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European Journal of Heart Failure 2005 7(7):1149-1155; doi:10.1016/j.ejheart.2004.12.011
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© 2005 European Society of Cardiology

The value of B-type natriuretic peptide and big endothelin-1 for detection of severe pulmonary hypertension in heart transplant candidates

Milos Kubáneka,*, Ivan Máleka, Josef Kautznera, Markéta Hegarováa, Martin Wiendla, Petr Lupineka, Ludmila Karasováb and Vera Lánskác

a Department of Cardiology, Institute for Clinical and Experimental Medicine Videnská 1958/9, Prague 140 21, Czech Republic
b Department of Clinical Chemistry, Institute for Clinical and Experimental Medicine Prague, Czech Republic
c Department of Medical Statistics, Institute for Clinical and Experimental Medicine Prague, Czech Republic

* Corresponding author. Fax: +42 4024728225. E-mail address: mikb{at}medicon.cz


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: Severe pulmonary hypertension (PH) and increased pulmonary vascular resistance (PVR) are important risk factors that predict early postoperative mortality after orthotopic heart transplantation. The aim of our study was to determine the value of B-type natriuretic peptide (BNP) and big endothelin-1 (big ET1) for prediction of severe PH in heart transplant candidates.

Methods: The study population included 43 potential heart transplant candidates (38 males, mean age 52±7 years). All underwent repeated right-heart catheterizations (2–5 studies) at an interval of 3–4 months, giving a total of 124 examinations, associated with blood sampling for BNP and big ET1 analysis. Severe PH was defined as the mean pulmonary artery pressure (MPAP)>40 mmHg.

Results: Significantly high PVR (PVR>3.0 Wood units and TPG>15 mmHg) was noted on 12 occasions in 10 patients; always in the presence of severe PH. Low BNP levels (<67 pg/ml) ruled out the presence of severe PH with a 100% sensitivity, however, with a low specificity (34%). An increase in plasma BNP>30 pg/ml (>40% of initial value) in subjects with a previous MPAP–40 mmHg detected development of severe PH with a 100% sensitivity and an 80–88% specificity. As a total of 58% of patients presented repeatedly with MPAP≤40mmHg, serial BNP testing could reduce the need for hemodynamic studies in this subgroup down to 12–20%.

Conclusions: Serial BNP testing in hemodynamically stable heart transplant candidates with MPAP–40 mmHg allows reliable detection of development of severe PH, and may significantly reduce the need for repeated right-heart catheterizations in these patients.

Key Words: B-type natriuretic peptide • Big endothelin-1 • Congestive heart failure • Pulmonary hypertension • Orthotopic heart transplantation

Received April 13, 2004; Revised October 12, 2004; Accepted December 20, 2004


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Increased left ventricular filling pressure in congestive heart failure (CHF) results in subsequent development of pulmonary venous hypertension. Both the mean pulmonary capillary wedge pressure (PCWP) and the mean pulmonary artery pressure (MPAP) appear to correlate significantly with the plasma levels of B-type natriuretic peptide (BNP) [1]. This peptide is secreted mainly from heart ventricles in a response to ventricular volume expansion and pressure overload. Additional role is played by norepinephrine, angiotensin II and endothelin-1 [2,3].

A proportion of heart transplant candidates present with an increase in pulmonary vascular resistance (PVR) secondary to vasoconstriction and structural changes in the pulmonary vascular bed. The principal mediators responsible for pulmonary vasomotion are nitric oxide (NO) and endothelin-1 (ET1). CHF is associated with impaired NO-dependent vasodilatation in the pulmonary vascular bed [4,5]. ET1 itself is a potent vasoconstrictor that is both produced and metabolized in the pulmonary vessels [6–8]. Compared with physiological status, when approximately 50% of circulating ET1 is cleared in the lungs [9], ET1 spillover from the pulmonary circulation has been demonstrated in CHF. This finding has been attributed both to a reduced pulmonary clearance and an increased production of ET1 [10–13]. Importantly, ET1 spillover from the pulmonary vascular bed correlates positively with PVR in CHF patients [12]. As a result, the plasma levels of ET1 and its precursor–big ET1, show a positive correlation with pulmonary artery pressures and PVR [14–16].

