CN114460201B - Diagnostic markers for distinguishing Ischemic Heart Disease (IHD) from Ischemic Heart Failure (IHF) - Google Patents
Diagnostic markers for distinguishing Ischemic Heart Disease (IHD) from Ischemic Heart Failure (IHF) Download PDFInfo
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
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- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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Abstract
The invention relates to a group of diagnostic markers for distinguishing ischemic heart disease (IHD) and ischemic heart failure (IHF). The markers are steroid hormones, preferably including pregnenolone (Preg), Progesterone (P) and 17 ‑ α‑ Hydroxyprogesterone (17 ‑ Hydroxyprogesterone, 17OH ‑ P), cortisol, cortisone, testosterone (T), dihydrotestosterone (DHT), estrone (E1), estradiol (E2), estriol (E3), androstenedione (A4), corticosterone (Cort), deoxycortisone (11 ‑ Deoxycorticosterone, Dec) Deoxycortisol (11-Deo), Aldosterone (Ald), Dehydroepiandrosterone (DHEA), 17-Deo α‑ 17 ‑ Hydroxypregnenolone (17OH ‑ Preg), and Dehydroepiandrosterone sulfate (DHEA ‑ S).
Description
Technical Field
The invention belongs to the technical field of diagnosis, and particularly relates to a group of diagnosis markers for distinguishing Ischemic Heart Disease (IHD) from Ischemic Heart Failure (IHF).
Background
Near 70% of Heart Failure (HF) syndromes are attributable to underlying Ischemic Heart Disease (IHD). Ischemic Heart Failure (IHF) increases the risk of mortality and readmission compared to non-ischemic etiology. Despite efforts to address the critical preventive risk factors for ischemic heart disease, the incidence of HF hospitalization has not changed significantly and is expected to increase.
Although many potential markers associated with heart failure have been discovered, few have found widespread use for mainstream clinical testing. There is therefore a need for new plasma biomarkers to assist in identifying patients diagnosed with ischemic heart failure.
Based on this, the present invention has been proposed.
Disclosure of Invention
The invention first relates to the use of a set of biomarkers in distinguishing Ischemic Heart Disease (IHD) from Ischemic Heart Failure (IHF), said biomarkers being present in a blood sample, a serum sample, a plasma sample or a blood lipid fraction obtained therefrom of a patient, said biomarkers being steroid hormones,
preferably, the steroid hormone comprises: pregnenolone (Pregnenolone, preg), progesterone (progestrone, P), 17-alpha-Hydroxyprogesterone (17-hydroxprogesterone, 17 OH-P), cortisol (Cortisone), cortisone (Cortisone), testosterone (Testosterone, T), dihydrotestosterone (DHT), estrone (Estrone, E1), estradiol (Estradiol, E2), estriol (Estriol, E3), androstenedione (A4), corticosterone (Coricosterone, cort), deoxycorticosterone (11-deoxycortisone, 11-Deo), aldosterone (aldterone, aldd), dehydroepiandrosterone (Dehydroepiandrosterone, DHEA), 17-alpha-Pregnenolone (17-hydroenol, E2), estriol (Estriol, E3), androstenedione (17-hydroenol, 62, and Dehydropregnenolone (DHEA).
The ischemic heart failure patient (IHF) refers to
(1) Patients who have had ischemic symptoms/signs or electrocardiographic ischemic changes in the past and have had at least one epicardial coronary stenosis >70% in angiography; or (b)
(2) Heart failure patients with a history of Myocardial Infarction (MI) or coronary revascularization.
Preferably, the biomarker is quantified by LC-MS/MS.
Preferably, the distinguishing between Ischemic Heart Disease (IHD) and Ischemic Heart Failure (IHF) is to perform area under ROC curve calculation on concentration values of androstenedione (A4), deoxycorticosterone (Doc), 17-alpha-hydroxyprogesterone (17 OH-P), estrone (E1), estradiol (E2), estriol (E3), aldosterone (Ald), dehydroepiandrosterone (DHEA), testosterone (T), 11-deoxycortisol (11-Deo), 17-alpha-hydroxyprogesterone (17 OH-Preg), dehydroepiandrosterone sulfate (DHEA-S) pregnenolone (Preg), progesterone (P), cortisol (Cortisol), cortisone (Cortisol), dihydrotestosterone (DHT) and corticosterone (Cort) in biological samples of patients to be detected, and to diagnose IHF patients.
