N-terminal brain natriuretic peptide in scleroderma-associated pulmonary arterial hypertension.

We read with great interest the report by Williams et al.¹ regardingN-TproBNP levels in patients with scleroderma-associated pulmonaryarterial hypertension (SSc-PAH). In studying a large cohortof scleroderma patients, the authors found that     

Pulmonary arterial brain natriuretic peptide concentration and cardiopulmonary hemodynamics during exercise in patients with essential hypertension

Brain natriuretic peptide (BNP) is secreted through the coronary sinus of the human heart. The purpose of this study was to determine whether BNP secretion from the heart is stimulated by exercise and to examine the relationship between pulmonary arterial BNP concentrations and hemodynamic measurements, especially cardiopulmonary hemodynamics, during exercise in patients with essential hypertension. The exercise protocol consisted of three fixed workloads (25, 50, 75 W) on a bicycle ergometer in the supine position. The mean pulmonary arterial BNP level at rest was 14.8 +/- 4.1 pg/mL, and BNP values gradually increased with higher stages of exercise. At the maximum exercise stage, the BNP value increased to 40.9 +/- 6.5 pg/mL. Close correlations of pulmonary arterial pressure (PAP) and pulmonary arterial wedge pressure (PAWP) with pulmonary arterial BNP level were observed at four points at rest and during each stage of exercise. In contrast, heart rate, mean blood pressure, cardiac index (CI), and stroke index (SI) were not correlated with BNP values. Results suggest that cardiac secretion of BNP was increased during exercise in essential hypertensive subjects, and the observed increase of BNP may be related to elevated PAP and PAWP. The enhancement of BNP secretion during exercise in these patients may reflect increased redistribution of blood to the cardiopulmonary compartment.     

N-terminal brain natriuretic peptide in scleroderma-associated pulmonary arterial hypertension: reply

We read with interest the comments of Mathai and Hassoun, andagree that caution is required in using an NTproBNP level of     

Characterization of brain natriuretic peptide in long-term follow-up of pulmonary arterial hypertension

STUDY OBJECTIVES: Pulmonary arterial hypertension (PAH) leads to substantial morbidity and mortality. Noninvasive parameters in the follow-up assessment of PAH could be helpful in clinical decision making. The brain natriuretic peptide (BNP) has been shown to correlate with the functional status and prognosis of these patients and could be a valuable parameter in this respect. The aim of our study was to investigate whether BNP levels could reflect clinical and hemodynamic changes, including the response to therapy during long-term follow-up in patients with PAH. STUDY DESIGN: We measured pulmonary hemodynamics, functional parameters including the 6-min walk distance (6MWD), and plasma BNP levels at baseline and after a mean (+/- SEM) follow-up period of 12.6 +/- 1.5 months in patients with PAH. RESULTS: In group A (n = 18), with decreasing BNP levels mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) decreased (PAP, 60.89 +/- 3.44 to 53.47 +/- 3.24 mm Hg; PVR, 1,207.47 +/- 111.75 to 942.35 +/- 103.15 dyne.s.cm(-5); p < 0.01) and 6MWD increased (408.24 +/- 29.57 to 470 +/- 25.54 m; p < 0.01). In group B (n = 12), with increasing BNP levels mean PAP and PVR increased (PAP, 52 +/- 3.31 to 60.17 +/- 5.03 mm Hg; PVR, 946.13 +/- 115.35 to 1,236.6 +/- 180.23 dyne . s . cm(-5); p < 0.01) and mean 6MWD decreased from 463.64 +/- 27.77 to 367.27 +/- 38.87 m (p < 0.05). Comparing groups revealed statistically significant differences regarding changes in PAP (group A, -11.58 +/- 3.57%; group B, +13.29 +/- 5.44%; p = 0.001) and PVR (group A, -19.21 +/- 5.87%, group B, +30.35 +/- 7.72%; p < 0.001). Correlations existed between the changes in BNP levels and pulmonary hemodynamics. CONCLUSION: We concluded that BNP levels parallel changes in pulmonary hemodynamics and functional parameters, including the 6MWD, in PAH patients. Consequently, we suggest BNP as a parameter for the follow-up assessment of PAH patients.     

