KR20230155990A - Hypertension diagnosis technology through retinal imaging. - Google Patents

Abstract

The purpose of the present invention is to provide a method for diagnosing high blood pressure using a non-invasive method using PS-OCT, a method for providing high blood pressure diagnostic information with high accuracy and sensitivity, and a device for diagnosing high blood pressure using the same. The method of providing hypertension diagnosis information according to the present invention can distinguish hypertension, hypertension risk group, and normal blood pressure with high sensitivity and specificity through the BBI value. The hypertension diagnosis device according to the present invention is economically efficient by using PS-OCT. Non-invasive diagnosis of high blood pressure is possible through the human retina, providing excellent safety and convenience.

Description

Hypertension diagnosis technology through retinal imaging.}

The present invention relates to a method of providing diagnosis information for high blood pressure obtained through retinal images measured using PS-OCT, and a high blood pressure diagnostic device that diagnoses high blood pressure using the diagnostic information.

Cardiovascular disease is one of the major causes of death worldwide, and the need for technology to diagnose and monitor vascular disease by analyzing the characteristics of blood vessels in vivo is being discussed. The blood vessel wall is composed of organized fibrous connective tissue, and since the fibrous structure is deformed due to cardiovascular disease, vascular disease can be diagnosed by examining tissue loss in the blood vessel wall. In particular, because the blood vessels of the eye and heart share common vasculature properties, cardiovascular conditions can be diagnosed non-invasively through image analysis of the retinal vasculature.

Methods used to measure the properties of blood vessels include computed tomography angiography, vascular ultrasound and magnetic resonance angiography, some of which are invasive or require dyes and involve complex operating procedures. Additionally, existing methods have a maximum resolution of about 150 μm, which does not provide sufficient resolution to diagnose early or irreversible changes in blood vessel wall tissue.

However, optical imaging methods have the advantage of superior resolution than magnetic resonance imaging (MRI) and no risk of exposure to radiation. OCT (optical coherence tomography) is an interferometer-based imaging technique that can non-invasively acquire cross-sectional and tomographic images of the eye and retina. OCT images are the interference signal between the backscattered light returning from the sample and the reference arm of the interferometer. It is created by detecting . This method uses a safe level of near-infrared rays and is stable in the body because sufficient backscattering occurs even for images with a high signal-to-noise ratio (SNR), allowing light to easily pass through tissue.

In particular, polarization-sensitive OCT can use polarized light to investigate deeply resolved polarization properties of tissue, such as birefringence, polarization uniformity, and changes in fast axis orientation. According to our previous paper, we used PS-OCT to measure retinal nerve fiber birefringence, the degree of polarization uniformity of the retinal pigment epithelium (RPE), the retardation induced by Henle's fiber layer, and the retardation induced by the RPE-Bruch's membrane complex. Signals can be measured.

In previous studies, blood vessel wall thickness information was used to diagnose hypertension, but blood vessel wall thickness was not sensitive enough to differentiate between hypertensive and normal blood pressure subjects to be used as an indicator of high blood pressure. Accordingly, the need for a diagnostic method that can distinguish between hypertensive and normal blood pressure subjects with high sensitivity and specificity using new values appropriate for use as a marker for hypertension is being discussed.

The purpose of the present invention is to provide a method for diagnosing high blood pressure using a non-invasive method using PS-OCT, a method for providing high blood pressure diagnostic information with high accuracy and sensitivity, and a device for diagnosing high blood pressure using the same.

The present disclosure provides the birefringence value and blood vessel wall thickness of the eye measured using PS-OCT;

A method of providing hypertension diagnosis information using values calculated through the correlation between the birefringence value and blood vessel wall thickness is provided.

The calculated value is the BBI (blood vessel wall birefringence index) value calculated according to Equation 1,

The birefringence value can be calculated according to Equation 2.

[Equation 1]

(△n: birefringence value)

[Equation 2]

(λ: Wavelength of incident light (μm), DPPR/UD: Double-pass phase delay per unit depth (°/μm))

The method of providing hypertension diagnosis information according to an embodiment of the present disclosure may be to diagnose hypertension when the BBI value satisfies any one or more of Equation 3 and Equation 4.

[Equation 3]

(BBI (artery): Arterial vessel wall birefringence index)

[Equation 4]

(BBI (vein): venous vessel wall birefringence index)

The method of providing hypertension diagnosis information according to an embodiment of the present disclosure may be to diagnose hypertension when the BBI value satisfies Equation 3 and Equation 4.