More preferably, the concentration of the hormone is calculated as a weighted diagnostic score using a calculation formula based on a multivariate logic model to distinguish Ischemic Heart Failure (IHF) patients, said calculation formula being:
(A4)*0.73+(Doc)*0.81+(17OH-P)*0.20+(E1)*0.85+(E2)*0.05+(E3)*0.20+(Ald)*0.78-(DHEA)*0.07-(T)*0.24-(11-Deo)*1.80-(17OH-Preg)*0.52-(DHEA-S)*0.86；
wherein, the concentration value (unit is ng/ml) of each hormone metabolite x quantified through LC-MS/MS is converted into (x-mu/sigma) and then substituted into the formula, mu is the mean value of all sample hormone concentration values after log10 conversion, and sigma is the standard deviation of all hormone concentration values after log10 conversion;
if the combined cut-off value of 12 steroid hormones is greater than or equal to-0.43, then Ischemic Heart Failure (IHF) is judged, otherwise the subject is not an IHF patient.
The invention also relates to the application of a group of biomarkers in preparing a detection kit for detecting Ischemic Heart Failure (IHF),
the biomarker is present in a blood sample, a serum sample, a plasma sample or a blood lipid fraction obtained therefrom of a patient, the biomarker is a steroid hormone,
preferably, the steroid hormone comprises: pregnenolone (Pregnenolone, preg), progesterone (progestrone, P), 17-alpha-Hydroxyprogesterone (17-hydroxy progestrone, 17 OH-P), cortisol (Cortisone), cortisone (Cortisone), testosterone (Testosterone, T), dihydrotestosterone (DHT), estrone (Estrone, E1), estradiol (Estradiol, E2), estriol (Estriol, E3), androstenedione (A4), corticosterone (Coricostelone, cort), deoxycorticosterone (Deoxycorticosterone, doc), deoxycortisol (11-deoxycortisone, 11-Deo), aldosterone (Aldosterone, ald), dehydroepiandrosterone (dehydropregstrosterone, DHEA), 17-alpha-hydroxy Pregnenolone (17-hydroenol, E, 17-hydroxy, 62, and S-hydrosulfate, S, 38 ea.
The ischemic heart failure patient (IHF) refers to
(1) Patients who have had ischemic symptoms/signs or electrocardiographic ischemic changes in the past and have had at least one epicardial coronary stenosis >70% in angiography; or (b)
(2) Heart failure patients with a history of Myocardial Infarction (MI) or coronary revascularization.
Preferably, the detection kit is a kit based on an LC-MS/MS technical route; the detection kit contains reagents required for extracting and measuring the biomarker.
Preferably, the method for detecting Ischemic Heart Failure (IHF) comprises the step of calculating ROC area under curve of concentration values of androstenedione (A4), deoxycorticosterone (Doc), 17-alpha-hydroxyprogesterone (17 OH-P), estrone (E1), estradiol (E2), estriol (E3), aldosterone (Ald), dehydroepiandrosterone (DHEA), testosterone (T), 11-deoxycortisol (11-Deo), 17-alpha-hydroxy pregnenolone (17 OH-Preg), dehydroepiandrosterone sulfate (DHEA-S) pregnenolone (Preg), progesterone (P), cortisol (Cortisol), cortisone (Cortisone), dihydrotestosterone (DHT) and corticosterone (Cort) in biological samples of patients to be detected.
