Prognostic value of sequential measurements of amino-terminal prohormone of B-type natriuretic peptide in ambulatory heart failure patients

BACKGROUND: We evaluated the prognostic value of sequential NT-proBNP values in ambulatory heart failure patients after discharge, investigating whether the current value or the recent percent change is more important. METHODS AND RESULTS: In 166 patients, NT-proBNP was measured at discharge from heart failure hospitalisation and three months later. The combined endpoint of death or heart failure rehospitalisation was evaluated after a maximum of 18 months or at follow-up closure. During a mean observation time of 14+/-4 months, 63 patients (38%) reached the endpoint. In multiple Cox analysis, NT-proBNP three months after discharge (NT-proBNP-3Mo) and NT-proBNP percent change (NT-proBNP-%change) were the only independent predictors of the endpoint among various clinical and laboratory variables. After definition of a high- (n=83, 57% endpoints) and a low-NT-proBNP patient subgroup (n=83, 19% endpoints) according to the median NT-proBNP-3Mo (1751 pg/ml), NT-proBNP-%change was the strongest predictor in the high-NT-proBNP subgroup. In the low-NT-proBNP subgroup, NT-proBNP-3Mo was the only independent predictor. CONCLUSIONS: In ambulatory heart failure patients, the prognostic value of sequential NT-proBNP measurements depends on the magnitude of the current NT-proBNP value. Recent percent changes in NT-proBNP provide important prognostic information in patients with high NT-proBNP but not in patients with low NT-proBNP.     

Brain and other natriuretic peptides: molecular aspects

Natriuretic peptides have emerged as important candidates for development of diagnostic tools and therapeutic agents in cardiovascular disease. The family contains of three major peptides-ANP, BNP, CNP-that participate in cardiovascular and cardiorenal homeostasis. Each of these natriuretic peptides binds differentially to specific receptors that signal through different mechanisms. They are cleared enzymatically by neutral endopeptidase as well as by receptor-mediated endocytosis. Because of its fast induction and specific expression in overt heart failure, BNP seems the most promising natriuretic peptide. It is predominantly synthesized in the cardiac ventricles, released as pre-proBNP and then enzymatically cleaved to BNP and the N-terminal portion of BNP(NT-proBNP). Blood measurements of BNP and NT-proBNP have been shown to identify patients with LV dysfunction. This review focuses on the physiology of natriuretic peptides as a group and brain natriuretic peptide in more detail, its structure and regulation as well as its effects at the cellular level.     

Natriuretic peptides in patients with atrial fibrillation and advanced chronic heart failure: determinants and prognostic value of (NT-)ANP and (NT-pro)BNP.

AIMS: To study the determinants of natriuretic peptides in advanced chronic heart failure (CHF) patients with and without atrial fibrillation (AF) and to evaluate the prognostic value of natriuretic peptides in AF compared with sinus rhythm patients with advanced CHF. METHODS AND RESULTS: The study group comprised 354 advanced CHF patients [all New York Heart Association (NYHA) III/IV], including 76 AF patients. AF patients were older (70+/-7 vs. 67+/-8; P=0.01), and non-ischaemic CHF was more common (42 vs. 19%; P=0.002) than in sinus rhythm patients, but left-ventricular ejection fraction was comparable (0.23+/-0.08 vs. 0.24+/-0.07; P=ns). At baseline, (NT-)ANP and NT-proBNP levels were significantly higher in AF patients, compared with those in sinus rhythm. By multivariate regression analysis, AF was identified as independent determinant of (NT-)ANP, but not of (NT-pro)BNP levels. After a mean follow-up of 3.2+/-0.9 (range 0.4-5.4) years, cardiovascular mortality was comparable (55 vs. 47%; P=ns). In both groups, AF and sinus rhythm, NT-proBNP [AF: adjusted HR 5.8 (1.3-25.4), P=0.02; sinus rhythm: adjusted HR 3.1 (1.7-5.7), P<0.001] was an independent risk indicator of cardiovascular mortality. CONCLUSION: In advanced CHF patients, AF affects (NT-)ANP levels, but not (NT-pro)BNP levels. NT-proBNP is an independent determinant of prognosis in advanced CHF, irrespective of the rhythm, AF, or sinus rhythm.     

