CN109799330B - Application of neuraminic acid and neuraminidase inhibitor in chronic heart failure - Google Patents
Application of neuraminic acid and neuraminidase inhibitor in chronic heart failureDownload PDFInfo
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Abstract
Translated fromChinese
Description
Technical Field
The invention discloses application of neuraminic acid and neuraminidase inhibitors in chronic heart failure, particularly relates to application of neuraminic acid and neuraminidase inhibitors in diagnosis and prognosis evaluation of chronic heart failure diseases, and belongs to the field of diagnosis, prevention and treatment of cardiovascular diseases.
Background
Chronic heart failure is a clinical syndrome of different cardiovascular diseases developing to the final stage, and is caused by initial myocardial damage (such as myocardial infarction, cardiomyopathy, hemodynamic overload, inflammation and the like) of any reason, changes of myocardial structure and function, finally ventricular pump blood and/or filling hypofunction, poor prognosis, high mortality and one of the most main causes threatening human health and increasing medical burden. At present, the treatment of chronic heart failure mainly comprises beta receptor blockers and angiotensin converting enzyme inhibitors as main drugs, and diuretics, cardiac glycosides, tube expanders and other drugs as auxiliary drugs, but most patients still cannot control the development of the disease and move to the end stage heart failure. Therefore, there is a need to fully research and understand the pathogenesis of chronic heart failure, find new therapeutic targets and adopt more effective measures to improve or delay the progression of heart failure, reduce the mortality and hospitalization rate of heart failure; on the other hand, the risk factors for chronic heart failure are not fully elucidated, and therefore there is a need to find new risk factors and to adopt more effective risk assessment methods.
Neuraminic acid is the major sialic acid in mammalian cells, which adheres to the ends of glycan chains to stabilize the cell surface receptor glycoprotein structure, maintaining the cell intact. Neuraminidase has exoglycosidase activity, can crack alpha-glycosidic bonds between cell surface sialic acid and adjacent lactose, plays a role in recognizing receptors for influenza virus infected cells in the whole life cycle of influenza viruses, and can promote viruses to enter the receptor cells, and the process plays a very important role in viral infection and spread, so the neuraminidase is an important target for anti-influenza drug development. The current clinically used neuraminidase inhibitor oseltamivir phosphate plays an important role in the prevention and treatment of influenza.
Plasma neuraminic acid is an inflammation marker and an inflammation prediction factor which are equivalent to C-reactive protein, and is also obviously increased in cancer and autoimmune diseases as a potential tumor marker. In addition, researchers find that the level of neuraminic acid in blood plasma is in obvious positive correlation with coronary heart disease events, and influenza virus neuraminidase inhibitor drugs (oseltamivir and zanamivir) can effectively inhibit the activity of neuraminidase in eukaryotes, reduce myocardial ischemia injury and prompt new application of anti-influenza drugs in treating coronary heart disease. However, no studies have revealed a role for neuraminic acid in chronic heart failure and corresponding clinical studies are lacking. In the invention, the applicant researches the risk and prognosis of N-acetylneuraminic acid and heart failure in a large sample of clinical chronic heart failure patients, and epidemiological follow-up research on the disease development of the patients, determines the application of the neuraminic acid in the chronic heart failure, and provides a theoretical basis and evidence-based basis for preventing, relieving and/or treating the chronic heart failure.
Disclosure of Invention
Aiming at the problems of difficulty in diagnosis and treatment of chronic heart failure and insufficient risk assessment in the prior art, the invention discovers a new biomarker-neuraminic acid, and proves that the neuraminic acid plays roles in diagnosis, prognosis biomarker and risk stratification in chronic heart failure and the role of the neuraminic acid as a drug target in preventing, relieving and/or improving chronic heart failure; therefore, the detection of the neuraminic acid level by the kit can be used for predicting and assisting the diagnosis of chronic heart failure or evaluating the prognosis of chronic heart failure, and the neuraminic acid level is controlled by a medicament so as to carry out more intensive diagnosis and subsequent treatment on diseases, obtain a favorable course of disease and have great application value in clinic.
The invention aims to provide a biomarker, namely neuraminic acid, for diagnosing, risk stratification and/or evaluating prognosis of chronic heart failure.
In a second aspect, the present invention provides the use of a biomarker for diagnosis, risk stratification and/or assessment of the prognosis of chronic heart failure.
The third object of the invention is to provide a new therapeutic target with the biomarker, which can reduce the high neuraminic acid level in the plasma of chronic heart failure patients through neuraminidase inhibitors, thereby achieving the effect of preventing, relieving and/or improving chronic heart failure.