More preferably, the concentration of the hormone is calculated as a weighted diagnostic score using a calculation formula based on a multivariate logic model to diagnose Ischemic Heart Failure (IHF), said calculation formula being:
(A4)*0.73+(Doc)*0.81+(17OH-P)*0.20+(E1)*0.85+(E2)*0.05+(E3)*0.20+(Ald)*0.78-(DHEA)*0.07-(T)*0.24-(11-Deo)*1.80-(17OH-Preg)*0.52-(DHEA-S)*0.86；
wherein, the concentration value (unit is ng/ml) of each hormone metabolite x quantified through LC-MS/MS is converted into (x-mu/sigma) and then substituted into the formula, mu is the mean value of all sample hormone concentration values after log10 conversion, and sigma is the standard deviation of all hormone concentration values after log10 conversion;
if the combined cut-off value of 12 steroid hormones is greater than or equal to-0.43, ischemic Heart Failure (IHF) is diagnosed, otherwise the subject is not an IHF patient.
The invention also relates to an LC-MS/MS detection kit for detecting Ischemic Heart Failure (IHF), which is characterized in that the kit comprises:
(1) Extracting and measuring the 18 steroid hormone;
(2) A standard for external standard quantification of the biomarker and an internal reference substance;
the reference substances are shown in the following table
Drawings
FIGS. 1 and 18 are chromatograms of steroid hormones.
FIG. 2, a graph comparing steroid hormone levels of IHF and IHD patients.
FIG. 3 ROC curves of steroid hormone diagnostic IHF.
Detailed Description
The experimental methods used in the following examples are conventional methods unless otherwise specified.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
The method for detecting steroid hormones in biological samples (including blood samples, serum samples, plasma samples or blood lipid fractions or blood lipoprotein fractions obtained therefrom) in the following examples was carried out according to the following method:
in tandem mass spectrometry system equipped with ultra-high pressure liquid chromatography
Tandem Xevo TQS triple quadrupole mass spectrometers (Waters corp.) were used for detection. The mass and count of detected peaks obtained by mass spectrometry are converted into a list of the corresponding classes of steroid hormone concentrations. A standard curve (calibration curve) is generated to determine the dynamic quantitative range of each steroid hormone detected.
A strict threshold is applied to separate the background noise from the actual steroid hormone peak. Each sample was controlled and acceptable only when the acceptance criteria were met. The mass and count of the detected peaks are converted into a list of the names of the corresponding classes of steroid hormones, and based on the ratio of the measured steroid hormone to the internal standard, quantification is performed using a standard curve and their concentrations are obtained from the sample volumes. The standard curves were prepared by mixing known amounts of internal references (see table 1 below) with various steroid hormone standards (see table 2 below).
TABLE 1 internal reference substances
TABLE 2 steroid hormone standards
| Standard substance | Goods number | Branding | |
| T | testosterone | T-037 | Sigma |
| Preg | pregnenolone | P-104 | Sigma |
| P | progesterone | P-069 | Sigma |
| E3 | estriol | E-074 | Sigma |
| E2 | estradiol | E-060 | Sigma |
| E1 | estrone | E-075 | Sigma |
| Doc | deoxycorticosterone | D-105 | Sigma |
| DHT | dihydrotestosterone | D-073 | Sigma |
| DHEA-S | dehydroepiandrosterone sulfate | D-065 | Sigma |
| DHEA | dehydroepiandrosterone | D-063 | Sigma |
| Cortisone | cortisone | C-117 | Sigma |
| Cortisol | cortisol | C-106 | Sigma |
| Cort | corticosterone | C-130 | Sigma |
| Ald | aldosterone | A-096 | Sigma |
| A4 | androstenedione | A-075 | Sigma |
| 17OH-Preg | 17-α-hydroxypregnenolone | H-105 | Sigma |
| 17OH-P | 17-α-hydroxyprogesterone | H-085 | Sigma |
| 11-Deo | 11-deoxycortisol | D-061 | Sigma |
The sample extraction operation steps are as follows:
1. standard preparation
1) The primary mother liquor (1 mg/ml) was dissolved in methanol and each was dissolved in methanol to prepare a stock solution of 0.1mg/ml, which was stored at-80℃until use.
2) 2ug/ml standard was prepared: the standard substance/methanol mixed solution is prepared according to the volume ratio of 1:49 (one part of eighteen standard substances with volume being 1 times of that of the methanol solution with volume being 49 times of that of the standard substance), and the mixed standard substance concentration solution with the volume ratio of 2ug/ml can be obtained.