Natriuretic peptides and therapeutic applications

Since the discovery of atrial natriuretic factor by de Bold et al., there has been tremendous progress in our understanding of the physiologic, diagnostic and therapeutic roles of the natriuretic peptides (NPs) in health and disease. Natriuretic peptides are endogenous hormones that are released by the heart in response to myocardial stretch and overload. Three mammalian NPs have been identified and characterized, including atrial natriuretic peptide (ANP or atrial natriuretic factor), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). In addition, Dendroaspis natriuretic peptide (DNP) has been isolated from the venom of Dendroaspis angusticeps (the green mamba snake), and urodilatin from human urine. These peptides are structurally similar and they consist of a 17-amino-acid core ring and a cysteine bridge. Both ANP and BNP bind to natriuretic peptide receptor A (NPR-A) that are expressed in the heart and other organs. Activation of NPR-A generates an increase in cyclic guanosine monophosphate, which mediates natriuresis, inhibition of renin and aldosterone, as well as vasorelaxant, anti-fibrotic, anti-hypertrophic, and lusitropic effects. The NP system thus serves as an important compensatory mechanism against neurohumoral activation in heart failure. This provides a strong rationale for the use of exogenous NPs in the management of acutely decompensated heart failure. In this article, the therapeutic applications of NPs in the acute heart failure syndromes are reviewed. Emerging therapeutic agents and areas for future research are discussed.     

慢性心力衰竭患者外周血中血浆肾素活性和利钠肽水平的变化及卡维地洛对其影响

目的　观察慢性心力衰竭 (心衰 )患者外周血中血浆肾素活性 (PRA)、心钠肽 (ANP)及脑钠肽 (N BNP)水平的变化及卡维地洛对其影响。方法　 6 0例慢性心衰患者随机分为常规治疗组 (血管紧张素转换酶抑制 +利尿剂 +地高辛 )和卡维地洛组 (常治疗药物 +卡维地洛 ) ,随访 12w ,采用放射免疫法测定二组治疗前后和 30例健康体检者 (正常对照组 )外周血中PRA、ANP、及N BNP水平。同时使用核素心室显像测定心衰患者左心室射血分数 (LVEF)。结果　心衰患者外周血中PRA、ANP及N BNP水平较正常对照组显著升高 ,其中ANP及N BNP水平在卡维地洛治疗前与LVEF负相关 ,在卡维地洛治疗后与LVEF密切相关 ,但PRA水平与LVEF无关。治疗后卡维地洛组外周血中PRA、ANP及N BNP水平较常规治疗组下降更明显。结论　外周血中ANP及N BNP水平在慢性心衰的病理生理机制中起着重要作用 ,甚至在 β受体阻滞剂治疗后仍可用于指导心衰患者的治疗。β受体阻滞剂能抑制心衰患者神经内分泌的过度激活。     

N-terminal brain natriuretic peptide is a more powerful predictor of mortality than endothelin-1, adrenomedullin and tumour necrosis factor-alpha in patients referred for consideration of cardiac transplantation

BACKGROUND: The selection of patients for cardiac transplantation is notoriously difficult. We have demonstrated that N-terminal brain natriuretic peptide (NT-proBNP) is a powerful predictor of mortality in advanced heart failure and is superior to the traditional markers of chronic heart failure (CHF) severity. However, the comparative prognostic power of endothelin-1 (Et-1), adrenomedullin (Adm) and tumour necrosis factor-alpha (TNF-alpha) in this patient group is unknown. METHODS AND RESULTS: We prospectively studied 150 consecutive patients with advanced CHF referred for consideration of cardiac transplantation. Blood samples for NT-proBNP, Et-1, Adm and TNF-alpha analysis were taken at recruitment and patients followed up for a median of 666 days. The primary endpoint of all-cause mortality was reached in 25 patients and the secondary endpoint of all-cause mortality or urgent cardiac transplantation in 29 patients. The median values for NT-proBNP, Et-1, Adm and TNF-alpha were 1494 pg/ml [interquartile range 530-3930], 0.39 fmol/ml [0.10-1.24], 94 pg/ml [54-207] and 2.0 pg/ml [0-18.5] respectively. The only univariate and multivariate predictor of all-cause mortality (chi(2)=26.95, p<0.0001), or the secondary endpoint of all-cause mortality or urgent transplantation (chi(2)=31.23, p<0.0001), was an NT-proBNP concentration above the median value. CONCLUSION: A single measurement of NT-proBNP in patients with advanced CHF can help identify patients at the highest risk of death, and is a better prognostic marker than Et-1, Adm and TNF-alpha.     