The technical purpose of the invention is realized by the following technical scheme:
the invention aims to provide a biomarker for diagnosing, risk stratification and/or assessing prognosis of chronic heart failure, which comprises: neuraminic acid.
Further, the chronic heart failure includes congenital heart disease, coronary heart disease, acute myocardial infarction, rheumatic heart disease, hypertension, arrhythmia, myocarditis caused by various reasons, chronic heart failure caused by cardiomyopathy and the like.
In a second aspect, the present invention provides the use of a biomarker for the preparation of a reagent or kit for the diagnostic and/or prognostic assessment of chronic heart failure.
Further, by measuring plasma neuraminic acid levels in humans, if the plasma neuraminic acid levels in humans are significantly elevated, the humans are considered to have chronic heart failure and/or a poorer prognosis.
The application determines that neuraminic acid in plasma plays a diagnostic and prognostic biomarker role in chronic heart failure through a multicenter large sample clinical test. The significant increase of plasma neuraminic acid level in patients with chronic heart failure confirms that neuraminic acid can be used as a biomarker for diagnosing chronic heart failure diseases. Therefore, detection of the level of neuraminic acid in plasma can be used to predict and aid in the diagnosis of chronic heart failure or to assess the prognosis of chronic heart failure.
It is a second aspect of the present invention to provide the use of a biomarker for the preparation of a reagent or kit for the prognosis or assisted prognosis of risk stratification and/or adverse events of chronic heart failure.
Furthermore, by detecting the plasma neuraminic acid level of a human body, the high plasma neuraminic acid level is obviously related to adverse cardiovascular events and is independent of traditional risk factors such as N-terminal brain natriuretic peptide, high-sensitive C-reactive protein and the like.
According to the application, long-term follow-up of study population proves that high-level neuraminic acid in plasma is obviously related to adverse cardiovascular events, and the elevated neuraminic acid in the plasma is taken as a risk factor, is independent of traditional risk factors such as N-terminal brain natriuretic peptide and high-sensitivity C-reactive protein, can forecast worse prognosis, and provides a new forecasting factor and risk stratification for chronic heart failure.
The third purpose of the invention is to use the biomarker as a therapeutic target in the preparation of a medicament for preventing, relieving and/or improving chronic heart failure, and the biomarker can achieve the effect of preventing, relieving and/or improving chronic heart failure by reducing the high neuraminic acid level in the plasma of a patient with chronic heart failure.
Further, the neuraminidase inhibitor can reduce the high neuraminic acid level in the plasma of a patient with chronic heart failure, thereby achieving the effect of preventing, relieving and/or improving the chronic heart failure.
Further, the neuraminidase inhibitor is oseltamivir phosphate.
The invention has the beneficial effects that:
1. the invention proves the relevance of the neuraminic acid and the chronic heart failure through a large number of experiments, the plasma neuraminic acid level is obviously increased in patients with the chronic heart failure, and the neuraminic acid can be used as a biomarker, so that a reagent or a kit for detecting the neuraminic acid is prepared, the detection of the neuraminic acid level in the isolated plasma can be used for predicting and assisting in diagnosing the chronic heart failure or evaluating the prognosis of the chronic heart failure, the detection means is quick and convenient, the efficiency and the accuracy of the diagnosis and the prognosis evaluation of the chronic heart failure are greatly improved, so that the disease can be more intensively diagnosed and subsequently treated, a favorable course of disease is obtained, and the invention has great clinical application value.
2. The invention proves that the high-level plasma neuraminic acid is obviously related to adverse cardiovascular events and is independent of the traditional risk factors, and a new forecasting factor and risk stratification are provided for chronic heart failure; meanwhile, neuraminic acid can be complemented with the traditional marker, so that the sensitivity and the accuracy of risk prediction of chronic heart failure are improved, and corresponding treatment measures are taken as soon as possible.
3. The invention not only provides a new diagnosis mode, a forecasting factor and risk stratification for chronic heart failure, but also provides a new treatment target for chronic heart failure, and the neuraminidase inhibitor can reduce the high neuraminic acid level in the plasma of a patient with chronic heart failure, improve the myocardial damage of the chronic heart failure, help to prevent, relieve and improve the chronic heart failure and greatly reduce the hospitalization death rate of the patient with chronic heart failure by inhibiting the activity of neuraminidase.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.