肺动脉高压血浆脑钠肽及血尿酸水平与血流动力学变化的相关性研究

目的:探讨血浆脑钠肽(BNP)、血尿酸(SUA)在评估肺动脉高压(PH)患者血流动力学变化的临床价值。方法:选择在2012年1月至2014年1月,我院的PH患者48例,其中男性7例,女性41例,年龄18~65岁,平均(44.5±10.9)岁,进行血浆BNP、SUA以及右心导管(RHC)检查,比较血浆BNP、SUA与RHC测得的肺动脉收缩压(SPAP)、肺动脉平均压(m PAP)、全肺血管阻力(PVR)的相关性。结果:入选患者中特发性肺动脉高压(IPAH)27例(56.3%),继发性PH 21例(43.7%),其中包含结缔组织病(先心病)相关性肺动脉高压(CTDPH)10例(20.8%),先心病相关性肺动脉高压(CHDPH)5例(10.4%),慢性血栓栓塞性肺动脉高压(CTEPH)6例(12.5%)。血浆BNP:209.02(88.01,455.01)ng/L;SUA:(399.74±132.81)μmol/L;RHC测SPAP:(91.54±24.34)mm Hg(1mm Hg=0.133k Pa),m PAP:(55.73±16.42)mm Hg,PVR:1 409.50(867.20,1 880.12)达因.s·cm-5。相关性分析显示,血浆BNP、SUA与RHC中的血流动力学参数具有良好的相关性,且为正相关;结论:血浆BNP、SUA在评估肺动脉高压患者病情、预后等方面有较好的临床价值。     

B型利钠肽在结缔组织病相关肺动脉高压中的诊断价值

目的 通过观察结缔组织病(CTD)相关肺动脉高压(PAH)患者外周血B型利钠肽(BNP)和N末端B型利钠肽原(NT-proBNP)的水平,探讨BNP在CTD相关PAH中的诊断价值.方法 对2006-2009年北京协和医院收治的30例CTD合并PAH患者进行超声心动图、右心导管检查及外周血BNP和NT-proBNP水平测定.结果 (1)30例CTD相关PAH患者全部为女性,年龄(39.5±11.6)岁,均经右心导管检查证实为PAH.患者血BNP水平[(325.2±426.3)(8.0～1590.0)ng/L]、NT-proBNP水平[(1444.9±1651.4)(55.0～7839.6)ng/L]升高.(2)不同程度PAH患者WHO临床功能分级、右心房压(RAP)、右心室舒张末压(RVEDP)、肺毛细血管楔压(PCWP)、肺血管阻力(PVR)、心指数(CI)、混合静脉血氧饱和度(SvO2)、左心室舒张末内径(LVEDd)、右房大小、右心室与左心室舒张末内径比值(RV/LV)、三尖瓣跨瓣压差(TGP)、心包积液发生情况、NT-proBNP差异有统计学意义.(3)应用受试者工作特征曲线(ROC)分析NT-proBNP、BNP对重度PAH的诊断价值,其曲线下面积(AUC)分别为0.74、0.64,提示NT-proBNP优于BNP.NT-proBNP为745.2 ng/L对区分重度PAH的敏感性为68.8%,特异性为57.1%;BNP为141.5 ng/L时的敏感性为62.5%,特异性为64.3%.(4)相关性分析:NT-proBNP与WHO临床功能分级、RAP、RVEDP、平均肺动脉压(MPAP)、PVR呈正相关(r分别为0.55、0.55、0.36、0.53、0.69,P＜0.05),与CI、S(v)O2呈负相关(r分别为-0.58、-0.62,P≤0.001).BNP与RAP、MPAP、PVR呈正相关(r分别为0.42、0.40、0.61,P＜0.05),与CI、S(v)O2呈负相关(r分别为-0.46、-0.54,P=0.005),与RVEDP、WHO临床功能分级无相关性(r分别为-0.46、-0.54,P＞0.05).NT-proBNP与LVEDd呈负相关(r=-0.41,P=0.025),与RA1、RA2、RV、RV/LV比值、TGP呈正相关(r分别为0.40、0.53、0.55、0.49、0.45,P＜0.05).BNP与RA1、RA2、RV、RV/LV比值、TGP呈正相关(r分别为0.39、0.45、0.37、0.40、0.36,P＜0.05).NT-proBNP、BNP均与心包积液明显相关(r分别为0.46、0.43,P＜0.05).结论 CTD相关PAH患者血BNP、NT-proBNP均升高,与WHO临床功能分级、血流动力学参数、超声心动图反映右心室功能参数之间有显著的相关性.提示BNP是判断CTD合并PAH严重程度和预后的一种简单、无创和可信的指标.