A method of providing hypertension diagnosis information according to an embodiment of the present disclosure is when the BBI value does not satisfy any of Equation 3 and Equation 4,

If one or more of Equation 5 and Equation 6 are satisfied, prehypertension may be diagnosed.

[Equation 5]

[Equation 6]

In the method for providing hypertension diagnosis information according to the present disclosure, the eye may be a retina.

In the hypertension diagnosis device including PS-OCT that detects birefringence value and blood vessel wall thickness through optical coherence tomography signals for the eye according to an embodiment of the present disclosure,

The PS-OCT is,

A light source unit that emits light; Polarization control unit; A detection unit that measures interference signals; and

control unit; Including,

High blood pressure may be diagnosed through the BBI value calculated by the control unit through Equation 1 and Equation 2.

[Equation 1]

(△n: birefringence value)

[Equation 2]

(λ: Wavelength of incident light (μm), DPPR/UD: Double-pass phase delay per unit depth (°/μm))

The wavelength of the light may be 400 to 1500 nm.

The eye may be a retina.

The method of providing high blood pressure diagnosis information according to an embodiment of the present invention uses BBI values to distinguish high blood pressure group, high blood pressure risk group, and normal group according to specific numerical ranges, and can effectively diagnose high blood pressure with high sensitivity and specificity.

The hypertension diagnosis device according to the present invention uses PS-OCT, which is simpler and more economical than diagnosing hypertension using other equipment such as magnetic resonance angiography, vascular ultrasound, and computed tomography angiography.

In addition, the hypertension diagnostic device of the present invention provides a non-invasive diagnostic method through the human retina, and has high safety and convenience.

Figure 1 shows a schematic diagram of investigating the polarization characteristics of retinal blood vessel walls using PS-OCT.
Figure 2 shows histological examination images and graphical diagrams of retinal layers.
Figure 3 shows the vessel wall thickness and DPPR/UD values of various blood vessels in the normal blood pressure group and the hypertensive patient group, measured using PS-OCT.
Figure 4 shows DPPR/UD values for the vessel wall thickness in (A) arteries and (B) veins of the normal blood pressure group and the hypertensive patient group, measured using PS-OCT.
Figure 5 shows DPPR/UD values in (A) arteries and (B) veins of the normal blood pressure group and the hypertensive patient group, measured using PS-OCT.
Figure 6 shows blood vessel wall thickness values in (A) arteries and (B) veins of the normal blood pressure group and the hypertensive patient group, measured using PS-OCT.
Figure 7 shows BBI values in (A) arteries and (B) veins of the normal blood pressure group and the hypertensive patient group.
Figure 8 shows BBI values for each of the normal blood pressure group and the hypertensive patient group shown in Figure 7.

Hereinafter, the present invention will be described in detail. Terms used in this specification, if not separately defined, should be interpreted as generally understood by those skilled in the art. The drawings and examples of this specification are intended to enable those skilled in the art to easily understand and practice the present invention. Content that may obscure the gist of the invention may be omitted from the drawings and examples, and the present invention is limited to the drawings and examples. It doesn't work.

As used herein, the singular forms “a,” “an,” and “the” are intended to also include the plural forms, unless the context clearly dictates otherwise.

In addition, the numerical range used in the present invention includes the lower limit and upper limit and all values within the range, increments logically derived from the shape and width of the defined range, all double-limited values, and numerical ranges defined in different forms. Includes all possible combinations of upper and lower limits. Unless otherwise specified in the specification of the present invention, values outside the numerical range that may occur due to experimental error or rounding of values are also included in the defined numerical range.

In this specification, terms such as include, have, have, etc. mean the presence of features or components described in the specification, and, unless specifically limited, indicate the possibility of adding one or more other features or components. It is not excluded in advance.

In this specification, “method of providing hypertension diagnosis information” refers not only to providing the values and numerical ranges used to diagnose high blood pressure, but also to diagnosing high blood pressure and whether a high blood pressure risk group is present using the numerical values and numerical ranges. it means.

The method for providing hypertension diagnosis information according to the present disclosure calculates information capable of diagnosing hypertension through image data measured using PS-OCT (polarization-sensitive optical coherence tomography), and the information is used in diagnosing hypertension. It has high accuracy and sensitivity, and has the following characteristics.

