CN113484435B - Application of substance for detecting plasma branched chain amino acid and branched chain alpha keto acid level and product - Google Patents
Application of substance for detecting plasma branched chain amino acid and branched chain alpha keto acid level and product Download PDFInfo
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Abstract
The invention relates to the technical field of biology, in particular to application of a substance for detecting the levels of Branched Chain Amino Acid (BCAA) and branched chain alpha-keto acid (BCKA) in preparation of a product for predicting long-term adverse prognosis risk of a patient with heart failure due to reduction of chronic left ventricular ejection fraction to be detected and a product. According to the invention, BCAA and BCKA are brought into research, and the ratio of BCAA/BCKA is found to be capable of predicting the long-term poor prognosis of the patient with chronic ventricular ejection fraction reduction heart failure, thereby providing clues for improving the prognosis of the patient with chronic ventricular ejection fraction reduction heart failure.
Description
Technical Field
The invention relates to the technical field of biology, in particular to application of a substance for detecting the levels of branched chain amino acid and branched chain alpha keto acid and a product.
Background
Chronic heart failure (hereinafter referred to as heart failure) is the final clinical manifestation of cardiovascular disease development and is a complex clinical syndrome, which is clinically classified into heart failure with preserved left ventricular ejection fraction (HFpEF) and heart failure with reduced left ventricular ejection fraction (HFrEF). In recent years, the survival rate of chronic HFrEF patients has been significantly improved, but there is still a greater potential risk of all-cause death or readmission of heart failure, and therefore, it is extremely important to further search for risk factors affecting the prognosis of chronic HFrEF patients.
Protein metabolism, one of the three major metabolites, particularly Branched Chain Amino Acids (BCAAs), has recently received attention. BCAAs include leucine, isoleucine, and valine, which are essential amino acids in the human body. BCAA is decomposed by aminotransferase to produce alpha-ketoisoacetate, alpha-keto-1-methylpentanoic acid and alpha-ketoisovalerate, collectively referred to as Branched chain alpha-ketoacids (BCKA), which undergo irreversible oxidative decarboxylation into the Krebs cycle under the catalysis of the mitochondrial rate-limiting enzyme Branched chain alpha-ketoacid dehydrogenase complex. Plasma BCAA metabolic levels as a hotspot in recent studies of numerous diseases, the literature reports that BCAA is metabolically disturbed in pathological states, manifested by a significant decrease in the activity and content of BCAA catabolic enzymes in tissues and organs, and an increase in the content of BCAA and its intermediate metabolite, BCKA, in plasma and tissues (Lian K, et al. Amplified administration of biochemical molecules of branched-chain amino acids in metabolic microorganisms. DIABETES 2015,64 (1): 49-59.). We have previously found that elevated plasma BCAA levels in patients with chronic Heart Failure (Han Peng, a correlation between Branched Chain Amino acid levels and risk of congestive Heart Failure, J.Heart 2019), a Defect in BCAA metabolism may contribute to the development of Heart Failure (Sun, H.et al cam defects of Branched-Chain Amino Acids patients Heart Failure, circulation 133,2038-2049, doi: 2016), higher plasma BCAA levels may increase the risk of long-term adverse events in patients with acute myocardial infarction combined with acute Heart Failure (X. Du et al, acquired Branched-Chain Amino acid levels are associated with associated adverse events with long-term adverse events in patients with acute Heart Failure (X. Du et al., acquired Branched-Chain events in tissues with STEMI and acid Heart Failure. Life Sci 209,167-172 (2018)). However, few studies suggest that plasma BCAA levels in chronic congestive heart failure patients are significantly reduced, but they do not report a relationship between BCAA levels and prognosis (the branched chain ammonia Liu Xiaoli master paper in chronic congestive heart failure patients), thereby suggesting that BCAA may be controversial for the assessment of prognosis in chronic heart failure patients. BCKA as a metabolite of BCAA, whose levels were previously found to be significantly altered in chronic HFrEF patients and correlated with disease development, but was not reported on the predictive efficacy of long-term adverse events in chronic HFrEF patients. Therefore, in response to the dispute between BCAAs in predicting the prognostic efficacy of chronic HFrEF heart failure patients, the present invention contemplates establishing a BCAA/BCKA ratio in combination with BCAAs and BCKAs to predict the risk of long-term adverse event occurrence (prognosis) in chronic HFrEF patients.
Disclosure of Invention
The invention mainly aims to provide application of a substance for detecting the levels of branched-chain amino acids and branched-chain alpha keto acids of a heart failure patient with the chronic left ventricular ejection fraction reduction to be detected in preparing a product for predicting the long-term adverse prognosis risk of the patient.
Wherein the adverse prognostic risk includes all-cause death and readmission for heart failure.
Wherein the ratio of the branched chain amino acid level and the branched chain alpha-keto acid level of the patient with the chronic left ventricular ejection fraction reduction to be detected is an independent risk factor for predicting the long-term adverse prognosis risk of the patient with the chronic left ventricular ejection fraction reduction to be detected.
