# US 12,055,535 B2 · Trimethylamine compounds as risk predictors of cardiovascular disease

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- Number: US 12,055,535 B2
- Document ID: US12055535B2
- Status: Granted
- Kind: B2
- Application number: 16/781,409
- Filed: 2020-02-04
- Published: 2020-06-04
- Granted: 2024-08-06
- 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/US12055535B2

## 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 sample comprising:
a) obtaining a sample, wherein said sample is from a non-TMANO treated human subject who is known to be at risk for cardiovascular disease (CVD) or is known to have CVD, wherein said sample is a urine sample, serum sample, or plasma sample;
b) introducing at least a portion of said sample into an analytical device under conditions such that the concentration of TMANO present in said 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 sample being higher than a control value derived from a human general population or a group of humans without symptoms of cardiovascular disease.

### Claim 2 (depends on 1)

The method of claim 1, wherein the analytic device comprises a mass spectrometer.

### Claim 3 (depends on 1)

The method of claim 1, wherein the analytic device comprises an NMR spectrometer.

### Claim 4 (depends on 1)

The method of claim 1, wherein the analytic device comprises a UV/Vis spectrometer.

### Claim 5 (depends on 1)

The method of claim 1, wherein said control value is derived from a group without symptoms of cardiovascular disease.

### Claim 6 (depends on 1)

The method of claim 1, wherein said subject has chest pain.

### Claim 7 (depends on 1)

The method of claim 1, wherein said sample is a urine sample.

### Claim 8 (depends on 1)

The method of claim 1, wherein said sample is a plasma sample.

### Claim 9 (depends on 1)

The method of claim 1, wherein said sample is a serum sample.

### Claim 10 (depends on 1)

The method of claim 1, wherein said sample is obtained from said subject after the administration of a CVD therapeutic.