WO2020149846A1 - Methods for predicting major adverse cardiovascular events and/or death in patients with coronary heart disease - Google Patents

Methods for predicting major adverse cardiovascular events and/or death in patients with coronary heart disease Download PDF

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WO2020149846A1
WO2020149846A1 PCT/US2019/014084 US2019014084W WO2020149846A1 WO 2020149846 A1 WO2020149846 A1 WO 2020149846A1 US 2019014084 W US2019014084 W US 2019014084W WO 2020149846 A1 WO2020149846 A1 WO 2020149846A1
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mir
heart disease
coronary heart
death
patients
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Tiffany WU
Wan-lin WU
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Chi-Hua Foundation
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    • C12Q2600/118—Prognosis of disease development
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
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    • C—CHEMISTRY; METALLURGY
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/178—Oligonucleotides characterized by their use miRNA, siRNA or ncRNA

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  • the present invention relates to a method for predicting major adverse cardiovascular events and/or death in patients suffering from coronary heart disease, and more particularly to the method for analyzing the microRNA expression of a coronary heart disease patient to predict whether the patient is at high risk for major adverse cardiovascular events and/or death.
  • Coronary heart disease is the most common disease caused by atherosclerotic degeneration. Due to cholesterol or fat accumulates on the inner wall of arterial blood vessels to form a blood clot, and the blood clot would block the coronary artery and cause heart hypoxia. It causes common cardiovascular symptoms such as chest pain, shortness of breath, upper limb pain, night sweats, and vomiting. If the artery is completely blocked by the blood clot, and then oxygen cannot be transported the heart, which would lead to a heart attack or heart tissue damage.
  • Major adverse cardiovascular events include recurrent angina pectoris, acute myocardial infarction, severe arrhythmia, heart failure, cardiac death, nonfatal myocardial infarction, non-fatal stroke, death from stroke, etc.
  • the main factors are hypertension, diabetes, hyperlipidemia, atrial fibrillation, smoking, and poor living habits.
  • the methods for diagnosing coronary heart disease include: electrocardiogram, cardiac ultrasound, cardiac tomography and other imaging diagnostic methods and biomarkers. Because there is no biomarker for predicting MACE or death in patients with coronary heart disease currently, patients with coronary heart disease can only be tracked by regular cardiac imaging diagnosis, and a good life style to reduce the incidence of adverse cardiovascular events.
  • MicroRNA is a ribonucleic acid (RNA) molecule about 21 to 23 nucleotides long and regulates the expression of other genes in eukaryotes widely. miRNA is transcribed from DNA but does not translate into proteins (belonging to non-coding RNA). The miRNA binds to the target messenger ribonucleic acid (mRNA), thereby inhibiting the expression of the gene after transcription, and plays an important role in regulating gene expression, cell cycle, and development timing of the organism. Current research has found that miRNA has many functions, such as cancer markers, early cancer detection biomarkers, and exogenous miRNA that can be detected in the blood. SUMMARY OF THE INVENTION
  • the object of the present invention is to provide a method for predicting major adverse cardiovascular events and/or death in patients with coronary heart disease by detecting the microRNA expression.
  • the technical method of the present invention is to analyze the expression amount of at least one target microRNA in the serum of coronary heart disease patients, and the target microRNA is selected from one or any combination of: has-miR-1468, has-miR-1307, has-miR-200c, has-miR-574, has-miR-432, has-miR-3615, has-miR-3605, and has-miR-181a-2.
  • the expression of target microRNA in the patient is lower than one predetermined value, it indicates that the patient belongs to a high-risk group that will suffer from MACE or death in the future.
  • clinicians will be able to custom-design a better treatment strategy to improve the clinical outcomes of patients with coronary heart disease.
  • FIG. 1 is a comparison diagram of target miRNA expression levels in example 1 of the present invention.
  • FIG. 2 is a Kaplan-Meier survival analysis diagram of target has-miR-1468 in example 2 of the present invention.
  • FIG.3 is a Kaplan-Meier survival analysis diagram of target has-miR-1307 superscripted in example 2 of the present invention.
  • This example is used to analyzes the difference of microRNA expression in patients with coronary heart disease who have suffered from MACE or death and those who have no MACE, and then to find out detecting biomarker.
  • Plasma samples were selected from blood sample in the present example as follows.
  • Recurrent MACE After 5 years of follow-up, the plasma samples from patients with coronary heart disease who have suffered from major adverse cardiovascular events or death.
  • the coronary heart disease patients with expression of has-miR-1468 and has-miR-1307 lower than the RPKM cut-off value were prone to have MACE or death, and the survival rate of Kaplan-Meier survival analysis decreased significantly via long-term follow-up.
  • the coronary heart disease patients with expression of has-miR-1468 and has-miR-1307 higher than the 15 RPKM cut-off value the physiological conditions were stable. Therefore, the expressions of these target miRNAs compared with their RPKM cut-off value could be used as a basis for predicting whether a MACE or death would occur in patients with coronary heart disease.
  • the expressions of the target miRNAs found in the present embodiment in patients with coronary heart disease were related to the major adverse cardiovascular events and death.
  • those with expression of single or multiple miRNAs lower than RPKM cut-off values would have higher risk for future MACE or death.
  • the single or combined target miRNAs of the present invention could be used to predict the risk of MACE or death in the future. That is to say, the method proposed by the present invention has important values for clinical decision making and patient care.
  • RT-PCR reverse transcriptase-polymerase chain reaction
  • qPCR quantitative real-time PCR
  • ddPCR digital droplet PCR
  • SAGE serial analysis of gene expression
  • MPSS massively parallel signature sequencing
  • ELISA ELISA
  • ISH massively parallel signature sequencing
  • MS mass spectrometry
  • SNPs single nucleotide polymorphisms