Abstract：

Objective To explore the potential role of brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide(NT-proBNP) in the assessment of patients with connective tissuediseases(CTD) associated pulmonary arterial hypertension (PAH). Methods Thirty patients with CTD associated PAH were evaluated by WHO function, echocardiography, right heart catheterization and blood biomarkers. All the clinical data was analyzed statistically. Results All patients [age (39.5 ± 11.6) yr]were female. Both NT-proBNP and BNP were significantly increased and significantly correlated ( all P ＜0. 05 ) respectively with mean pulmonary arterial pressure ( r = 0. 53 and r = 0. 40 ), right arterial pressure ( r = 0. 55 and r = 0. 42 ), pulmonary vascular resistance ( r = 0. 69 and r = 0. 61 ), cardiac index ( r = - 0. 58and r = - 0. 46), mixed venous blood oxygen saturation ( r = - 0. 62 and r = - 0. 54 ), pericardial effusion ( r = 0. 46 and r = 0. 43 ), right atrial sizes ( r = 0. 40 and 0. 53, and r = 0. 39 and 0. 45 ) and right ventricular size ( r = 0. 55 and r = 0. 37 ). Furthmore, NT-proBNP, but not BNP, significantly correlated with WHO function class ( r = 0. 55 ). Conclusion Blood NT-proBNP and BNP were elevated in patients with CTD associated PAH and paralleled the extent of function class, pulmonary hemodynamic changes and right ventricular remodeling.     

Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension

STUDY OBJECTIVES: Baseline prognostic assessment in patients with pulmonary hypertension (PH) may help in the selection of treatment. High plasma levels of natriuretic peptide type B have been reported in patients with right ventricular (RV) dysfunction and suggest poor prognosis in patients with idiopathic pulmonary arterial hypertension (IPAH). We prospectively assessed the correlation of N-terminal brain natriuretic peptide (NT-proBNP) with echocardiographic and hemodynamic indexes of RV function as well as with baseline functional status and long-term survival of PH patients.Patients and design: Fifty-five consecutive patients with a mean (+/- SD) age of 41 +/- 15 years and severe PH (including 36 patients with IPAH) were followed up for up to 36 months. Serum samples for NT-proBNP were secured, and 6-min walk test (6 MWT), RV catheterization, and echocardiography were all performed on the same day, before the introduction of targeted treatment. RESULTS: The median baseline serum NT-proBNP concentration was 1,674 pg/mL (range, 51 to 10,951 pg/mL). NT-proBNP concentration correlated with 6MWT distance (r = 0.6; p < 0.001), cardiac index, pulmonary vascular resistance, and right atrial pressure (RAP), but not with pulmonary arterial pressure. NT-proBNP levels were also related to the ratio of the diastolic area of the RV and the LV, and to pericardial effusion during echocardiography. Receiver operating characteristic analysis identified > or = 1,400 pg/mL as the best NT-proBNP threshold predicting fatal outcome for the entire study group as well as for IPAH patients (sensitivity, 88% and 100%, respectively; specificity, 53% and 56%, respectively). In multivariate analysis, NT-proBNP, troponin T, and RAP were identified as independent factors for poor prognosis for the entire study group, while only NT-proBNP and RAP were identified as markers for poor prognosis in the IPAH subgroup. CONCLUSIONS: NT-proBNP level is related to the right heart morphology and dysfunction in PH patients. A serum NT-proBNP level of > or = 1,400 pg/mL was found to be useful in identifying patients with poor long-term prognosis both in the whole studied group and in the IPAH subgroup.     