Wherein, the substance for detecting the level of the branched chain amino acid is a substance for detecting the level of leucine, isoleucine and valine in a blood plasma sample to be detected; the detection branched chain a keto acid level is a substance for detecting the levels of alpha-ketoisoacetic acid, alpha-keto-1-methylvaleric acid and alpha-ketoisovaleric acid in a plasma sample to be detected.
A second object of the invention is to provide a product for predicting the risk of long-term adverse prognosis for heart failure patients with decreased chronic left ventricular ejection fraction. The kit specifically comprises a substance for detecting the levels of branched-chain amino acids and branched-chain alpha keto acids and an readable carrier recording the following standards: the higher the ratio of branched-chain amino acid levels to branched-chain alpha keto acid levels in heart failure patients with decreased chronic left ventricular ejection fraction, the higher the risk of adverse events.
Wherein the substance for detecting the level of the branched chain amino acid is a substance for detecting the level of leucine, isoleucine and valine in a blood plasma sample to be detected; the detection branched chain alpha keto acid level is a substance for detecting the levels of alpha-ketoisoacetic acid, alpha-keto-1-methylvaleric acid and alpha-ketoisovaleric acid in a plasma sample to be detected.
Wherein the ratio of branched chain amino acid level to branched chain alpha keto acid level is the ratio of the sum of leucine, isoleucine and valine levels to the sum of alpha-ketoisoacetic acid, alpha-keto-1-methylvaleric acid and alpha-ketoisovaleric acid.
The invention has at least the following beneficial effects:
according to the invention, BCAA and BCKA are simultaneously brought into research, the relation between the BCAA/BCKA ratio and the long-term prognosis of the heart failure patient with the decreased chronic left ventricular ejection fraction is explored, the long-term adverse prognosis of the heart failure patient with the decreased chronic left ventricular ejection fraction can be predicted by the BCAA/BCKA ratio, the prediction efficiency of the blood plasma BCAA/BCKA ratio on the long-term adverse prognosis of the chronic HFrEF patient is higher than that of BCAA, and a brand-new solution is provided for improving the prognosis.
Drawings
FIG. 1 is a KM survival curve analysis of BCAA/BCKA ratio versus incidence of adverse events in chronic HFrEF patients;
FIG. 2 is the result of analyzing risk factors affecting the occurrence of adverse events using COX regression single factor analysis;
FIG. 3 is the analysis result of the risk factors affecting the occurrence of adverse events using COX regression multifactor analysis;
FIG. 4 is an analysis result of accuracy of predicting bad events using ROC curve analysis of BCAA level and BCAA/BCKA ratio.
Detailed description of the preferred embodiments
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In the research process, the BCKA is found to be a metabolite of BCAA, the level of the BCKA is obviously changed in a pathological state, the BCAA/BCKA ratio is established in combination with the BCAA and the BCKA to predict the occurrence risk of long-term adverse events of chronic HFrEF patients, the dispute of the existing BCAA in CVD can be solved, the prediction accuracy can be obviously improved, and the method is completed.
The embodiment of the invention provides that the BCAA/BCKA ratio is an independent risk factor for long-term adverse prognosis of a patient with chronic left ventricular ejection fraction reduction heart failure, and further provides application of a substance for detecting the BCAA and BCKA levels of the patient with chronic left ventricular ejection fraction reduction heart failure to be detected in preparation of a product for predicting long-term adverse prognosis risk of the patient with chronic left ventricular ejection fraction reduction heart failure to be detected. The BCAA and the BCKA are simultaneously brought into research, and the BCAA/BCKA ratio is found to be capable of predicting the long-term adverse prognosis of the patient with the chronic left ventricular ejection fraction reduction, so that a clue is provided for improving the prognosis, the prediction accuracy is increased, and a reliable prediction method is provided.
In particular, poor prognostic risk includes all-cause death and readmission for heart failure.
Specifically, the ratio of the BCAA to BCKA level of the heart failure patient with the chronic ventricular ejection fraction reduction to be detected is an independent factor for predicting the long-term adverse prognosis risk of the heart failure patient with the chronic ventricular ejection fraction reduction to be detected.
The substance for detecting the BCAA level is a substance for detecting the levels of leucine, isoleucine and valine in a plasma sample to be detected, and the substance for detecting the BCKA level is a substance for detecting the levels of alpha-ketoisoacetic acid, alpha-keto-1-methylvaleric acid and alpha-keto-isovaleric acid in the plasma sample to be detected.
The embodiment of the invention also provides a product for predicting long-term adverse prognosis risk of heart failure patients with chronic left ventricular ejection fraction reduction, which comprises a substance for detecting BCAA and BCKA levels and a readable carrier recording the following standards: the higher the BCAA/BCKA ratio of heart failure patients with decreased chronic left ventricular ejection fraction, the higher the risk of adverse events.
Specifically, the substance for detecting the BCAA level is a substance for detecting the levels of leucine, isoleucine and valine in the blood plasma sample to be detected, and the substance for detecting the BCKA level is a substance for detecting the levels of alpha-ketoisoacetic acid, alpha-keto-1-methylvaleric acid and alpha-ketoisovaleric acid in the blood plasma sample to be detected.
