The clearance of BNP modeled using the NT-proBNP-BNP relationship

BACKGROUND: The ventricular myocardium simultaneously secretes two natriuretic peptides useful in the evaluation of heart failure: BNP, hormonally active, and NT-proBNP, the N-terminal end, non-hormonally active, but ultimately their concentrations differ and their clearance patterns are poorly defined. METHODS: We measured NT-proBNP and BNP in patients with and without heart failure and compared their concentrations using regression analysis. RESULTS: The relationship between NT-proBNP with BNP is nonlinear. Between 45 and 70 pmol of BNP/L (class II heart failure) the slope is much higher than in other ranges and the NT-proBNP/BNP ratio reaches its maximum in patients with class II NYHA heart failure. CONCLUSIONS: The difference in concentration for NT-proBNP and BNP can be related to the diffusion across the renal basement membrane. Their ratio is nonlinear because BNP is cleared faster than in patients with class II heart failure than other classes or normal, suggesting a change in a non-renal mode of clearance.     

利钠肽在急性心力衰竭预后评估及指导治疗中的作用

利钠肽(BNP与NT-proBNP)是预测急性心衰预后及评估急性心衰治疗效果可靠的指标.日常临床决策加用利钠肽检测提高了急性心衰高危患者的发现率,而这些患者往往需要加强追踪及强化治疗.现就利钠肽在评估急性心衰预后及指导心衰治疗中的价值作如下综述.     

Impact of glomerular filtration rate on urinary BNP and NT-proBNP levels in heart failure

B-type natriuretic peptide (BNP) and its inactive amino-terminal fragment (NT-proBNP) are diagnostic tools for heart failure (HF), but less is understood regarding the effects of renal function on their urinary concentrations. The objective was to analyze the influence of renal function, as estimated glomerular filtration rate (eGFR), on BNP and NT-proBNP concentrations in 90 HF outpatients (65 ± 12 years; 73% men), grouped according to eGFR below or above 60 mL/min. Patients with worse eGFR had higher serum NT-proBNP (p < 0.01) and BNP (p < 0.01) than patients with higher eGFR: NT-proBNP, but urinary levels did not reach statistical differences. In addition, a direct significant correlation between filtered load of serum NT-proBNP or BNP with their concentrations in urine was found in patients with eGFR above 60 mL/min (r = 0.66, p < 0.001 and r = 0.338, p < 0.05) and below 60 mL/min (r = 0.63, p < 0.001 and r = 0.406, p < 0.01). However, after normalizing urinary natriuretic peptide concentrations by their filtered load, we obtained a significant inverse and exponential relation in patients with worse renal function for NT-proBNP and BNP (r = -0.87, p = 0.001; and r = -0.71, p < 0.001, respectively) and in patients with eGFR>60 mL/min (r = -0.84, p < 0.001; and r = -0.72, p < 0.001, respectively). In conclusion, similar urinary NT-proBNP and BNP excretion was obtained in patients with high or low eGFR. Furthermore, despite the direct correlation between filtered load of serum natriuretic peptides with their urinary levels, an inverse an exponential relationship was obtained after normalizing urinary concentrations. Therefore, glomerular filtration does not seem to be the major determinant of both urinary peptide concentrations.     

Natriuretic peptides - physiology, pathophysiology and clinical use in heart failure

The natriuretic peptides - atrial, brain and C-type - were discovered during the last twenty years. Their effects on cardiovascular, renal, cerebral and other tissues through guanylyl cyclase were uncovered. Over the past decade natriuretic peptides (NPs) became a very useful tool in the management of heart failure patients. Results of many clinical trials have shown that BNP and NT-proBNP are helpful for diagnosis of heart failure. They are also independent markers of prognosis not only in heart failure patients but also in patients with other cardiovascular diseases. Recently published data document the utility of NPs in guiding treatment of heart failure patients. In this article, we focus on basic biochemical and physiological characteristics of NPs as well as on their significance in management of heart failure patients. Some limitations and pitfalls of NPs levels interpretation in diagnosing heart failure are also discussed.     