Acute and chronic effects of sildenafil in patients with pulmonary arterial hypertension

Sildenafil and inhaled nitric oxide (iNO) relax smooth muscle by inhibiting the degradation and stimulating the production of cyclic guanosine monophosphate, respectively. We compared the acute pulmonary vasodilator effects of sildenafil, iNO, and epoprostenol and asked whether the combination of iNO with sildenafil had additive pulmonary vasodilator effects. We assessed the effects of extended use of sildenafil in a small cohort of patients. Twenty patients with pulmonary arterial hypertension underwent an acute vasodilator trial with sildenafil (all patients), iNO and iNO plus sildenafil (11), and epoprostenol (19). We also provided sildenafil to patients who were ineligible for, or had clinical deterioration on epoprostenol, treprostinil, or bosentan. Mean+/-se pulmonary artery pressure dropped by 13+/-3%, 19+/-4%, 14+/-3%, and 26+/-4% with epoprostenol, iNO, sildenafil, and iNO+sildenafil, respectively. Cardiac index increased with epoprostenol and sildenafil. A correlation was found between the effects of iNO and epoprostenol. Nine out of ten patients who were started on long-term sildenafil treatment alone or in combination with other vasodilators had symptomatic improvement. Three died of right heart failure. In conclusion, sildenafil is a potent acute pulmonary vasodilator, an effect that is potentiated by combination with iNO. Long-term therapy of pulmonary hypertension with sildenafil alone or in combination with other agents appears to be safe and well tolerated.     

Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension

BACKGROUND: Plasma brain natriuretic peptide (BNP) level increases in proportion to the degree of right ventricular dysfunction in pulmonary hypertension. We sought to assess the prognostic significance of plasma BNP in patients with primary pulmonary hypertension. METHODS AND RESULTS: Plasma BNP was measured in 60 patients with primary pulmonary hypertension at diagnostic catheterization, together with atrial natriuretic peptide, norepinephrine, and epinephrine. Measurements were repeated in 53 patients after a mean follow-up period of 3 months. Forty-nine of the patients received intravenous or oral prostacyclin. During a mean follow-up period of 24 months, 18 patients died of cardiopulmonary causes. According to multivariate analysis, baseline plasma BNP was an independent predictor of mortality. Patients with a supramedian level of baseline BNP (> or = 150 pg/ml) had a significantly lower survival rate than those with an inframedian level, according to Kaplan-Meier survival curves (p < 0.05). Plasma BNP in survivors decreased significantly during the follow-up (217 +/- 38 to 149 +/- 30 pg/ml, p < 0.05), whereas that in nonsurvivors increased (365 +/- 77 to 544 +/- 68 pg/ml, p < 0.05). Thus, survival was strikingly worse for patients with a supramedian value of follow-up BNP (> or = 180 pg/ml) than for those with an inframedian value (p < 0.0001). CONCLUSIONS: A high level of plasma BNP, and in particular, a further increase in plasma BNP during follow-up, may have a strong, independent association with increased mortality in patients with primary pulmonary hypertension.     