Wherein the ratio of BCAA to BCKA levels is the ratio of the sum of leucine, isoleucine and valine levels to the sum of α -ketoisoacetic acid, α -keto-1-methylvaleric acid and α -ketoisovaleric acid.
Detailed description of the preferred embodiments
The experimental method comprises the following steps:
chronic left ventricular ejection fraction reduction of cardiology hospitalization in Cijing Hospital from 6 months in 2018 to 1 month in 2020 is selected222 patients with heart failure (HFrEF), with diabetes excluded, were collected from their medical records for baseline data. Patient plasma samples for BCAA and BCKA levels were detected using liquid chromatography tandem mass spectrometry (LC-MS/MS) technique by transferring 40. Mu.L of human plasma into a 1.5mL Eppendorf tube and adding 10. Mu.L of internal standard working fluid (50. Mu.g/mL IS-1,5. Mu.g/mL IS-2) and 160. Mu.L acetonitrile. After vortex mixing for 5 minutes, the mixture was centrifuged at 15000g for 5 minutes at 4 ℃. Then 100. Mu.L of the supernatant was transferred to another 1.5mL Eppendorf tube, dried under vacuum at 37 ℃ and dissolved in 40. Mu.L of water/methanol (80, v/v). Finally, the recombined extract was centrifuged (4 ℃,15000g,5 min), and the supernatant was transferred to an autosampler and put on a machine into a Sciex Triple Quad TM 4500MD analyzing and providing the detection result. Calculating the BCAA/BCKA ratio of each patient, sequentially arranging the BCAA/BCKA ratios from low to high, and performing triage to obtain three groups of BCAA/BCKA ratios, namely an L group, an M group and an H group. One year later, patients were followed up on the phone and adverse events were recorded: all-cause death and heart failure were readmitted. The experiment was approved by the fourth university of military medical ethics committee (KY 20172019-1). All participants received written informed consent.
As a result:
a total of 222 chronic HFrEF patients were enrolled, followed one year post-surgery, and 43 patients had all-cause deaths or readmission of heart failure, 21 of which were admitted and 23 of which were admitted, with the test results shown in table 1.
TABLE 1 one year prognosis after PCI surgery in patients with chronic heart failure
The results of KM survival curve analysis using GraphPad Prism 9.0 for BCAA/BCKA ratio on the incidence of adverse events in chronic HFrEF patients are shown in fig. 1, where L, M and H groups are shown from top to bottom.
As can be seen in fig. 1, as the BCAA/BCKA ratio of the patient increases, the incidence of adverse events in the patient increases significantly (fig. 1, p = 0.001).
The results of the analysis of adverse events using COX regression single factor analysis are shown in figure 2.
As shown in fig. 2, BCAA/BCKA ratios are risk factors for increasing the occurrence of long-term adverse events in chronic HFrEF patients.
The results of the analysis of adverse events using COX regression multifactorial analysis are shown in figure 3.
As can be seen in FIG. 3, the plasma BCAA/BCKA ratio is an independent risk factor for increasing long-term adverse events in chronic HFrEF patients. Adopting BCAA/BCKA ratio to analyze, and determining the ratio of Adjusted HR 2.618;95% ci; p = 0.001). The larger the ratio of BCAA/BCKA is, the larger the risk of adverse event occurrence is, and the adverse event occurrence rate is 2.618 times of the prior rate every time the adverse event occurs by one quantile.
The results of analysis of the accuracy of predicting unfavorable events using ROC curves for BCAA levels and BCAA/BCKA ratios are shown in fig. 4.
As can be seen from fig. 4, the plasma BCAA/BCKA ratio predicted a higher efficacy than BCAA for long-term poor prognosis in chronic HFrEF patients.
Although the present application has been described with reference to preferred embodiments, it is not intended to limit the scope of the claims, and many possible variations and modifications may be made by one skilled in the art without departing from the spirit of the application.
Claims (2)
1. The application of a substance for detecting the level of branched chain amino acid and branched chain alpha keto acid of a patient with heart failure with the chronic left ventricular ejection fraction to be detected in preparing a product for predicting the long-term adverse prognosis risk of the patient with heart failure with the chronic left ventricular ejection fraction to be detected; the ratio of the branched chain amino acid level and the branched chain alpha keto acid level of the heart failure patient with the chronic left ventricular ejection fraction to be detected is an independent risk factor for predicting the long-term adverse prognosis risk of the heart failure patient with the chronic left ventricular ejection fraction to be detected; the substance for detecting the level of the branched chain amino acid is a substance for detecting the levels of leucine, isoleucine and valine in a blood plasma sample to be detected; the detection of the branched chain alpha-keto acid level is used for detecting substances of alpha-ketoisocaproic acid, alpha-keto-1-methylvaleric acid and alpha-ketoisovaleric acid in a plasma sample to be detected.
2. The use according to claim 1, wherein the adverse prognostic risk includes all-cause death and readmission to heart failure.
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