Figure 1 demographic and clinical characteristics of the study group. NYHA, new york heart association; LVEDD, left ventricular end diastolic diameter; NT-proBNP, N-terminal brain natriuretic peptide; hsCRP, high sensitive C-reactive protein; HDL, high density lipoprotein cholesterol; LDL, low density lipoprotein cholesterol; ACEI, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor II antagonist; neu5Ac, N-acetylneuraminic acid.
Figure 2 long-term follow-up results from the study population in triplicate based on neuraminic acid levels.
Correcting age and gender;
correcting age, gender, history of diabetes, history of hypertension, history of ischemic disease, history of stroke, history of smoking, history of alcohol consumption, and cardiovascular association rating of heart failure, new york; correcting age, sex, history of diabetes, history of hypertension, history of ischemic disease, history of stroke, history of smoking, history of drinking and NYHA grade, NT-proBNP, hsCRP and digoxin, diuretic, angiotensin enzyme inhibitor, angiotensin receptor antagonist, beta receptor blocker and history of spironolactone administration; HR, hazard ratio; CI, trusted interval.
FIG. 3.Kaplan-Meier curves showing plasma Neu5Ac level triage and risk of major endpoint events (cardiac death and heart transplantation).
FIG. 4.Kaplan-Meier curves showing plasma Neu5Ac level triage and risk of all-cause death.
FIG. 5.Kaplan-Meier curves showing plasma Neu5Ac level triage and risk of recurrent heart failure.
FIG. 6 ROC curves containing Neu5Ac and not containing Neu5 Ac. AUC including Neu5 Ac: 0.755, AUC without Neu5 Ac: 0.721, p ═ 0.021. Model variables included age, gender, systolic blood pressure, history of diabetes, low density lipoprotein cholesterol, high density lipoprotein cholesterol, history of smoking, and hypersensitive C-reactive protein. ROC, receiver operating characteristics; AUC, area under the curve; neu5Ac, N-acetylneuraminic acid.
FIG. 7.Kaplan-Meier curves showing the median plasma Neu5Ac levels (0.761 μ M) and the median hscRP levels (4.650mg/L) and risk of primary endpoint events (cardiac death and heart transplantation).
FIG. 8 Hazard Ratio (HR) of various subgroups of study population to plasma Neu5Ac levels. Subgroup analysis one-way Cox risk proportional regression analysis was used, based on Neu5Ac level triage. With reference to the 1 st third quantile, the 2 nd third quantile hazard ratio is on the left side, and the 3 rd third quantile hazard ratio is on the right side. Since only 149 patients had no history of hypertension, the hazard ratio could not be calculated. LEDD, left ventricular end diastolic inner diameter; EF, ejection fraction.
Detailed Description
The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without any inventive step, are within the scope of the present invention.
Example 1
High plasma Neu5Ac levels associated with severe chronic heart failure
Study population and study design: frommonth 1 in 2008 tomonth 3 in 2017, hospitalized patients with chronic heart failure were continuously admitted at two medical centers (affiliated peer hospital of peer medical college of science and technology university in wuhan city, north Hubei, and affiliated second hospital of river-north stone house, Hebei medical university) at the same time. Inclusion criteria included: age greater than 18 years, heart failure NYHA grades II-IV. The diagnosis of heart failure is determined according to diagnosis standards and procedures of ACC/AHA on the basis of physical examination, laboratory examination and heart color ultrasound. Exclusion criteria included: heart failure due to severe valvular disease; patients have life-threatening complications such as severe liver dysfunction, renal dysfunction; the survival time of the malignant tumor patient is less than 1 year; second or third degree atrioventricular block (except for pacemaker implantation in a patient); acute myocardial infarction or unstable angina occurring within one month; patients who were denied follow-up. The primary endpoint events were cardiac death and heart transplantation, and the secondary endpoint events were all-cause death, recurrence of heart failure, re-hospitalization for cardiovascular reasons, and re-hospitalization for all reasons. Follow-up visits are made by professional cardiology nurses through regular visits, serial telephone follow-up visits and data reviews.
Neu5Ac (N-acetylneuraminic acid) assay: peripheral blood is extracted from an empty stomach in an EDTA anticoagulation tube, and serum is taken out and frozen in a refrigerator at the temperature of 80 ℃ below zero for analysis immediately after 3000 r/min centrifugation. Plasma Neu5AC levels were detected using liquid chromatography-mass spectrometry tandem at the cardiovascular institute at the university of beijing.