Significance of plasma N-terminal pro-brain natriuretic peptide in patients with systemic sclerosis-related pulmonary arterial hypertension

OBJECTIVES: A single centre pilot study to investigate the role of the plasma N-terminal pro-brain natriuretic peptide (N-T proBNP) assay to risk stratify patients with suspected pulmonary arterial hypertension (PAH) from a background SSc population. METHODS: Out of 49 SSc patients, 23 had and 26 did not have PAH. Right ventricular haemodynamic variables, six-minute walk test and plasma N-T proBNP levels were recorded from patients catheterised for suspected PAH (23 with PAH and 11/26 without PAH). RESULTS: Mean value of N-T proBNP for SSc patients with PAH was 3365 (standard error 1095) pg/ml compared to 347 (174) pg/ml for patients without PAH. There was a statistically significant correlation (P < 0.05) between N-T proBNP values and (i) mean pulmonary artery pressure (r = 0.53), (ii) right ventricular end diastolic pressure (r = 0.59) and (iii) pulmonary vascular resistance (r = 0.49). Receiver operator characteristic curve analysis showed that a cut-off value of 395.34 pg/ml had a sensitivity of 0.69 and specificity of 1.0. CONCLUSIONS: N-T proBNP estimation in systemic sclerosis-related pulmonary hypertension is a potentially useful diagnostic tool with a high specificity and negative predictive value. This test has the potential to have an important role in risk stratification and monitoring of therapy in the future.     

N端脑钠肽原对西地那非联合辛伐他汀治疗女性肺动脉高压的评估

目的:探讨血浆N端脑钠肽原(NT-pro-BNP)对西地那非联合辛伐他汀治疗女性肺动脉高压患者疗效的评估情况。方法:将115例女性肺动脉高压患者分为西地那非联合辛伐他汀组(A组)38例(西地那非50mg,每日3次,辛伐他汀40mg,每日1次);西地那非组(B组)38例(西地那非50mg,每日3次);传统治疗组(C组)40例。连续治疗3个月,治疗前后测定右室收缩压、右室内径、肺功能[观察指标为第1秒用力呼气容积(FEV1)占用力肺活量(FVC)的百分比(FEV1/FVC)]、动脉血氧分压、6min步行距离(6-MWD)、明尼苏达心力衰竭生活质量(MLHFQ)评分及血浆NT-pro-BNP水平。结果:与C组比较,A、B组NT-Pro-BNP水平、右室收缩压及MLHFQ评分治疗后明显下降,FEV1/FVC及6-MWD较治疗前明显增加,且A组变化较B组更加显著;治疗后,A、B两组右室内径缩小、FEV1增加及动脉血氧分压提高,但A组并未显示出额外获益;血浆NT-Pro-BNP水平与右室收缩压呈正相关(r=0.72,P=0.003),与MLHFQ评分成正相关(r=0.47,P=0.007),与动脉血氧分压呈负相关(r=-0.57,P=0.013),与6-MWD亦呈负相关(r=-0.61,P=0.004)。结论:对西地那非联合辛伐他汀治疗多种病因所致的女性肺动脉高压,NT-pro-BNP可作为评估其疗效的一项简易、无创、可靠的生化指标。     

Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension.