2. Internal reference preparation
2mg/L internal reference mixture was prepared: the internal reference/methanol mixed solution is prepared according to the volume ratio of 1:99 (one part of eighteen internal references with the volume of 1 times of that of methanol solution with the volume of 99 times of that of the eighteen internal references), and the solution with the internal reference concentration of 2ug/ml can be obtained.
3. Standard curve preparation:
1) 2. Mu.L of a methanol solution containing 2ug/ml of the internal reference was dissolved in 198. Mu.L of the methanol solution in a chromatographic flask to obtain a methanol solution containing 20ng/ml of the internal reference.
2) 14 chromatographic vials were taken and labeled Blank, S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, S12, S13, respectively. mu.L of methanol mixture containing 20ng/ml of internal reference was added to chromatographic vials of Blank, S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, S12, S13, respectively.
3) 20. Mu.L of the standard mixture of 2ug/ml was placed in a chromatographic flask S13, and 40ng/ml of the mixed standard S13 (the standard of the highest concentration) was prepared by dissolving in 80ul of 50% methanol, and the mixture was diluted to a gradient in subsequent chromatographic flasks S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, S12 (50. Mu.L each time) to obtain a standard curve. The concentrations of the corresponding standard curves in the S1-S13 chromatographic vials were, in order, 0.097ng/ml, 0.195ng/ml, 0.391ng/ml, 0.781ng/ml, 1.562ng/ml, 3.125ng/ml, 6.25ng/ml, 12.5ng/ml, 25ng/ml, 50ng/ml, 100ng/ml, 200ng/ml, 400ng/ml.
4. Sample processing:
1) Thawing the sample/quality control plasma; 200. Mu.L of plasma was taken in a 12X 75mm glass tube and 300. Mu.L of methanol containing 20. Mu.L of an internal standard of 20ng/ml was added;
2) Shake for 1min, add 400ul water again, shake for 1min, centrifuge for 5min at 14000 g.
3) Taking 650ul of supernatant to carry out solid phase extraction separation; extracting plasma sample, transferring into 96-well plate, shaking for 1min, centrifuging at 4000 rpm for 5min, and analyzing by LC-MS/MS
5. Chromatographic column treatment:
when the column is replaced, for steroid hormone detection, 50% mobile phase B is washed for 20 minutes, then 100% mobile phase B is washed for 5 minutes, and finally 80% mobile phase B is washed for 10 minutes.
The sample extract (200. Mu.L) was loaded onto a column attached to ACQUITY UPLC BEH C8 (2.1 mm inner diameter X100 mm with 1.7 μm fractions) at a column temperature of 50 ℃.
Mobile phase a: an aqueous solution containing 0.3mM of amine fluoride,
mobile phase B: pure methanol solution, flow rate 0.3mL/min, gradient as shown in Table 3;
TABLE 3 mobile phase gradient setup
The ion source temperature was set to 550 ℃; and (3) constructing a standard curve by plotting the peak area ratio of the steroid hormone external standard/internal standard to the actual concentration, and calculating the content of the corresponding various steroid hormones in the sample according to the standard curve and the peak area ratio of the steroid hormone/internal standard in the sample.
The linear range of steroid hormone is 0.005-40ng/ml, standard curve r 2 >0.995。
Example 1 plasma steroid hormone detection in Ischemic Heart Failure (IHF) and Ischemic Heart Disease (IHD) patients
Steroid hormone testing was performed on 153 IHF and 167 age-sex matched IHD patients according to the method described in the present invention.
The 18 steroid hormone standard chromatogram is shown in figure 1,
FIG. 2 is a scatter plot of the difference in steroid hormone levels between IHD and IHF patients, as can be seen
1. As compared with IHD patients, the concentrations of E1, E2, E3 and Ald in the IHF group patients are obviously increased (P < 0.05), and the concentrations of DHEA-S,17OH-Preg,11-Deo, DHEA, A4, doc,17OH-P and T are obviously reduced (P < 0.05).
2. In the IHF group, the E1, E2, E3 and Ald concentrations were significantly increased (P < 0.05), and the DHEA-S,17OH-Preg,11-Deo, DHEA, A4, doc,17OH-P and T concentrations were significantly decreased (P < 0.05).