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Abstract

The present invention provides a method for predicting major adverse cardiovascular events and/or death in patients suffering from coronary heart disease, selecting at least one target from microRNAs has-miR-1468, has-miR-1307, has-miR-200c, has-miR-574, has-miR-432 has-miR-3615, has-miR-3605 and has-miR-181a-2, microRNA to analyze the microRNA expression of the specimen of a coronary heart disease patient. According to the expression, it can be used as a predictor of major adverse cardiovascular events and death in patients suffering coronary heart disease.

Description

METHODS FOR PREDICTING MAJOR ADVERSE
CARDIOVASCULAR EVENTS AND/OR DEATH IN PATIENTS WITH
CORONARY HEART DISEASE BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for predicting major adverse cardiovascular events and/or death in patients suffering from coronary heart disease, and more particularly to the method for analyzing the microRNA expression of a coronary heart disease patient to predict whether the patient is at high risk for major adverse cardiovascular events and/or death.
2. Description of the Prior Arts
Coronary heart disease is the most common disease caused by atherosclerotic degeneration. Due to cholesterol or fat accumulates on the inner wall of arterial blood vessels to form a blood clot, and the blood clot would block the coronary artery and cause heart hypoxia. It causes common cardiovascular symptoms such as chest pain, shortness of breath, upper limb pain, night sweats, and vomiting. If the artery is completely blocked by the blood clot, and then oxygen cannot be transported the heart, which would lead to a heart attack or heart tissue damage.
Patients with coronary heart disease are at a much higher risk of major adverse cardiovascular events and deaths than the average person. It is estimated that patients with coronary heart disease have a risk of major adverse cardiovascular events (MACE) or death of more than 20% within five years. Major adverse cardiovascular events include recurrent angina pectoris, acute myocardial infarction, severe arrhythmia, heart failure, cardiac death, nonfatal myocardial infarction, non-fatal stroke, death from stroke, etc. The main factors are hypertension, diabetes, hyperlipidemia, atrial fibrillation, smoking, and poor living habits.
More than one-third of patients in developing countries die from coronary heart disease, and the average age of the disease is gradually reduced. In addition, the number of deaths from coronary heart disease has increased year by year. According to statistics from the World Health Organization, the number of deaths due to coronary heart disease increased by 40% in 2013 compared with 1990. Patients with coronary heart disease are like an untimely bomb due to patients and their families do not know when it will be diseased or dead and cause great stress.
At present, the methods for diagnosing coronary heart disease include: electrocardiogram, cardiac ultrasound, cardiac tomography and other imaging diagnostic methods and biomarkers. Because there is no biomarker for predicting MACE or death in patients with coronary heart disease currently, patients with coronary heart disease can only be tracked by regular cardiac imaging diagnosis, and a good life style to reduce the incidence of adverse cardiovascular events.
MicroRNA (miRNA) is a ribonucleic acid (RNA) molecule about 21 to 23 nucleotides long and regulates the expression of other genes in eukaryotes widely. miRNA is transcribed from DNA but does not translate into proteins (belonging to non-coding RNA). The miRNA binds to the target messenger ribonucleic acid (mRNA), thereby inhibiting the expression of the gene after transcription, and plays an important role in regulating gene expression, cell cycle, and development timing of the organism. Current research has found that miRNA has many functions, such as cancer markers, early cancer detection biomarkers, and exogenous miRNA that can be detected in the blood. SUMMARY OF THE INVENTION
The object of the present invention is to provide a method for predicting major adverse cardiovascular events and/or death in patients with coronary heart disease by detecting the microRNA expression.