Intérêt du dosage des peptides natriurétiques en urgence dans la dyspnée aiguë

Acute dyspnea often leads to an emergency room visit. B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) are natriuretic peptide factors secreted by ventricular myocytes when pressure is exerted on the ventricular wall. BNP fights against the activation of the renin-angiotensin-aldosterone system, while NT-proBNP exhibits no activity in this regard. Elevated blood levels of these factors correlate with a variety of functional indices for left-sided heart failure. Several studies have demonstrated their usefulness as markers of left-sided heart failure, the main cause of acute dyspnea seen in emergency rooms. The diagnostic performance of BNP and NT-proBNP appears to be identical; it is, however, greater than that of the emergency room physician. BNP and NT-proBNP have high sensitivity and specificity in the diagnosis of acute heart failure. Briefly, when BNP is less than 100 pg/ml, heart failure is very unlikely (NT-proBNP <500 pg/ml); when it is greater than 400 pg/ml (NT-proBNP >2000 pg/ml); when it is greater than 400 pg/ml (NT-proBNP >2000 pg/ml), it is very likely. The early measurement of BNP in emergency room situations improves the care of patients presenting with acute dyspnea and makes it possible to reduce hospitalisation costs.     

NT-proBNP and BNP values in cardiac patients with different degree of left ventricular systolic dysfunction

We investigated the performance of brain natriuretic peptides (BNP and NT-proBNP) in detecting various degrees of left ventricular systolic dysfunction. The NT-proBNP assay (Roche) and the BNP assay (Bayer Shionoria) were performed in 46 patients (mean age 50 years; range 20-79 years) with various types of heart disease (chronic heart failure due to coronary artery disease, cardiomyopathy, acquired valve disease, congenital heart diseases) and different impairment of left ventricular systolic dysfunction was assessed by echocardiography. Patients were divided into four groups according to the left ventricular ejection fraction (LVEF) correlated with clinical severity. Significant differences in medians of NT-proBNP and BNP values between all groups were determined (P= 0.0161 for NT-proBNP and P=0.0180 for BNP). For identifying patients with severe systolic dysfunction (LVEF<40%), receiver operating characteristic (ROC) analysis for both BNP and NT-proBNP was performed. The diagnostic performances expressed as areas under the curve were of 0.69 for NT-proBNP (cut off value 367 pg/ml) and 0.60 for BNP (cut off value 172 pg/ml). However, the BNP showed higher sensitivity (85 % vs. 63 %) and a higher positive predictive value (69 % vs 55 %) than the NT-proBNP. The negative predictive values of BNP and NT-proBNP were similar (70 % and 71 % respectively). Brain natriuretic peptides are promising markers for the diagnosis of severe left ventricular systolic dysfunction.     

The value of (NT-pro) BNP in the diagnosis,prognosis and treatment of congestive heart failure

Congestive heart failure constitutes one of the major causes of morbidity and mortality in Western countries. However, it is often misdiagnosed and the validity of the diagnosis is often difficult to establish. The clinical signs are not very sensitive and symptoms are nonspecific. Secretion of natriuretic peptides is increased in situations of cardiac overload. Testing the levels of these peptides, especially BNP and NT-proBNP, appears to offer a significant advance in the diagnosis and treatment of heart failure. In this article we would like to discuss the value of natriuretic peptides in congestive heart failure and give a short review of the literature.     

Kidneys extract BNP and NT-proBNP in healthy young men.

