# US 11,439,309 B2 · Assessment of coronary heart disease with carbon dioxide

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- Number: US 11,439,309 B2
- Document ID: US11439309B2
- Status: Granted
- Kind: B2
- Application number: 14/115,860
- Filed: 2012-05-07
- Published: 2014-03-27
- Granted: 2022-09-13
- Earliest claimed: 2011-05-05
- Assignees: Cedars-Sinai Medical Center
- Applicants: Rohan Dharmakumar; Debiao Li; Sotirios A. Tsaftaris
- Inventors: Rohan Dharmakumar; Debiao Li; Sotirios A. Tsaftaris
- Web page: https://patentgrep.com/patent/US11439309B2

## CPC

- A61B 5/02007: {Evaluating blood vessel condition, e.g. elasticity, compliance}
- A61B 5/0035: {adapted for acquisition of images from more than one imaging mode, e.g. combining MRI and optical tomography}
- A61B 5/02028: {Determining haemodynamic parameters not otherwise provided for, e.g. cardiac contractility or left ventricular ejection fraction}
- A61B 5/026: Measuring blood flow {(A61B3/1233, A61B3/1241 take precedence)}
- A61B 5/055: involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
- A61B 5/145: Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value {; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue} (non-radiation detecting or locating of foreign bodies in blood A61B5/06)
- A61B 5/4884: {inducing physiological or psychological stress, e.g. applications for stress testing}
- A61B 6/032: {Transmission computed tomography [CT]}
- A61B 6/4417: {related to combined acquisition of different diagnostic modalities}
- A61B 7/02: Stethoscopes
- A61B 8/0883: {for diagnosis of the heart}
- A61B 8/4416: {related to combined acquisition of different diagnostic modalities, e.g. combination of ultrasound and X-ray acquisitions}
- A61B 8/488: {involving Doppler signals}
- A61D 7/00: Devices or methods for introducing solid, liquid or gaseous remedies or other materials into or onto the bodies of animals (for reproduction or fertilisation A61D19/00)
- A61M 16/12: by mixing different gases
- G01R 33/4806: {Functional imaging of brain activation}
- G01R 33/481: {MR combined with positron emission tomography [PET] or single photon emission computed tomography [SPECT]}
- G01R 33/4812: {MR combined with X-ray or computed tomography [CT]}
- G01R 33/4814: {MR combined with ultrasound}
- G01R 33/60: using electron paramagnetic resonance (G01R33/24, G01R33/62 take precedence)
- A61B 5/7257: {using Fourier transforms}
- A61B 6/037: {Emission tomography}
- A61B 6/507: {for determination of haemodynamic parameters, e.g. perfusion CT}
- A61B 6/508: {for non-human patients}
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- A61D: VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}
- G01R: MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES (indicating correct tuning of resonant circuits H03J3/12)

## Abstract

The invention provides methods for diagnosing coronary heart disease in a subject in need thereof comprising administering an admixture comprising CO2 to a subject to reach a predetermined PaCO2 in the subject to induce hyperemia, monitoring vascular reactivity in the subject and diagnosing the presence or absence of coronary heart disease in the subject, wherein decreased vascular reactivity in the subject compared to a control subject is indicative of coronary heart disease. The invention also provides methods for increasing sensitivity and specificity of BOLD MRI.

## Claims

### Claim 1

A method of producing coronary vasodilation and monitoring vascular reactivity in a subject comprising:
(a) administering an admixture comprising carbon dioxide (CO2) to attain two or more predetermined arterial partial pressure of carbon dioxide (PaCO2) levels within a range from 20 mmHg to 65 mmHg in the subject,
wherein at least two of the two or more predetermined PaCO2 levels exhibit an increase of at least 20 mmHg within the range from 20 mmHg to 65 mmHg and correspond to an increase in CO2 concentration in the administered admixture and/or an increase in length of time of the administered admixture, such that a hyperemic response in the subject's myocardium is induced due to the increase in the PaCO2 level, and
wherein the admixture is administered for at least one minute to maintain each of the at least two of the two or more predetermined PaCO2 levels;
(b) imaging the subject's myocardium at each respective maintained level of the at least two of the two or more predetermined PaCO2 levels to obtain respective images corresponding to the increase in the PaCO2 level; and
(c) quantifying vascular reactivity from the respective images, wherein images obtained at the predetermined PaCO2 level corresponding to the hyperemic response identify a region of the myocardium in which the vascular reactivity is impaired in individuals with coronary heart disease.