As the increased PVR is known to be associated with a high risk of right-heart failure after orthotopic heart transplantation and with early postoperative mortality, evaluation of the severity of PH, transpulmonary pressure gradient (TPG) and PVR are particularly important in heart transplant candidates. For this reason, repeated invasive measurements of pulmonary artery pressures are mandatory in these patients. Therefore, identification of a reliable noninvasive predictor of severe PH would be desirable. The aim of our study was to determine the value of BNP and big ET1 for prediction of severe PH (MPAP>40 mmHg) in heart transplant candidates. The rationale was to minimize the number of repeated right-heart catheterization procedures.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Study population
A total of 43 patients with stable and severe CHF were studied. All were admitted between July 2001 and September 2002, and evaluated as potential candidates for orthotopic heart transplantation. Only patients with repeated right-heart catheterization were included. The demographic and basic clinical characteristics are listed in Table 1.


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  		Table 1 Patient characteristics at the baseline examination (n=43)

 
2.2. Right heart catheterization
Right-heart catheterization was performed after overnight fasting, using a 7F Swan–Ganz catheter. Internal jugular vein was used for venous access. Pulmonary artery and right heart pressures were recorded, and cardiac output was measured by the thermodilution technique. Two to five studies were performed in each patient at an interval of 3–4 months, giving a total of 124 measurements. All hemodynamic studies were performed in the catheterization laboratory using the hemodynamic monitor Microlab V 4.14 (GE Marquette, Milwaukee, USA). No significant complications were observed. The level of PVR that constitutes high risk for orthotopic heart transplantation was defined as PVR>3 Wood units in the presence of TPG>15 mmHg.

2.3. Biochemical assays
Blood samples were drawn from an antecubital vein in the morning before the right-heart catheterization, following 30 min of bed rest in the supine position. Blood for measurement of the plasma levels of BNP was transferred to a chilled tube containing ethylenediaminetetraacetic acid (EDTA) (1 mg/ml) and aprotinin (500 kallikrein inactivator U/ml). Blood for measurement of big ET1 was withdrawn into a chilled tube with EDTA (1 mg/ml). Test tubes were immediately placed on ice and centrifuged at 4 °C. Plasma samples were stored at –70 °C until assay.

Plasma BNP concentrations were measured using a specific immunoradiometric assay (nonextracted) for human BNP (Shionogi Co. Ltd., Osaka, Japan) as reported previously [1]. The normal range varied between 5.9 and 18.6 pg/ml, with a detection limit 2 pg/ml and standard range between 0 and 2000 pg/ml. The intraassay and interassay coefficients of variation were 2.6% (n=7) and 4.6% (n=7), respectively. Plasma big ET1 levels were determined using direct enzyme immunoassay for the quantitative determination of human big endothelin-1 (Biomedica, Vienna, Austria) as reported previously [9]. The normal range was defined below 0.7 fmol/ml in human EDTA plasma, with a detection limit of 0.05 fmol/ml and standard range between 0.05 and 15.6 fmol/ml. The intraassay coefficient and interassay coefficients of variation were <5% (n=11) and <7% (n=12), respectively.

2.4. Statistical analysis
Continuous variables were expressed as the mean±SD. When comparing patients with different numbers of measurements, their data were statistically weighted according to the number of measurements. Intergroup comparisons were performed using Student's t test for independent samples. Linear regression analysis was used to determine the relationship between continuous variables. To evaluate the predictive value of BNP, receiver operating characteristic (ROC) analysis was performed, the area under the curve (AUC) calculated and possible cut-off points were selected. A p value <0.05 was regarded as statistically significant.