Renal metabolism of the cardiac marker NH2-terminal-pro-brain natriuretic peptide (NT-proBNP) has been suggested. Therefore, we determined the renal extraction ratios of NT-proBNP and its bioactive coproduct brain natriuretic peptide (BNP) at rest and during exercise. In addition, the cerebral ratios were evaluated. Ten young healthy men were investigated at baseline, during moderate cycle exercise (heart rate: 140, Borg scale: 14-15), and in the recovery with BNP and NT-proBNP measured from the brachial artery and the jugular and renal veins, and the renal and cerebral extraction ratios (Ext-Ren and Ext-Cer, respectively) were calculated. Cardiac output, stroke volume, heart rate, mean arterial pressures, and estimated glomerular filtration were determined. BNP and NT-proBNP were extracted by the kidneys but not by the brain. We observed no effect of exercise. The mean values (+/- SE) of Ext-Ren of NT-proBNP were similar (0.19 +/- 0.05, 0.21 +/- 0.06, and 0.12 +/- 0.03, respectively) during the three sessions (P > 0.05). Also the Ext-Ren of BNP were similar (0.18 +/- 0.07, 0.15 +/- 0.11, and 0.14 +/- 0.06, respectively; P > 0.05). There were no significant differences between Ext-Ren of BNP and NT-proBNP during the three sessions (P > 0.05). The Ext-Cer of both peptides varied insignificantly between -0.21 +/- 0.15 and 0.11 +/- 0.08. The renal extraction ratio of both BNP and NT-proBNP is approximately 0.15-0.20. There is no cerebral extraction, and short-term moderate exercise does not affect these values. Our findings suggest that the kidneys extract BNP and NT-proBNP to a similar extent in healthy young men.     

Novel bifunctional natriuretic peptides as potential therapeutics

Synthetic atrial natriuretic peptide (carperitide) and B-type natriuretic peptide (BNP; nesiritide) are used to treat congestive heart failure. However, despite beneficial cardiac unloading properties, reductions in renal perfusion pressures limit their clinical effectiveness. Recently, CD-NP, a chimeric peptide composed of C-type natriuretic peptide (CNP) fused to the C-terminal tail of Dendroaspis natriuretic peptide (DNP), was shown to be more glomerular filtration rate-enhancing than BNP in dogs. However, the molecular basis for the increased responsiveness was not determined. Here, we show that the DNP tail has a striking effect on CNP, converting it from a non-agonist to a partial agonist of natriuretic peptide receptor (NPR)-A while maintaining the ability to activate NPR-B. This effect is specific for human receptors because CD-NP was only a slightly better activator of rat NPR-A due to the promiscuous nature of CNP in this species. Interesting, the DNP tail alone had no effect on any NPR even though it is effective in vivo. To further increase the potency of CD-NP for NPR-A, we converted two different triplet sequences within the CNP ring to their corresponding residues in BNP. Both variants demonstrated increased affinity and full agonist activity for NPR-A, whereas one was as potent as any NPR-A activator known. In contrast to a previous report, we found that DNP binds the natriuretic peptide clearance receptor (NPR-C). However, none of the chimeric peptides bound NPR-C with significantly higher affinity than endogenous ligands. We suggest that bifunctional chimeric peptides represent a new generation of natriuretic peptide therapeutics.     

A glycosylated form of the human cardiac hormone pro B-type natriuretic peptide is an intrinsically unstructured monomeric protein

The N-terminal fragment of pro B-type natriuretic peptide (NT-proBNP) and proBNP are used as gold standard clinical markers of myocardial dysfunction such as cardiac hypertrophy and left ventricle heart failure. The actual circulating molecular forms of these peptides have been the subject of intense investigation particularly since these analytes are measured in clinical assays. Conflicting data has been reported and no firm consensus on the exact nature of the molecular species exists. Because these clinical assays are immunoassay-based, specific epitopes are detected. It is conceivable then that certain epitopes may be masked and therefore unavailable for antibody binding, thus the importance of determining the nature of the circulating molecular forms of these analytes. This situation is an unavoidable Achilles’ heel of immunoassays in general.A recombinant O-linked glycosylated form of proBNP has been show to mimic some of the properties of extracted plasma from a heart failure patient. In particular the recombinant and native material co-migrated as diffuse Western-immunostained bands on SDS-PAGE and each band collapsed to an apparent homogeneous band following deglycosylation. Thus, glycosylated-proBNP may be one such circulating form. Here we provide extensive physiochemical characterization for this O-linked protein and compare these results to other described circulating species, non-glycosylated-proBNP and NT-proBNP. It will be shown that glycosylation has no influence on the secondary and quaternary structure of proBNP. In fact, at moderate concentration in benign physiological neutral pH buffer, all three likely circulating species are essentially devoid of major secondary structure, i.e., are intrinsically unstructured proteins (IUPs). Furthermore, all three proteins exist as monomers in solution. These results may have important implications in the design of NT-proBNP/BNP immunoassays.     