### Claim 2 (depends on 1)

The method of claim 1, comprising the step of administering a radiotracer to the subject, and wherein the vascular reactivity corresponding to the two or more predetermined PaCO2 levels is monitored using at least one of positron emission tomography (PET) and single photon emission computed tomography (SPECT).

### Claim 3 (depends on 1)

The method of claim 1, comprising the step of administering a contrast agent to the subject, and wherein the vascular reactivity corresponding to the two or more predetermined PaCO2 levels is monitored using first-pass perfusion magnetic resonance imaging (MRI).

### Claim 4 (depends on 1)

The method of claim 1, wherein the vascular reactivity corresponding to the at least one two or more predetermined PaCO2 levels is monitored using one of blood oxygen-level-dependent (BOLD) MRI and first-pass perfusion MRI.

### Claim 5 (depends on 1)

The method of claim 1, wherein the vascular reactivity corresponding to the two or more predetermined PaCO2 levels is monitored via BOLD MRI.

### Claim 6 (depends on 1)

The method of claim 1, wherein the admixture comprising CO2 is administered via inhalation.

### Claim 7 (depends on 1)

The method of claim 1, wherein the admixture comprising CO2 is administered in a stepwise manner.

### Claim 8 (depends on 1)

The method of claim 1, wherein the admixture comprising CO2 is administered to alter the subject's PaCO2 level in a block manner.

### Claim 9 (depends on 8)

The method of claim 8, wherein the administering of CO2 to alter the subject's PaCO2 level in a block manner is repeated over time.

### Claim 10 (depends on 9)

The method of claim 9, wherein the at least two of the two or more predetermined PaCO2 levels are attained via inhalation of the admixture and are selected from the group consisting of 20 mmHg and 40 mmHg, 20 mmHg and 50 mmHg, 30 mmHg and 50 mmHg, 20 mmHg and 60 mmHg, 30 mmHg and 60 mmHg, and 40 mmHg and 60 mmHg.

### Claim 11 (depends on 1)

The method of claim 1, wherein the at least two of the two or more predetermined PaCO2 levels are levels selected from the group consisting of 20 mmHg and 40 mmHg, 20 mmHg and 50 mmHg, 30 mmHg and 50 mmHg, 20 mmHg and 60 mmHg, 30 mmHg and 60 mmHg, 40 mmHg and 60 mmHg, and, 45 mmHg and 65 mmHg.

### Claim 12 (depends on 1)

The method of claim 1, wherein the vascular reactivity is monitored using any one or more of positron emission tomography (PET), single photon emission computed tomography (SPECT), computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography/computed tomography (SPECT/CT), positron emission tomography/computed tomography (PET/CT), ultrasound, electrocardiogram (ECG), Electron-beam computed tomography (EBCT), echocardiogram (ECHO), and electron spin resonance (ESR).

### Claim 13 (depends on 1)

The method of claim 1, wherein the subject is selected from the group consisting of a human, a monkey, an ape, a dog, a cat, a cow, a horse, a goat, a pig, a rabbit, a mouse and a rat.

### Claim 14 (depends on 1)

The method of claim 1, wherein the administering of the admixture comprising CO2 alters the PaCO2 level in the subject and a PaO2 level in the subject.

### Claim 15 (depends on 1)

The method of claim 1, wherein the vascular reactivity is monitored using fractional flow reserve.

### Claim 16 (depends on 1)

The method of claim 1, wherein each of the two or more of predetermined PaCO2 levels is a level in a range of 30 to 65 mmHg.

### Claim 17 (depends on 16)

The method of claim 16, wherein the admixture maintains each of the at least two of the two or more of predetermined PaCO2 levels for a period of time, the admixture administered for each respective period of time, each respective period of time independently selected from the group consisting of 20 minutes, 15 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, and 1 minute.

### Claim 18 (depends on 1)

The method of claim 1, wherein the admixture maintains each of the two or more predetermined PaCO2 levels for a period of time, the admixture administered for each respective period of time, each respectively period of time independently selected from the group consisting of 20 minutes, 15 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, and 2 minutes.

### Claim 19 (depends on 1)

The method of claim 1, wherein the administering of the admixture comprising CO2 alters the PaCO2 level in the subject, which does not alter arterial partial pressure of O2 (PaO2).

### Claim 20 (depends on 1)

The method of claim 1, wherein the subject has coronary artery narrowing or stenosis, and the method identifies the region of the subject's myocardium in which the vascular reactivity is impaired due to the coronary artery narrowing or stenosis.

### Claim 21 (depends on 1)

The method of claim 1, wherein the subject is a human, and the admixture comprising CO2 is administered in a free-breathing manner without anesthesia.