2.5. Ethics
The investigation conforms with the principles outlined in the Declaration of Helsinki, and was approved by the regional ethics committee. All subjects gave their written informed consent prior to their participation in the study.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
Hemodynamic data and neurohormone levels are listed in Table 2. Severe PH (MPAP>40 mmHg) was observed on 30 examinations in 18 patients. Normal pressure levels in the pulmonary circulation or a mild-to-moderate PH (MPAP≤40 mmHg) were documented on 94 examinations in 25 patients. Significantly high PVR was present on 12 occasions, in 10 patients; always in the presence of severe PH. Severe PH was associated with significantly higher BNP levels as compared with the rest of the measurements (338.4±122.0 vs. 206.0±113.4 pg/ml; n=30 vs. n=94; p<0.0001) and only with a slight increase in big ET1 levels (3.91±1.04 vs. 3.31±1.58 fmol/ml; n=30 vs. n=94; p=0.0568). High left ventricular filling pressure ( PCWP>18 mmHg) was associated with a significant increase in BNP (319.3±126.5 vs. 139.3±79.81 pg/ml; n=70 vs. n=54; p<0.0001) and in big ET1 (4.13±1.76 vs. 2.60±0.73 fmol/ml; n=70 vs. n=54; p<0.0001).


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  		Table 2 Results of neurohumoral and hemodynamic studies

 
Table 3 shows correlations of BNP and big ET1 levels with hemodynamic parameters. The mean of the first two measurements in each patient was used (n=43). It is apparent that only BNP showed significant correlations with hemodynamic data. Closer correlations were obtained when evaluating repeated measurements in individual patients. Fig. 1 depicts a significant correlation between changes in two consecutive measurements of BNP and corresponding changes in MPAP (r=0.47, n=81; p<0.001) or PCWP (r=0.46, n=81; p<0.001). The correlation remained significant when calculating the change in BNP and the hemodynamic parameter as the difference between the first and second measurement in each patient. The correlation coefficients were as follows: (r=0.43, n=43; p<0.01) for the change in MPAP and (r=0.37, n=43; p<0.05) for the change in PCWP.


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  		Table 3 Correlation between BNP, big ET1 and hemodynamic variables (n=43)

 


Figure 1
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  		Fig. 1 Correlation between delta MPAP and delta BNP. Correlation between delta PCWP and delta BNP.

 
Fig. 2 presents the ROC curve displaying the value of BNP for prediction of severe PH. The AUC was 0.70 (95% confidence interval: 0.62–0.78). It is evident, that single BNP determination does not have a sufficient discriminatory power. However, low BNP levels (<67 pg/ml) excluded the presence of severe PH with 100% sensitivity. On the other hand, the specificity of the test was as low as 34%.


Figure 2
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  		Fig. 2 The ROC curve illustrates the sensitivity and specificity of a single BNP determination for prediction of severe PH. The AUC was 0.70 (95% confidence interval: 0.62–0.78). Low BNP levels (<67 pg/ml) ruled out the presence of severe PH with a 100% sensitivity, but the specificity of the test was as low as 34%.

 
Deterioration of mild-to-moderate PH into severe PH was observed in 12 patients (Group A). A control group (Group B) comprised 25 patients whose MPAP remained ≤40 mmHg. Two consecutive measurements of BNP obtained before and after deterioration of hemodynamics in Group A, and the changes in BNP between the first two measurements in Group B were used in an attempt to predict progression of PH. Deterioration of PH in Group A was associated with a significant increase in BNP levels ({Delta}BNP 191.6±134.7 vs. –39.4±107 pg/ml, p<0.001) as compared with Group B (Fig. 3). The ROC curve (Fig. 4) illustrates the sensitivity and specificity of a change in BNP levels in discrimination of Group A from Group B. The AUC reached in this case 0.95 (95% confidence interval: 0.83–0.99). An increase in plasma BNP>30 pg/ml (>40% of initial value) separated Group A from Group B with a 100% sensitivity and 88% specificity. The positive and negative predictive values of this parameter were 80% and 100%, respectively. Both groups differed significantly even when calculating the change in BNP among all consecutive follow-up visits in Group B (n=35). In Group A and Group B, {Delta}BNP reached the values of 191.6±134.7 pg/ml and –27.0±139 pg/ml, respectively; (p<0.001). The parameter {Delta}BNP>30 pg/ml (>40% of initial value) distinguished Group A from Group B with a 100% sensitivity and 80% specificity.


Figure 3
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  		Fig. 3 Deterioration of mild-to-moderate PH (MPA≤40 mmHg) into the range of severe PH (MPAP>40 mmHg) was noted in 12 patients (Group A). A control group (Group B) comprised 25 patients whose MPAP remained ≤40 mmHg. Deterioration of PH in Group A was associated with a significant increase in BNP levels.