Natriuretic peptides: their role in diagnosis and therapy

Cardiac natriuretic peptide hormones, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), are synthesized and secreted by the heart, producing several biological effects, such as natriuresis, vasorelaxation and hypotension. During the last decade these peptides, especially BNP, have received increasing attention as potential markers of cardiovascular disease. Their measurements can be used to diagnose heart failure, including diastolic dysfunction, and using them has been shown to save money. BNP levels can enable the differentiation between dyspnoic patients secondary to ventricular dysfunction and subjects with primary respiratory disorders. Moreover, there is good evidence that natriuretic peptides may have a diagnostic role in arterial hypertension, acute coronary syndromes, pulmonary hypertension, some valvular heart disease and some disorders affecting other systems (diabetes or thyroid disorders). In this paper we discuss the clinical utility of assessment of natriuretic peptide hormones in the diagnosis of various clinical conditions and their use as pharmacological agents.     

N 端脑钠肽前体在心血管疾病中的研究进展

N端脑钠肽前体(NT-proBNP)为脑钠肽(BNP)生成过程中产生的无活性肽段残片,其与BNP等摩尔量分泌。近年来,NT-proBNP的检测在心血管领域的作用越来越得到国内外学者的关注。NT-proBNP在心血管疾病的诊断、预后、分级等方面都具有重要的价值。本文主要介绍NT-proBNP在心血管疾病中的研究进展。     

N端脑钠肽前体在心血管疾病中的研究进展

N端脑钠肽前体（NT-proBNP）为脑钠肽（BNP）生成过程中产生的无活性肽段残片,其与BNP等摩尔量分泌。近年来,NT-proBNP的检测在心血管领域的作用越来越得到国内外学者的关注。NT-proBNP在心血管疾病的诊断、预后、分级等方面都具有重要的价值。本文主要介绍NT-proBNP在心血管疾病中的研究进展。     

BNP及NT-proBNP与2型糖尿病关系的研究进展

BNP及NT-proBNP是诊断心衰的重要指标。近年来BNP及NT-proBNP与2型糖尿病关系的研究有了新的进展。我们收集近年来国内外关于2型糖尿病中BNP及NT-proBNP的相关文献并进行研究。结果显示2型糖尿病合并冠心病、高血压、糖尿病肾病患者BNP或NT-proBNP有升高趋势。单纯2型糖尿病及糖尿病视网膜病变患者以及低血糖患者BNP或NT-proBNP差异无统计学意义。高血压、年龄、性别、体重指数、肾功能及心脏结构功能改变是2型糖尿病患者BNP及NT-proBNP的影响因素。降糖药物对2型糖尿病患者BNP及NT-proBNP水平的研究尚少,糖尿病病程、FPG以及HbA1c对BNP及NT-proBNP的影响尚存在争议。BNP及NT-proBNP升高对2型糖尿病合并冠心病、高血压、糖尿病肾病患者病情评估,预后判断及诊治具有非常重要的意义。降糖药物、糖尿病病程、FPG以及HbA1c对BNP及NT-proBNP的影响需要进一步研究。     