As shown in FIG. 3, the IHF patient can be distinguished more accurately by establishing a combined scoring model based on the levels of 17-alpha-hydroxyprogesterone (17 OH-P), testosterone (T), estrone (E1), estradiol (E2), estriol (E3), androstenedione (A4), deoxycorticosterone (Doc), 11-deoxycortisol (11-Deo), aldosterone (Ald), dehydroepiandrosterone (DHEA), 17-alpha-hydroxy pregnenolone (17 OH-Preg), and dehydroepiandrosterone sulfate (DHEA-S), with an area under the AUC curve of 0.82 (95% confidence interval of 0.78-0.87).
The weighted diagnostic scores for the hormones are calculated as the sum of the product of the coefficients of each hormone metabolite in the multivariate logic model and the corresponding metabolite levels for each individual, wd-score = Σnk = 1 βk x steroid k, where βk is the coefficient of the kth hormone metabolite from the final multivariate logistic model and steroidk is the plasma level of the kth hormone metabolite.
The above results indicate that steroid hormones have a better differential diagnostic ability for IHF.
The above results demonstrate that: in ischemic heart disease patients, a number of different kinds of plasma steroid hormones are important biomarkers for diagnosing ischemic heart failure, which helps identify high risk patients in need of more aggressive therapeutic intervention.
Finally, it should be noted that the above embodiments are only for helping the person skilled in the art to understand the essence of the present invention, and are not intended to limit the protection scope of the present invention.
Claims (3)
1. The application of a group of biomarkers in preparing a detection kit for distinguishing ischemic heart disease patients from ischemic heart failure patients,
the biomarker is present in a plasma sample of the patient;
the biomarker is 12 steroid hormone, and the steroid hormone is: 17-alpha-hydroxyprogesterone abbreviated as 17OH-P, testosterone abbreviated as T, estrone abbreviated as E1, estradiol abbreviated as E2, estriol abbreviated as E3, androstenedione abbreviated as A4, deoxycorticosterone abbreviated as Doc, 11-deoxycortisol abbreviated as 11-Deo, aldosterone abbreviated as Ald, dehydroepiandrosterone abbreviated as DHEA, 17-alpha-hydroxy pregnenolone abbreviated as 17OH-Preg, and dehydroepiandrosterone sulfate abbreviated as DHEA-S;
the ischemic heart failure patient refers to:
(1) Patients who have had ischemic symptoms/signs or electrocardiographic ischemic changes in the past and have had at least one epicardial coronary stenosis >70% in angiography; or (b)
(2) Heart failure patients with a history of myocardial infarction or coronary revascularization;
the method is characterized in that the concentration value of 12 steroid hormones in plasma samples of patients to be detected is used for carrying out weighted diagnosis score calculation on the concentrations of the hormones by using a calculation formula based on a multivariate logic model as a principle so as to diagnose ischemic heart failure, wherein the calculation formula is as follows:
(A4)*0.73+(Doc)*0.81+(17OH-P)*0.20+(E1)*0.85+(E2)*0.05+(E3)*0.20+(Ald)*0.78-(DHEA)*0.07-(T)*0.24-(11-Deo)*1.80-(17OH-Preg)*0.52-(DHEA-S)*0.86；
wherein each hormone metabolite x is subjected to x-mu/sigma conversion through a concentration value quantified by LC-MS/MS and then substituted into the formula, mu is the mean value of all sample hormone concentration values log10 after conversion, sigma is the standard deviation of all hormone concentration values log10 after conversion, and the concentration value unit is ng/ml;
if the combined cut-off value of 12 steroid hormones is greater than or equal to-0.43, the patient is an ischemic heart failure patient.
2. The use according to claim 1, wherein the detection kit is a kit based on LC-MS/MS technology route; the detection kit contains reagents required for extracting and measuring the biomarker.
3. The use according to claim 1 or 2, wherein the kit further comprises a standard for external standard quantification of the biomarker and an internal reference substance, the internal reference substance being as shown in the following table
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