Statistical analysis method: the distribution of continuous variables was represented by the Kolmogorov-Smirnov test (K-S test), the distribution of normally distributed variables, and the results were expressed as mean. + -. standard deviation or median (IQR). Comparisons between normally distributed variables were made using one-way analysis of variance (ANOVA), and non-normally distributed variables were tested by Kruskal-Wallis. Categorical variables are expressed in counts (percentages) and percentage variable comparisons are checked by chi-square. The correlation between Neu5Ac and NT-pro-BNP and hscRP was assessed by the Pearson's or Spearman's assay based on the data distribution.
The experimental results are as follows: 1119 patients with chronic heart failure were grouped, and the demographic and clinical basic data are shown in FIG. 1. The highest group of people, older, more male, had a higher incidence of diabetes, stroke, severe cardiac symptoms (NYHA classification) and a faster heart rate, larger Left Ventricular End Diastolic Diameter (LVEDD), lower Left Ventricular Ejection Fraction (LVEF), higher N-terminal forebrain natriuretic peptide (NT-pro-BNP), higher hypersensitive C reactive protein (hsCRP), more people took digoxin, diuretic, angiotensin enzyme inhibitor, angiotensin receptor antagonist, beta receptor blocker and spironolactone (fig. 1) according to Neu5Ac level. These results suggest that high plasma Neu5Ac levels are associated with severe chronic heart failure; the correlation between Neu5Ac and NT-pro-BNP and hsCRP was analyzed and found to positively correlate Neu5Ac levels with NT-pro-BNP (r 0.408, p <0.001) and hsCRP (r 0.413, p < 0.001).
Example 2
Chronic heart failure patients with high plasma Neu5A levels have an increased risk of developing adverse cardiovascular events
And carrying out long-term follow-up on the study population. Of the five years of follow-up, only 2 (0.2%) were missed. A total of 182 (16.2%) deaths, of which 149 (13.3%) died from cardiac causes, 3 (0.30%) had heart transplants; 401 (35.8%) were hospitalized again, of which 297 (26.5%) were hospitalized for cardiac reasons; 259 people (23.1%) have recurrent heart failure.
Statistical analysis method: the median levels of Neu5Ac and clinical endpoint events were shown using a Kaplan-Meier survival curve, and a time series test (log-rank test) was used for statistical evaluation of survival curves. Hazard Ratios (HR) were evaluated using single and multi-factor Cox proportional hazards regression and 95% confidence intervals, based on Neu5Ac triage levels. The results correct for traditional risk factors including age, sex, systolic blood pressure, history of diabetes, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (LDL), history of smoking, NT-proBNP, and hscRP.
The experimental results are as follows: patients with heart failure were divided into three groups based on the Neu5Ac triage level, and Kaplan-Meier survival analysis showed that Neu5Ac levels had a clear dose-dependent relationship with the risk of developing complex primary endpoint events (cardiac death and heart transplantation) (2 rd triage: 1 st triage: uncorrected hazard ratio, 2.23; 95% CI: 1.29-3.86, p ═ 0.004; 3 rd triage: 1 st triage: uncorrected hazard ratio, 5.49, 95% CI: 3.36-9.00, p <0.001) (fig. 2 and 3). The overall cause mortality and heart failure recurrence rates were significantly higher for the 2 nd and 3 rd quantiles compared to the 1 st third quantile (overall cause mortality: 2 nd third quantile over 1 st quantile: uncorrected hazard ratio, 2.06, 95% CI: 1.25-3.38, p ═ 0.004; 3 rd third quantile over 1 st quantile: uncorrected hazard ratio, 5.35, 95% CI: 3.45-8.32, p < 0.001. heart failure recurrence: 2 nd third quantile over 1 st quantile: uncorrected hazard ratio, 1.59, 95% CI: 1.15-2.18, p ═ 0.005; 3 rd third quantile over 1 st quantile: uncorrected hazard ratio, 1.75, 95% CI: 1.28-2.39, p <0.001) (fig. 2-5).
After age and gender correction, Neu5Ac levels remained associated with adverse clinical events (cardiac death and heart transplantation: 2 rd quartile to 1 st quartile to uncorrected hazard ratio, 2.24, 95% CI: 1.29-3.88, p 0.004, 3 rd quartile to 1 st quartile to uncorrected hazard ratio, 4.87, 95% CI: 2.96-8.00, p < 0.001. heart failure rate: 2 nd quartile to 1 st quartile to uncorrected hazard ratio, 1.59, 95% CI: 1.15-2.19, p 0.005, 3 rd quartile to 1 st quartile to uncorrected hazard ratio, 1.61, 95% CI: 1.17-2.20, p 0.003) (fig. 2).