The present disclosure provides the birefringence value and blood vessel wall thickness of the eye measured using PS-OCT;

A method of providing hypertension diagnosis information using values calculated through the correlation between the birefringence value and blood vessel wall thickness is provided. The changes in the birefringence value and blood vessel wall thickness are due to the characteristics of the blood vessel wall due to high blood pressure, and their correlation can provide accurate hypertension diagnosis information.

The calculated value is the BBI (blood vessel wall birefringence index) value calculated according to Equation 1,

The birefringence value (Δn) of the eye can be calculated according to Equation 2.

[Equation 1]

(△n: birefringence value)

[Equation 2]

(λ: Wavelength of incident light (μm), DPPR/UD: Double-pass phase delay per unit depth (°/μm))

The eye may be a retina, and in the present disclosure, retinal blood vessels adjacent to the ONH (optic nerve head) can be evaluated in order to reveal optical properties of blood vessel wall tissue due to high blood pressure.

Measurement of the retinal blood vessel wall using PS-OCT of the present disclosure is not affected by the white coat effect, hormones, or other blood levels because it is affected only by the intrinsic mechanical properties of the blood vessel wall. In addition, PS-OCT technology is economical because it requires a relatively low cost compared to magnetic resonance angiography, vascular ultrasound, and computed tomography angiography.

The blood vessel wall of the retina is made up of three main layers: the intima, media, and adventitia. The inner membrane is composed of endothelium, and the thickness of the endothelium increases due to the accumulation of extracellular matrix substances under the influence of high blood pressure. The tunica media is composed of muscle tissue within an extracellular matrix of elastic fibers, and birefringence is observed. Under the influence of high blood pressure, the media undergoes degenerative changes such as fibrinoid necrosis and apoptosis, and destruction of elastic fibers and muscle remodeling. The outermost layer of blood vessels, the adventitia, is made up of connective tissue and elastic membrane, and when high blood pressure occurs, the connective tissue decomposes.

The blood vessel wall birefringence index (BBI) value is a value that combines the blood vessel wall thickness and the birefringence value into one number, and can be calculated through Equation 2 and Equation 3 above. The BBI value reflects the health status of vascular tissue and can be used as diagnostic information to effectively distinguish between healthy blood vessels and hypertensive blood vessels.

The DPPR/UD value of the retinal vessel wall is lower in the hypertensive group than in the normal group, and this decrease in birefringence may be a result of the breakdown of elastic fibers and loss of segmental and muscle tissue.

The method of providing hypertension diagnosis information quantifies the loss of organic structure of blood vessel wall tissue that appears in the high blood pressure group, and reflects the lower birefringence value due to the increased blood vessel wall thickness and decreased fibrous tissue organization in the high blood pressure group.

When DPPR/UD and blood vessel wall thickness are used independently as hypertensive disease markers, they do not provide an accurate numerical range that can sufficiently distinguish between the hypertensive group and the normal group. Specifically, DPPR/UD and blood vessel wall thickness data may have overlapping ranges in the normal and high blood pressure groups, and the threshold value of blood vessel wall thickness data is smaller than the standard deviation, so it is a value that is difficult to trust as a marker of high blood pressure. Accordingly, the BBI value was introduced to overcome the inevitable errors that occur when diagnosing hypertension using DPPR/UD or blood vessel wall thickness thresholds independently. There is no overlapping range in BBI values between the hypertensive and normal groups, and the two subject groups can be clearly distinguished. Additionally, the difference between the thresholds of the high blood pressure group and the normal group is large enough to reliably distinguish the two groups.

BBI is a value that combines information on birefringence and retinal blood vessel wall thickness, and can distinguish between hypertensive and normal blood pressure blood vessel walls with high sensitivity.

A method of providing high blood pressure diagnosis information according to an embodiment may be to diagnose high blood pressure when the BBI value satisfies one or more of Equation 3 and Equation 4.

[Equation 3]

(BBI (artery): Arterial vessel wall birefringence index)

[Equation 4]

(BBI (vein): venous vessel wall birefringence index)

In another embodiment, a method of providing hypertension diagnosis information may be to diagnose hypertension when the BBI value satisfies Equation 3 and Equation 4.

Retinal arteries are more affected by high blood pressure than retinal veins, which may be due to the higher pressure and blood flow rate in the arteries.