Diagnostic value of a rapid test for B-type natriuretic peptide in patients presenting with acute dyspnoe: effect of age and gender

BACKGROUND: B-type natriuretic peptide (BNP) measurements are useful for diagnosing congestive heart failure (CHF) in patients presenting to the Emergency Department with acute dyspnoe. Whether the diagnostic accuracy of BNP is affected by the age and gender of the patients remains unknown. AIMS: To evaluate the accuracy of BNP testing for diagnosing CHF in an unselected group of patients admitted to the emergency department of a Norwegian teaching hospital with a principal complaint of shortness of breath and to assess whether the diagnostic accuracy of the test differs according to age and gender. METHODS: BNP levels in plasma were determined by a point-of-care device upon arrival in 155 patients presenting with acute dyspnoe. The diagnostic 'gold' standard for CHF was adjudicated by two independent cardiologists who were blinded to the BNP data. RESULTS: By univariate logistic regression analysis, BNP was strongly related to a diagnosis of CHF. In a multivariate model BNP provided additional prognostic information to patient age and gender, radiographic evidence of pulmonary congestion and cardiomegaly, and the presence of pulmonary rales and jugular vein distention by physical examination. There was no significant interaction between age and BNP or between gender and BNP with regard to the accuracy of diagnosing CHF. The area under the receiver-operating characteristics-curve was 0.86 (95% confidence interval 0.78-0.93) in women and 0.90 (0.82-0.97) in men. The area under the curves were 0.82 (0.73-0.92) and 0.88 (0.80-0.97) for patients (both genders) aged > or = 76 and <76 years, respectively. CONCLUSION: Point-of-care BNP measurement in the emergency department discriminates well between patients with dyspnoe of cardiac and non-cardiac origin regardless of age and gender.     

Diagnosis of elderly patients with heart failure

The prevalence and mortality of heart failure (HF) increase with age. As a result, the early diagnosis of HF in this population is useful to reduce cardiovascular morbidity and probably mortality. However, the diagnosis of HF in the elderly is a challenge. These challenges arise from the under-representation of elderly patients in diagnostic studies and clinical trials, the increasing prevalence of HF with relatively normal ejection fraction, the difficulty in accurate diagnosis, the underuse of diagnostic tests, and the presence of co-morbidities. Particularly in the elderly, symptoms and signs of HF may be atypical and can be simulated or disguised by co-morbidities such as respiratory disease, obesity, and venous insufficiency. This review aims to provide a practical clinical approach for the diagnosis of older patients with HF based on the scarce available evidence and our clinical experience. Therefore, it should be interpreted in many aspects as an opinion paper with practical implications. The most useful clinical symptoms are orthopnoea and paroxysmal nocturnal dyspnoea. However, confirmation of the diagnosis always requires further tests. Although natriuretic peptides accurately exclude cardiac dysfunction as a cause of symptoms, the optimal cut-off level for ruling out HF in elderly patients with other co-morbidities is still not clear. In our opinion, echocardiography should be performed in all elderly patients to confirm the diagnosis of HF, except in those cases with low clinical probability and a concentration of brain natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) lower than 100 or 400 pg/mL, respectively.     

