an NMR spectrometer, a UV/Vis spectrometer, or a mass spectrometer, and ii) equipment to provide physical separation of said TMANO prior to determining said concentration; and
c) graphically displaying said subject's risk of having cardiovascular disease as higher than normal based on determining said level of TMANO in said plasma or serum sample being higher than 12.4 μM.

### Claim 4

A method of detecting trimethylamine-n-oxide (TMANO) in a serum or plasma sample comprising:
a) obtaining a plasma or serum sample, wherein said plasma or serum sample is from a non-TMANO treated human subject;
b) introducing at least a portion of said plasma or serum sample into a mass spectrometer or NMR spectrometer under conditions such that the concentration of TMANO present in said plasma or serum sample is determined; and
c) graphically displaying said subject's risk of having cardiovascular disease as higher than normal based on determining said level of TMANO in said plasma or serum sample being higher than 4.1 μM.

### Claim 5

A method of detecting trimethylamine-n-oxide (TMANO) in a serum or plasma sample comprising:
a) obtaining a plasma or serum sample, wherein said plasma or serum sample is from a non-TMANO treated human subject;
b) introducing at least a portion of said plasma or serum sample into a mass spectrometer or NMR spectrometer under conditions such that the concentration of TMANO present in said plasma or serum sample is determined; and
c) graphically displaying said subject's risk of having cardiovascular disease as higher than normal based on determining said level of TMANO in said plasma or serum sample being higher than 7.0 μM.