 


Figure 4
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  		Fig. 4 The ROC curve illustrates the sensitivity and specificity of a change in BNP levels in discrimining Group A from Group B. The AUC was 0.95 (95% confidence interval: 0.83–0.99). An increase in plasma BNP>30 pg/ml distinguished Group A from Group B with a 100% sensitivity and 88% specificity.

 
Changes in hemodynamics and BNP levels were not associated with significant changes in renal function. Serum creatinine was stable in both groups: Group A 121.9±26.2 vs. 104.7±12.9 µmol/l, not significant (ns.), Group B 108.5±36.3 vs. 105.8±25.4 µmol/l, ns. We did not observe significant changes in pharmacotherapy. Doses of angiotensin-concerting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) and beta-blockers (BBs) are expressed as percentages of target daily doses (according to the latest ESC guidelines) [39]. Group A-ACEi: 11 pts, 79±35 vs. 83±29%, ns., ARBs: 1 pt, 50 vs. 50%, ns., BBs: 12 pts, 32±24 vs. 29±24%, ns., spironolactone: 12 pts, 73±28 vs. 67±16 mg/day, ns., furosemide: 12 pts, 192±90 vs. 178±67 mg/day, ns., hydrochlorothiazide: 6 pts, 15±11 vs. 19±6 mg/day, ns, digoxin: 2 pts, 0.125 vs. 0.125 mg/day, ns. Group B-ACEi: 22 pts, 69±36 vs. 71±36%, ns., ARBs: 2 pt, 50 vs. 50%, ns., BBs: 24 pts, 42±30 vs. 38±28%, ns., spironolactone: 24 pts, 52±18 vs. 53±17 mg/day, ns., furosemide: 25 pts, 141±88 vs. 152±101 mg/day, ns., hydrochlorothiazide: 7 pts, 23±4 vs. 18±11 mg/day, ns., digoxin: 8 pts, 0.141±0.041 vs. 0.109±0.041 mg/day, ns.


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
This is the first report to analyze the value of BNP and big ET1 for prediction of severe PH in candidates for orthotopic heart transplantation. Its main findings can be summarized as follows: (1) repeated BNP testing in heart transplant candidates with a previous MPAP≤40 mmHg allows reliable detection of development of severe PH, and may reduce the need for repeated right-heart catheterizations in these patients, (2) serial evaluation of BNP plasma levels in individual patients is more clinically relevant than isolated assessment of a single value.

Several studies have reported positive correlations of BNP, ET1 and big ET1 plasma levels with pulmonary artery pressures in patients with CHF [1,11,13,15,16]. However, only two studies evaluated the relationship between neurohormones and hemodynamics in clinical context. These studies showed that both BNP and big ET1 provide better prognostic information than hemodynamic variables [1,15]. Our study extended this conclusion to prediction of severe PH in heart transplant candidates using neurohormones and evaluation of repeated measurements. Correlations of BNP with hemodynamics corresponded with data in the literature [1,17,18]. The only exception was a lack of correlation between big ET1 and pulmonary artery pressures. This discrepancy could be explained by the use of different laboratory methods. In a previous study, the direct ELISA method yielded 3–4 times lower big ET1 levels in comparison with ELISA after plasma extraction [16]. However, extraction methods are difficult to use in routine clinical practice. In our study, we used the direct ELISA assay and 90% of values were within a narrow range of 1.1–5.0 fmol/ml. These results suggest a lower sensitivity of the direct ELISA method as compared with ELISA after plasma extraction.

4.1. Practical implications of BNP determination in the diagnosis of PH
Low BNP levels (<67 pg/ml) can rule out the presence of severe PH with 100% sensitivity, however the specificity of the test is relatively low (34%). The changes in plasma BNP in individual patients correlate significantly with changes in MPAP and PCWP. Despite the fact that this correlation is not narrow, the serial evaluation of BNP plasma levels allows estimation of significant changes in the hemodynamics, to assess the course of the disease, and adjust CHF management appropriately.