快速测定脑利钠肽预测充血性心力衰竭患者预后的价值

目的　探讨快速测定脑利钠肽预测充血性心力衰竭近期预后的价值。方法　 70例充血性心力衰竭住院患者 ,NYHA心功能Ⅲ级 3 7例、Ⅳ级 3 3例。入院时、出院前或临终前 2 4小时内分别测定血浆BNP ,分析住院治疗前后BNP水平变化与心源性死亡、3 0天内再住院事件的关系。结果　 2 3例患者出现终点事件 (因心功能恶化死亡 6例、再住院 17例 ) ,其入院时BNP水平 ( 15 16pg/ml± 872pg/ml)高于未发生临床终点者 ( 10 3 7pg/ml± 65 4pg/ml) ,P <0 .0 1;发生临床终点者住院期间BNP升高 3 18pg/ml ,而未发生终点事件的患者 ,住院期间BNP平均降低 3 5 9pg/ml ,P <0 .0 1;BNP升高组患者发生临床终点 68.2 % ,BNP降低组患者发生临床终点 16.7% ,P <0 .0 0 5。结论　BNP水平可预测失代偿充血性心力衰竭患者的近期预后     

NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study.

AIMS: Experience with amino-terminal pro-brain natriuretic peptide (NT-proBNP) testing for evaluation of dyspnoeic patients with suspected acute heart failure (HF) is limited to single-centre studies. We wished to establish broader standards for NT-proBNP testing in a study involving four sites in three continents. METHODS AND RESULTS: Differences in NT-proBNP levels among 1256 patients with and without acute HF and the relationship between NT-proBNP levels and HF symptoms were examined. Optimal cut-points for diagnosis and prognosis were identified and verified using bootstrapping and multi-variable logistic regression techniques. Seven hundred and twenty subjects (57.3%) had acute HF, whose median NT-proBNP was considerably higher than those without (4639 vs. 108 pg/mL, P<0.001), and levels of NT-proBNP correlated with HF symptom severity (P=0.008). An optimal strategy to identify acute HF was to use age-related cut-points of 450, 900, and 1800 pg/mL for ages <50, 50-75, and >75, which yielded 90% sensitivity and 84% specificity for acute HF. An age-independent cut-point of 300 pg/mL had 98% negative predictive value to exclude acute HF. Among those with acute HF, a presenting NT-proBNP concentration >5180 pg/mL was strongly predictive of death by 76 days [odds ratio=5.2, 95% confidence interval (CI)=2.2-8.1, P<0.001]. CONCLUSION: In this multi-centre, international study, NT-proBNP testing was valuable for diagnostic evaluation and short-term prognosis estimation in dyspnoeic subjects with suspected or confirmed acute HF and should establish broader standards for use of the NT-proBNP in dyspnoeic patients.     

Nonheart failure-associated elevation of amino terminal pro-brain natriuretic peptide in the setting of sepsis

In addition to its importance in clinical assessment, N-terminal pro-brain natriuretic peptide (NT pro-BNP) is a valuable marker for evaluation of treatment and prognosis of heart failure. However, there are situations where NT pro-BNP is not related to myocardial dysfunction. Two cases of sepsis with markedly elevated NT pro-BNP levels that are not indicative of depressed myocardial function are described.     

A direct comparison of the natriuretic peptides and their relationship to survival in chronic heart failure of a presumed non-ischaemic origin

The natriuretic peptides have been validated as sensitive and specific markers of left ventricular dysfunction; brain natriuretic peptide (BNP), N-terminal atrial natriuretic peptide (NT-proANP) and N-terminal brain natriuretic peptide (NT-proBNP) elevations have been associated with New York Heart Association (NYHA) Class I-IV heart failure. We directly compared the association of each of these markers with 1-year survival in 173 patients with chronic heart failure of a presumed nonischaemic origin entering the PRAISE-2 Trial, a clinical study which assessed the therapeutic effect of Amlodipine in patients with NYHA Class III and IV heart failure and a left ventricular ejection fraction (LVEF) <30%. BNP, NT-proBNP, and NT-proANP levels were all correlated with 1-year mortality by univariate Cox proportional hazards analyses. With respect to multivariate Cox proportional hazards regression models containing variables deemed significant in univariate analyses, NT-proANP alone was identified as an independent predictor of 1-year mortality when log-transformed continuous covariates were utilized in the analysis. When the analysis was repeated using dichotomous covariates, NT-proANP remained the most significant predictor of 1-year mortality, followed by NT-proBNP, NYHA classification and BNP. We conclude that all three natriuretic peptides are significant predictors of short-term mortality in subjects with chronic congestive heart failure (CHF) of a presumed nonischaemic origin. Larger prospective studies are required to validate the clinical utility of NT-proANP as a discriminating marker of short-term survival, and to validate proposed cutoffs of approximately 2300 pmol/l for NT-proANP, 1500 pg/ml for NT-proBNP, and 50 pmol/l for BNP as prognostic indicators of adverse short-term outcome.     