To achieve the above objective, the technical method of the present invention is to analyze the expression amount of at least one target microRNA in the serum of coronary heart disease patients, and the target microRNA is selected from one or any combination of: has-miR-1468, has-miR-1307, has-miR-200c, has-miR-574, has-miR-432, has-miR-3615, has-miR-3605, and has-miR-181a-2. When the expression of target microRNA in the patient is lower than one predetermined value, it indicates that the patient belongs to a high-risk group that will suffer from MACE or death in the future. With the prognostic information provided by this method, clinicians will be able to custom-design a better treatment strategy to improve the clinical outcomes of patients with coronary heart disease.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a comparison diagram of target miRNA expression levels in example 1 of the present invention.
FIG. 2 is a Kaplan-Meier survival analysis diagram of target has-miR-1468 in example 2 of the present invention.
FIG.3 is a Kaplan-Meier survival analysis diagram of target has-miR-1307 superscripted in example 2 of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLES
Without intent to limit the scope of the invention, exemplary instruments, apparatus, methods and their related results according to the embodiments of the present invention are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the invention. Moreover, certain theories are proposed and disclosed herein; however, in no way they, whether they are right or wrong, should limit the scope of the invention so long as the invention is practiced according to the invention without regard for any particular theory or scheme of action.
Example 1
This example is used to analyzes the difference of microRNA expression in patients with coronary heart disease who have suffered from MACE or death and those who have no MACE, and then to find out detecting biomarker.
Plasma samples were selected from blood sample in the present example as follows.
No MACE: After 5 years of follow-up, the plasma samples from patients with coronary heart disease who have not suffered from major adverse cardiovascular events or death.
Recurrent MACE: After 5 years of follow-up, the plasma samples from patients with coronary heart disease who have suffered from major adverse cardiovascular events or death.
First, the samples of two above groups were analyzed by next-generation sequencing to analyze the type and the expression of miRNA. The results were shown in FIG. 1. The plasma levels of the eight miRNAs were lower in the patients with
MACE or death than those without it. As shown in Table 1, the AUC’s under the cutoff value of eight miRNAs all exceeded 0.64 through ROC curve (AUC), and survival analysis showed all of these were significant negative predictors of MACE or death in patients with coronary heart disease.
Table 1 ' Plasma miRNAs that are significant predictors as cardiovascular events
5 or death in CAD patients
Figure imgf000007_0001
Example 2 Survival test
In this example, the occurrence of MACE or death of the patients with coronary heart disease and the expression of has-miR-1468 and has-miR-1307 in vivo were observed by long-term follow-up and Kaplan-Meier survival analysis.
10 As shown in Fig’s 2 and 3, the coronary heart disease patients with expression of has-miR-1468 and has-miR-1307 lower than the RPKM cut-off value were prone to have MACE or death, and the survival rate of Kaplan-Meier survival analysis decreased significantly via long-term follow-up. Conversely, in the coronary heart disease patients with expression of has-miR-1468 and has-miR-1307 higher than the 15 RPKM cut-off value, the physiological conditions were stable. Therefore, the expressions of these target miRNAs compared with their RPKM cut-off value could be used as a basis for predicting whether a MACE or death would occur in patients with coronary heart disease.
In summary, the expressions of the target miRNAs found in the present embodiment in patients with coronary heart disease were related to the major adverse cardiovascular events and death. In the patients with coronary heart disease, those with expression of single or multiple miRNAs lower than RPKM cut-off values would have higher risk for future MACE or death. Thus, the single or combined target miRNAs of the present invention could be used to predict the risk of MACE or death in the future. That is to say, the method proposed by the present invention has important values for clinical decision making and patient care.
The experimental methods of miRNA expression detection were not limited to the following: reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative real-time PCR (qPCR), digital droplet PCR (ddPCR), microarray, serial analysis of gene expression (SAGE), next-generation RNA sequencing, massively parallel signature sequencing (MPSS), ELISA, in situ hybridization (ISH), mass spectrometry (MS), RNA pull-down, and single nucleotide polymorphisms (SNPs).