According to one embodiment, a method of providing hypertension diagnosis information is provided when the BBI value does not satisfy any of Equation 3 and Equation 4,

If one or more of Equation 5 and Equation 6 are satisfied, prehypertension may be diagnosed.

[Equation 5]

[Equation 6]

The present disclosure relates to a hypertension diagnostic device including PS-OCT, which detects birefringence value and blood vessel wall thickness through optical coherence tomography signals for the eye,

The PS-OCT is,

A light source unit that emits light; Polarization control unit; A detection unit that measures interference signals; and

control unit; Including,

Provided is a high blood pressure diagnosis device that diagnoses high blood pressure through the BBI value calculated by the control unit through Equation 1 and Equation 2.

[Equation 1]

(△n: birefringence value)

[Equation 2]

(λ: Wavelength of incident light (μm), DPPR/UD: Double-pass phase delay per unit depth (°/μm))

The hypertension diagnosis device according to an embodiment of the present invention has high convenience because it can obtain hypertension diagnosis information non-invasively and obtain results immediately.

The eye may be an eyeball, and may specifically be a retina.

The light source radiates an optical signal to the eye, specifically the retina, and may include an amplification medium that amplifies the optical signal, and a variable filter that can change the pass band over time.

The polarization control unit may be a device that controls a single light from a light source to proceed as polarized light, and may detect an interference signal between reflected lights through the detection unit.

The control unit derives the BBI value using the DPPR/UD and blood vessel wall thickness values obtained through the interference signal of the detection unit, and can diagnose hypertension according to the range of the BBI value.

The wavelength of the light may be 400 to 1500 nm, specifically 400 to 1200 nm.

The following is only a reference for explaining in detail the method for providing high blood pressure diagnosis information and the high blood pressure diagnosis device according to the present invention through specific embodiments, and the present invention is not limited thereto, and may be implemented in various forms. Additionally, the terms used in the description in the present invention are only intended to effectively describe specific embodiments and are not intended to limit the present invention.

[Example 1] DPPR/UD and blood vessel wall thickness measurement using PS-OCT

<Experiment settings>

The PS-OCT system used in the experiment was introduced according to the inventor's prior literature ("Polarization properties of retinal blood vessel walls measured with polarization sensitive optical coherence tomography," Biomed. Opt. Express 12, 4340-4362 (2021)) . Accordingly, an optical fiber-based PS-OCT system with a 2.4 mm image aperture was equipped with a self-made single camera spectrometer and a Wollaston prism. The axial resolution of the system was estimated to be 6 μm, the lateral resolution was estimated to be 12.9 μm, and the study subject's astigmatism was corrected using a test lens. For approximately 4 seconds, 100 B-scans were acquired covering a 15°x15° (4.5 mm x 4.5 mm) region of the largest vessel near the optic nerve head (ONH). To place the beam in the center of the cornea, an additional pupil camera was introduced.

<Research subject recruitment and scanning protocol>

Participants recruited for this study ranged in age from 50 to 70 years and were classified as either healthy adults without signs of hypertension (normotensive group, N = 4) or hypertensive patients (N = 4). Measurements were approved by the Human Research Ethics Committee of the University of Western Australia, Australia, and complied with the Declaration of Helsinki. Informed consent was obtained from all participants before the experiment. As shown in Figure 1, participants were asked to sit in front of the system and focus on the fixation target. Defocus was corrected by moving the ophthalmic lens, and astigmatism was corrected with a test lens.

<Video analysis>

Stokes-based analysis was performed to obtain intensity and delay images. As shown in Figure 2, to determine the location of the vessel wall, the logarithmic intensity, delay, and blood flow cross-section B-scans containing the target vessel were found and realigned with respect to the retinal surface, and then an A-line boundary for the vessel was determined. The area between borders was averaged to obtain an intensity and delay plot, which was used to estimate the location of the vessel wall border. Finally, DPPR/UD was generated by applying a first-order polynomial through a least-squares linear fit with the DPPR data belonging to the blood vessel wall.

<DPPR/UD and blood vessel wall thickness measurement results>

DPPR/UD and blood vessel wall thickness results extracted from various blood vessels of the hypertensive patient group and the normal blood pressure group can be seen in Figure 3. DPPR/UD of the normal blood pressure group was significantly higher than that of the hypertensive patient group. In the normal blood pressure group, the average DPPR/UD fell from 0.60 ± 0.02°/μm, and in the hypertensive patient group, it dropped to an average of 0.36 ± 0.03°/μm. Wall thickness increased from 15 ± 1 μm in the normotensive group to approximately 21 ± 1 μm in the hypertensive group, and this difference is presumed to be a result of hypertension.