AIMS: The aims of this study were to evaluate the diagnostic value and to explore the prognostic value of N-terminal brain natriuretic peptide (N-TproBNP) in patients with systemic sclerosis (SSc) both with and without pulmonary arterial hypertension (PAH). METHODS AND RESULTS: N-TproBNP, six-minute walk distance (SMWD), haemodynamics (at right heart catheterization) or tricuspid gradient (by echocardiography), and survival were assessed in 109 patients with SSc. The study population included 68 individuals with PAH [mean pulmonary artery pressure (PAP) >25 mmHg and pulmonary capillary wedge pressure <15 mmHg] and 41 individuals without PAH. In patients with PAH, the prognostic value of baseline and change in WHO functional class, N-TproBNP levels, and SMWD were compared using Kaplan-Meier survival curves and Cox proportional hazard analysis. The mean duration of follow-up was 10 months (range 1-18 months). One year survival in patients with normal PAP was 100% when compared with 83.5% in those with SSc-PAH (P < 0.05). The patients without PAH had a mean N-TproBNP level of 139 pg/mL (SD 151); those with SSc-PAH had a significantly higher mean N-TproBNP level of 1474 pg/mL (SD 2642) (P = 0.0002). Among patients with PAH for every order of magnitude increase in N-TproBNP level there was a four-fold increased risk of death (P = 0.002 for baseline level and P = 0.006 for follow-up level). Baseline N-TproBNP levels were correlated positively with mean PAP (r = 0.62; P < 0.0001), pulmonary vascular resistance (PVR) (r = 0.81; P < 0.0001), and inversely with SMWD (r = -0.46; P < 0.0001). Among patients with SSc-PAH, 13 patients (19%) were in WHO functional classes II and had mean N-TproBNP levels of 325 pg/mL (SD 388). Fifty-three patients (78%) were in WHO classes III and IV and had significantly higher mean N-TproBNP levels of 1677 pg/mL (SD 2835) (P = 0.02). At an N-TproBNP level of 395 pg/mL, the sensitivity and specificity for predicting the presence of SSc-PAH were 56 and 95% respectively. CONCLUSION: Raised N-TproBNP levels are directly related to the severity of PAH. In screening programs, SSc patients with an N-TproBNP in excess of 395 pg/mL have a very high probability of having pulmonary hypertension. Baseline and serial changes in N-TproBNP levels are highly predictive of survival. A 10-fold increase in N-TproBNP level on therapy is associated with a greater than three-fold increase in mortality, and may indicate therapeutic failure.     

Atrial natriuretic peptide in diabetes mellitus patients with arterial hypertension]

The basal level of atrial natriuretic peptide (ANP) of the venous blood plasma was investigated in 105 diabetic patients with concomitant arterial hypertension (AH) as well as in 20 healthy persons of the same age. Analysis of the results of investigation was performed with respect to AH type (essential, atherosclerotic, nephrogenic) and expression of cardiac changes. An ANP level in diabetic patients without AH did not differ from that of the controls. In the presence of AH this level was increased 2-10-fold. The highest level of ANP was observed in patients with nephrogenic hypertension and marked cardiac disorders. The results obtained suggest the role of ANP in AH pathogenesis.     

Addition of sildenafil in patients with pulmonary arterial hypertension with inadequate response to bosentan monotherapy

BACKGROUND:

Pulmonary arterial hypertension (PAH) remains a progressive disease despite improvement when using one of three medication classes: prostanoids, endothelin receptor antagonists or phosphodiesterase-5 inhibitors. Combination therapy has been proposed for patients with unsatisfactory response to monotherapy.

OBJECTIVES:

To examine the effect of adding sildenafil to bosentan on 6 min walk distance (6MWD) and New York Heart Association (NYHA) classification in patients with PAH who achieved inadequate improvement with bosentan monotherapy.

METHODS:

Patients with idiopathic PAH or connective tissue disease-associated PAH, and who had either self-reported inadequate improvement in exercise tolerance or a decline in 6MWD after initial improvement, were included in the study (n=10). Data on 6MWD and NYHA class at baseline (before initiation of bosentan), three and six months after baseline, second baseline (before initiation of combination therapy with sildenafil), and three and six months after second baseline were analyzed for any changes.

RESULTS:

Mean time from initiation of bosentan monotherapy to initiation of combination therapy was 558 days (range 150 to 900 days). Six months after initiation of bosentan, 6MWD increased by 57.2 m above the baseline of 314.4 m. Six months after combination therapy, 6MWD was 62.80 m higher than the baseline before initiation of combination therapy of 339 m (P<0.02). The overall increase in 6MWD six months after combination therapy was higher than the first baseline by 87.4 m (P not significant). NYHA functional class did not improve with combination therapy in all patients.

DISCUSSION:

Initiating combination therapy in patients who achieve an inadequate improvement in exercise tolerance with mono-therapy may result in further improvement in exercise tolerance.