Claims

WHAT IS CLAIMED IS:
1. A method for predicting the occurrence of major adverse cardiovascular events and/or death in patients suffering from coronary heart disease comprising: detecting the expression amount of at least one target microRNA (miRNA) of a sample of a patient with coronary heart disease, wherein the target miRNA is selected from one or any combination of has-miR-1468, has-miR-1307, has-miR-200c, has-miR-574, has-miR-432, has-miR-3615, has-miR-3605, and has-miR-181a-2; and, when the expression of target miRNA in the coronary heart disease patient is lower than a predetermined value, the patient belongs to a high-risk group that will suffer from major adverse cardiovascular events and/or death.
2. The method of claim 1, wherein the predetermined value is a RPKM cutoff value generated by comparing and calculating the target miRNA expression in the blood sample of the coronary heart disease patients with MACE or death and those without it.
3. The method of claim 1, wherein the expressions of the target miRNAs are quantified using one of the following methodologies: Next-generation sequencing, reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative real-time PCR (qPCR), digital droplet PCR (ddPCR), microarray, serial analysis of gene expression (SAGE) ), next-generation RNA sequencing, massively parallel signature sequencing (MPSS), ELISA, in situ hybridization (ISH), mass spectrometry (MS), RNA pull-down, and single nucleotide polymorphisms (SNPs).
4. The method of claim 2, wherein the expressions of the target miRNAs are quantified using one of the following methodologies: Next-generation sequencing, reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative real-time PCR (qPCR), digital droplet PCR (ddPCR), microarray, serial analysis of gene expression (SAGE) ), next-generation RNA sequencing, massively parallel signature sequencing (MPSS), ELISA, in situ hybridization (ISH), mass spectrometry (MS), RNA pull-down, and single nucleotide polymorphisms (SNPs).
PCT/US2019/014084 2019-01-17 2019-01-17 Methods for predicting major adverse cardiovascular events and/or death in patients with coronary heart disease WO2020149846A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150064704A1 (en) * 2012-04-04 2015-03-05 Comprehensive Biomarker Center Gmbh Complex sets of mirnas as non-invasive biomarkers for early diagnosis of acute myocardial infarction
US20160251720A1 (en) * 2013-11-01 2016-09-01 The Trustees Of Columbia University In The City New York MicroRNA PROFILES IN HEART FAILURE: METHODS AND SYSTEMS FOR DETECTION AND USE

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150064704A1 (en) * 2012-04-04 2015-03-05 Comprehensive Biomarker Center Gmbh Complex sets of mirnas as non-invasive biomarkers for early diagnosis of acute myocardial infarction
US20160251720A1 (en) * 2013-11-01 2016-09-01 The Trustees Of Columbia University In The City New York MicroRNA PROFILES IN HEART FAILURE: METHODS AND SYSTEMS FOR DETECTION AND USE

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