Additionally, as shown in Figures 4 to 6, the DPPR/UD and vessel wall thickness results for individual arteries and veins were also similar to the above results. In particular, the average DPPR/UD of arteries decreased by 45% from 0.66 ± 0.07°/μm to 0.36 ± 0.02°/μm, while that of veins decreased by 36% from 0.53 ± 0.04°/μm to 0.34 ± 0.02°/μm. The DPPR/UD and blood vessel wall thickness ranges for diagnosing hypertension based on the above measurements are shown in Table 1.

[Example 2] Calculation of blood vessel wall birefringence index (BBI)

Using the DPPR/UD and blood vessel wall thickness values obtained through image analysis in Example 1, the BBI value was calculated as follows,

(△n: birefringence value)

where the birefringence was converted from DPPR/UD (°/μm) at λ=860 nm as

The above equation was multiplied to reflect double pass. Thickness, DPPR/UD, and BBI were measured four times and the average value was used.

<BBI value calculation result>

As shown in Figures 7 and 8, the BBI value describes the state of the blood vessel wall tissue by combining the blood vessel wall thickness and birefringence value into one parameter. The average BBI value of normal blood pressure artery wall was 27.9 m, which was lower than the average value of hypertensive artery wall tissue of 117.1 m. The average BBI of normotensive and hypertensive vein walls was 42.6 m and 131.8 m, respectively. This increase in BBI value is statistically significant. The 5th and 95th percentile estimates were calculated based on the histogram in Figure 7 and can be found in Table 2. Unlike the DPPR/UD and blood vessel wall thickness shown in Figures 5 and 6, the BBI value shown in Figure 7 does not overlap between the two groups of normal blood pressure and hypertension, so diagnosis based on BBI is a value with very high sensitivity as hypertension diagnostic information. You can see that it is.

Claims (9)

Eye birefringence and blood vessel wall thickness measured using PS-OCT;
A method of providing hypertension diagnosis information using values calculated through the correlation between the birefringence value and blood vessel wall thickness. According to paragraph 2,
The calculated value is the BBI (blood vessel wall birefringence index) value calculated according to Equation 1,
A method of providing hypertension diagnosis information, wherein the birefringence value is calculated according to Equation 2.
[Equation 1]

(△n: birefringence value)
[Equation 2]

(λ: Wavelength of incident light (μm), DPPR/UD: Double-pass phase delay per unit depth (°/μm)) According to paragraph 2,
A method of providing high blood pressure diagnosis information, wherein high blood pressure is diagnosed when the BBI value satisfies any one or more of Equation 3 and Equation 4.
[Equation 3]

(BBI (artery): Arterial vessel wall birefringence index)
[Equation 4]

(BBI (vein): venous vessel wall birefringence index) According to paragraph 2,
A method of providing high blood pressure diagnosis information, wherein high blood pressure is diagnosed when the BBI value satisfies Equation 3 and Equation 4. According to paragraph 3,
If the BBI value does not satisfy any of Equation 3 and Equation 4,
A method of providing hypertension diagnosis information in which prehypertension is diagnosed when one or more of Equation 5 and Equation 6 are satisfied.
[Equation 5]

[Equation 6]

According to paragraph 1,
A method of providing diagnosis information for high blood pressure, wherein the eye is a retina. In the hypertension diagnostic device including PS-OCT, which detects birefringence value and blood vessel wall thickness through optical coherence tomography signals for the eye,
The PS-OCT is,
A light source unit that emits light; Polarization control unit; A detection unit that measures interference signals; and
control unit; Including,
A high blood pressure diagnosis device that diagnoses high blood pressure through the BBI value calculated by the control unit through Equation 1 and Equation 2.
[Equation 1]

(△n: birefringence value)
[Equation 2]

(λ: Wavelength of incident light (μm), DPPR/UD: Double-pass phase delay per unit depth (°/μm)) In clause 7,
A device for diagnosing high blood pressure, wherein the wavelength of the light is 400 to 1500 nm. In clause 7,
A device for diagnosing high blood pressure, wherein the eye is a retina.