Pre-discharge B-type natriuretic peptide predicts early recurrence of decompensated heart failure in patients admitted to a general medical unit

BACKGROUND: B-type natriuretic peptide (BNP) represents a promising predictor of early (30 days) re-admission in patients with heart failure (HF) admitted to cardiology units. Whether BNP retains its predictive value in unselected patients admitted to general medical wards is unknown. METHODS: We determined BNP levels on admission and pre-discharge in 100 consecutive patients (71 male, mean age 78+/-10 years) admitted to a general medical unit due to decompensated HF. Follow-up after discharge was 30 days. RESULTS: Of the 100 patients, 86 had >/=1 comorbid conditions. Median BNP was 739 pg/ml on admission (25th-75th percentile 355-1333 pg/ml, respectively), and 414 pg/ml pre-discharge (25th-75th percentile 220-696 pg/ml). Seventeen patients were re-admitted or died within 30 days. Patients with pre-discharge BNP values >75th percentile (696 pg/ml) had greater risk of re-hospitalisation, as compared to values 75th percentile were associated with a 15.0 independent relative hazard (RH) of early re-admission or death (95% CI 4.2-53.8; p<0.0001). The other independent predictor was a NYHA class >/=III at discharge (RH 2.9; 95% CI 1.1-9.3; p<0.05). CONCLUSION: In a general medical unit, pre-discharge BNP levels were a strong independent predictor of early re-admission or death due to HF, irrespective of substantial comorbidity and advanced age.     

Elevated N-terminal pro-brain natriuretic peptide in Mycobacterium tuberculosis pulmonary infection without myocardial dysfunction

Increased levels of N-terminal pro-brain natriuretic peptide (NT pro-BNP) in infectious settings may not reflect myocardial depression. In addition to NT pro-BNP measurement, clinical assessment remains a valuable tool for diagnosis and prognosis of heart failure. A case of excessively increased NT pro-BNP level associated with Mycobacterium tuberculosis infection that was not indicative of myocardial dysfunction is described.     

慢性心力衰竭患者血浆利钠肽水平的变化

目的 :研究慢性心力衰竭 (CHF)患者血浆利钠肽 (ANP、BNP、CNP)水平的变化及其与心功能状态、心脏结构的关系 ,探讨其用于CHF诊断的价值。方法 :4 8例CHF患者为心力衰竭组 ,心功能按HYHA标准分级 :Ⅱ级 15例 ,Ⅲ级 2 4例 ,Ⅳ级 9例 ,基本病因为冠心病、扩张型心肌病、高血压性心脏病 ;对照组 10例 ,为健康体检者。用同位素放射免疫法和免疫放射法测定血浆ANP、BNP、CNP水平 ,心脏彩色多普勒超声诊断仪测量左室结构和功能。结果 :心力衰竭组血浆ANP、BNP水平均较对照组显著增高(P均 <0 0 1) ,并与心功能严重程度有关 ,但不同病因的CHF患者之间血浆ANP、BNP、CNP水平均无明显差异 (P均 >0 0 5 )。其中LVEF <4 5 %的患者 4 1例 ,其血浆BNP水平和LVEF负相关 (r=- 0 37,P <0 0 5 ) ,和左室舒张末期内径 (LVEDD)、左室心肌重量指数 (LVMI)呈正相关 (r均为 0 36 ,P均 <0 0 5 ) ,血浆ANP、BNP水平和肺动脉收缩压正相关 (P <0 0 5或P <0 0 1)。血浆CNP水平在CHF患者无明显升高 (P >0 0 5 )。结论 :血浆ANP、BNP水平可作为反映心功能状态的指标 ,其中血浆BNP水平更为敏感、特异并且和心脏结构相关 ,可作为CHF诊断及鉴别诊断的指标