In correctedmodel 2, elevated Neu5Ac levels remained strong predictors of major end-point events and all-cause mortality for age, gender, history of diabetes, history of hypertension, history of ischemic disease, history of stroke, history of smoking, history of alcohol consumption, and cardiovascular association grade correction in heart failure, i.e., 2.75% third quantile to 1 st quantile of uncorrected hazard ratio, 2.75%, 95% CI: 1.47-5.17, p 0.002, 3 third quantile to 1 st quantile of uncorrected hazard ratio, 5.25%, 95% CI: 2.94-9.39, p <0.001, all-cause mortality, 2 third quantile to 1 st quantile of uncorrected hazard ratio, 2.46%, 95% CI: 1.41-4.27, p 0.001, 3 third quantile to 1 st quantile to 4.69, and 7.47% CI: 4.47, 7.47 to 7.47).
In correctedmodel 3, corrected age, sex, history of diabetes, history of hypertension, history of ischemic disease, history of stroke, history of smoking, history of drinking and NYHA stratification, NT-proBNP, hsCRP and digoxin, diuretics, angiotensin enzyme inhibitors, angiotensin receptor antagonists, beta blockers and spironolactone intake history, elevated Neu5Ac levels still served as adverse cardiovascular event predictors (cardiac death and heart transplantation, 2 nd quartile to 1 st quartile to uncorrected hazard ratio, 3.10; 95% CI to 1.31-7.35, p ═ 0.010; tert 3vs. tert. 1: adjusted HR, 4.06; 95% CI to 1.78-9.28; p ═ 0.001; all-cause mortality, 3 rd quartile to 1 st to uncorrected hazard ratio, 3.08; 95% CI to 1.36.007; 95% CI to 0.88: 95.86: 8: terci to 4.09; t. tert. HR, 4.09; 4.95% r. 1.6: 6: 8: terci, p <0.001) (fig. 2).
Example 3
Neu5Ac has a greater predictive value in chronic heart failure patients than traditional risk factors
498 of the study population had hsCRP records with 2 missing visits, and the present application investigated whether Neu5Ac levels could help to predict prognosis in patients with chronic heart failure and whether the addition of Neu5Ac to a statistical model could improve the predictive value of models containing both traditional predictors and hsCRP. ROC curve analysis shows that the AUC is 0.675, and Neu5Ac is a good predictor of cardiac death and heart transplantation. The Logistic regression model was used to construct a model of traditional risk factors and hsCRP with or without Neu5Ac, and the receiver-operating characteristics (ROC) curve, the Area Under (AUC), the Net Reclassification Indexes (NRI) and the integrated differentiation improvements (ids) were used to assess the prognostic power of Neu5Ac for patients with chronic heart failure. All statistical tests were performed using R software (version 3.1.4, R Core Team, Vienna, Austria) with P <0.05 considered statistically significant.
The experimental results are as follows: addition of Neu5Ac to the traditional cardiovascular risk factor and hsCRP models showed that Neu5Ac significantly improved the predictive effect on the prognosis of chronic heart failure (AUC: 0.755 with Neu5Ac versus AUC: 0.721, p ═ 0.021 without Neu5Ac model) (see figure 6).
Subjects were classified into three risk classes (0-10%, 10% -20%, > 20%) with significant improvement in reclassification for subjects (NRI: 11.5%, p ═ 0.026; IDI: 0.016, p ═ 0.053). We found that the risk of cardiac death and heart transplantation in the high Neu5Ac group was greater in the stratified study according to the levels of Neu5Ac and hscRP than in the low Neu5Ac group (low hscRP and high Neu5Ac groups hazard ratio, 2.14, 95% CI: 0.99-4.64, p ═ 0.053; high hscRP and high Neu5Ac groups hazard ratio, 3.78, 95% CI: 1.99-7.19, p < 0.001). However, the hazard ratios were not different in the low-hs crp and low Neu5Ac group and the high-hs crp and low Neu5Ac group (fig. 7).
Example 4
High Neu5Ac levels in different subgroups all increased the risk of cardiac death and heart transplantation
Subsets of the population were analyzed for Hazard Ratio (HR) to plasma Neu5Ac levels. Subgroup analysis one-way Cox risk proportional regression analysis was used, based on Neu5Ac level triage.
The results of the experiment are shown in fig. 8, with a subgroup of patients with severe heart failure (defined as age, sex, history of hypertension, history of diabetes, ischemic heart disease, history of smoking, history of alcohol consumption, LVEDD and LVEF), in different categories, a subgroup with high Neu5Ac levels and an increased risk of cardiac death and heart transplantation.
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