利钠肽家族基因与心血管疾病研究新进展

利钠肽家族是一组由心肌细胞分泌的激素, 主要包括A型、B型和C型利钠肽, 具有相似的基因结构和生理学效应, 可对心血管系统产生血压调节、抗心肌肥厚、抗心肌纤维化和抗心肌弛缓等保护作用。利钠肽受体A、B和C亦介导多种生理活性, 调节心血管稳态。利钠肽受体A选择性结合A型、B型利钠肽。利钠肽受体B结合C型利钠肽。利钠肽受体C结合各型利钠肽, 通过受体介导的内化和退化作用清除血液循环中利钠肽。对利钠肽家族及其受体基因单核甘酸多态性及功能研究显示, 其与多种心血管疾病(房颤、高血压、心力衰竭等)的易感性相关。利钠肽家族及其受体基因缺失的转基因小鼠表现为心肌肥厚、心肌纤维化, 与高血压、心肌病及心力衰竭的发生发展相关。各种导致心肌肥厚和缺血性损伤的刺激均参与利钠肽及其受体基因的表达调控。临床将脑钠肽作为左室功能障碍和心力衰竭失代偿的一个预测指标。静脉注射重组脑钠肽已经成为治疗急性心力衰竭的有效手段。深入了解利钠肽家族基因变异及其信号调控有助于探索心血管疾病的病理生理机制, 为临床诊疗开辟新思路。     

Diagnostic Accuracy of Natriuretic Peptides for Heart Failure in Patients with Pleural Effusion: A Systematic Review and Updated Meta-Analysis

Background

Previous studies have reported that natriuretic peptides in the blood and pleural fluid (PF) are effective diagnostic markers for heart failure (HF). These natriuretic peptides include N-terminal pro-brain natriuretic peptide (NT-proBNP), brain natriuretic peptide (BNP), and midregion pro-atrial natriuretic peptide (MR-proANP). This systematic review and meta-analysis evaluates the diagnostic accuracy of blood and PF natriuretic peptides for HF in patients with pleural effusion.

Methods

PubMed and EMBASE databases were searched to identify articles published in English that investigated the diagnostic accuracy of BNP, NT-proBNP, and MR-proANP for HF. The last search was performed on 9 October 2014. The quality of the eligible studies was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies tool. The diagnostic performance characteristics (sensitivity, specificity, and other measures of accuracy) were pooled and examined using a bivariate model.

Results

In total, 14 studies were included in the meta-analysis, including 12 studies reporting the diagnostic accuracy of PF NT-proBNP and 4 studies evaluating blood NT-proBNP. The summary estimates of PF NT-proBNP for HF had a diagnostic sensitivity of 0.94 (95% confidence interval [CI]: 0.90–0.96), specificity of 0.91 (95% CI: 0.86–0.95), positive likelihood ratio of 10.9 (95% CI: 6.4–18.6), negative likelihood ratio of 0.07 (95% CI: 0.04–0.12), and diagnostic odds ratio of 157 (95% CI: 57–430). The overall sensitivity of blood NT-proBNP for diagnosis of HF was 0.92 (95% CI: 0.86–0.95), with a specificity of 0.88 (95% CI: 0.77–0.94), positive likelihood ratio of 7.8 (95% CI: 3.7–16.3), negative likelihood ratio of 0.10 (95% CI: 0.06–0.16), and diagnostic odds ratio of 81 (95% CI: 27–241). The diagnostic accuracy of PF MR-proANP and blood and PF BNP was not analyzed due to the small number of related studies.

Conclusions

BNP, NT-proBNP, and MR-proANP, either in blood or PF, are effective tools for diagnosis of HF. Additional studies are needed to rigorously evaluate the diagnostic accuracy of PF and blood MR-proANP and BNP for the diagnosis of HF.     

Atrial natriuretic peptides in heart failure: pathophysiological significance, diagnostic and prognostic value

Neurohormonal activation in patients with heart failure is dominated by the deleterious long-term effects of activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. The natriuretic peptides, including brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP), are also upregulated in heart failure, and partially counteract these deleterious effects by promoting vasodilation, natriuresis, and diuresis. Although BNP has been established as an important biomarker in the diagnosis and prognosis of heart failure, growing evidence suggests that measurement of plasma ANP, specifically its metabolite mid-regional pro-ANP, has similar diagnostic and prognostic value. Furthermore, its measurement may provide incremental diagnostic value when BNP levels fall into "grey zone" levels and may be a more potent prognostic marker of mortality.     

利钠肽家族基因与心血管疾病研究新进展

利钠肽家族是一组由心肌细胞分泌的激素,主要包括A型、B型和C型利钠肽,具有相似的基因结构和生理学效应,可对心血管系统产生血压调节、抗心肌肥厚、抗心肌纤维化和抗心肌弛缓等保护作用。利钠肽受体A、B和C亦介导多种生理活性,调节心血管稳态。利钠肽受体A选择性结合A型、B型利钠肽。利钠肽受体B结合C型利钠肽。利钠肽受体C结合各型利钠肽,通过受体介导的内化和退化作用清除血液循环中利钠肽。对利钠肽家族及其受体基因单核甘酸多态性及功能研究显示,其与多种心血管疾病(房颤、高血压、心力衰竭等)的易感性相关。利钠肽家族及其受体基因缺失的转基因小鼠表现为心肌肥厚、心肌纤维化,与高血压、心肌病及心力衰竭的发生发展相关。各种导致心肌肥厚和缺血性损伤的刺激均参与利钠肽及其受体基因的表达调控。临床将脑钠肽作为左室功能障碍和心力衰竭失代偿的一个预测指标。静脉注射重组脑钠肽已经成为治疗急性心力衰竭的有效手段。深入了解利钠肽家族基因变异及其信号调控有助于探索心血管疾病的病理生理机制,为临床诊疗开辟新思路。     

N末端脑钠肽前体在围冠状动脉搭桥术期的变化及意义

N-末端脑钠肽前体(N-terminal pro brain natriuretic peptide,NT-proBNP)是体内脑钠肽前体(proBNP)裂解成脑钠肽(brain natriuretic peptide,BNP)时的产物,NT-proBNP的血浆浓度及稳定性比BNP更高,半衰期更长,属于钠尿肽系统的重要一员,本身无生物学活性。NT-proBNP主要由正常的心肌细胞合成和分泌,在心肌损伤或坏死后迅速升高,可反映机体代偿病理改变和恢复循环的能力,是心功能障碍性疾病,如心力衰竭、左室肥厚等诊断、疗效监测和预后评估等最佳的心肌标志物,临床通过测定血浆NT-proBNP水平用于急慢性充血性心力衰竭(congestive heart failure,CHF)的诊治及预后,本文主要就NT-proBNP在围冠状动脉搭桥术(Coronary Artery Bypass Grafting,CABG)期的变化及临床意义的新进展进行综述。     

The precursor to B-type natriuretic peptide is an O-linked glycoprotein

Human pro-B-type natriuretic peptide (proBNP), the precursor for B-type natriuretic peptide (BNP), was expressed in Chinese hamster ovary cells (CHO) and compared by Western blot analysis to BNP cross-reacting material immunoprecipitated from the plasma of heart failure patients. Both recombinant and native forms co-migrated as a diffuse band centered around 25 kDa and were reduced to a 12 kDa species by treatment with a mixture of O-link deglycosylation enzymes. The 108-amino acid CHO-expressed protein was examined by tryptic mapping and LC-MS and found to be an O-linked glycoprotein. Determination of the sites of O-glycosyl addition by blank cycle sequencing of tryptic and Glu-C (Staphylococcus aureus V8 protease) peptides showed that there are seven sites of glycosylation confined to a 36-amino acid residue stretch within the center of the propeptide region. This data is consistent with previous observations of higher molecular weight isoforms of BNP.