Serial BNP determinations in heart transplant candidates on the waiting list appear to be the most helpful. These patients undergo repeated right-heart catheterization procedures to assess PH and PVR. In our study, a high PVR was seen only in the presence of severe PH. The results suggest that with the use of BNP testing, additional right-heart catheterization procedures can be avoided in patients without severe PH. An increase in plasma BNP>30 pg/ml (>40% of initial value) in subjects with a previous MPAP≤40 mmHg allows detection of development of severe PH with a 100% sensitivity and an 80–88% specificity. As a total of 58% of patients presented repeatedly with MPAP≤40 mmHg, serial BNP determinations could reduce the need for hemodynamic studies in this subgroup down to 12–20%. In addition to BNP monitoring, stable hemodynamics can also be predicted by a stable clinical status and stationary echocardiographic findings focused on the size and function of both ventricles, the degree of atrioventricular regurgitations, and Doppler estimates of PH.

4.2. Factors influencing the correlation between hemodynamics and plasma BNP levels
The correlation of hemodynamics and plasma BNP levels can be affected by the rate of changes in the evaluated parameters and by inter-individual differences in BNP secretion and degradation. While an invasive procedure reflects the current state of hemodynamics, BNP secretion is preceded by an intense BNP RNA transcription. Experimental data suggest that this process occurs within an hour after pressure overload of the cardiac atria and ventricles [19]. The plasma half-time of BNP is approximately 20 min. Consequently, plasma BNP reflects the status of hemodynamics over a longer period of time.

The factors affecting the secretion and degradation of BNP also vary inter-individually. BNP formation is influenced by a number of variables such as myocardial wall stress, a total myocardial mass, and other neurohormones (norepinephrine, angiotensin II and endothelin-1). Myocardial wall stress in the individual cardiac chambers is affected not only by actual filling pressures but, also, by chamber size and wall thickness. Another factor may be the presence of heart valve disease. BNP degradation is mediated by a neutral endopeptidase, C-type receptors for natriuretic peptides and, conceivably, by its metabolism in the kidneys [20]. Judging by epidemiological studies, BNP levels are also affected by the patient's age and sex [21]. Given these inter-individual differences, serial evaluation of changes in the plasma levels of BNP in individual patients is clinically more relevant than isolated assessment.

4.3. Current clinical applications of big ET1 and BNP in patients with heart failure
In CHF patients, big ET1 is used primarily as a prognostic marker [15,22–25]. Natriuretic peptides have been widely used in the evaluation of diagnosis and prognosis in patients with CHF; hence, they are also of value in long term CHF management. For diagnostic purposes, these peptides have been used for detecting LV systolic dysfunction and CHF in the population [26–30]. Their assessment may be helpful in differential diagnosis of acute dyspnea [31–33]. Natriuretic peptides are also valuable in establishing the prognosis of CHF patients when determined on single occasions [1], when determining BNP following optimization of pharmacotherapy [34], and when assessing the change in BNP after treatment of decompensated CHF [35]. The most interesting prospective areas of future use of natriuretic peptides appear to be pharmacotherapy optimization [36,37] and monitoring non-pharmacological therapy of CHF [38].

Our study suggests a new application for BNP determination in CHF. Serial BNP determinations in heart transplant candidates allow detection of the development of severe PH. In patients with baseline MPAP≤40 mmHg and stable BNP levels, it is possible to reduce the number of repeated right-heart catheterization procedures and to follow up these patients regularly on an outpatient basis. Such a policy is also cost effective. Moreover, serial BNP determination in individual patients allows monitoring of the course of the disease, provides additional information in those patients with worsening symptoms, and indicates the response to a change in therapy.

4.4. Study limitations
Only patients with relatively stable forms of CHF, mostly in NYHA Class III, were included into our study. Overt RV failure and/or a low cardiac output may be associated with a high PVR despite a lower degree of PH. Consequently, our results may not be applicable to patients with these conditions. Although the study was not designed as an echocardiography-based evaluation of PH, it might be advantageous to combine both noninvasive approaches when developing future studies.


   5. Conclusions
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Compared with big ET1 determination using direct ELISA, BNP determination appears to be more useful for the diagnosis of severe PH in patients with CHF. Repeated BNP determinations in individual patients showed a closer correlation with changes in hemodynamics and allowed a more reliable diagnosis of severe PH than evaluation of isolated BNP values. Low BNP levels (<67 pg/ml) ruled out the presence of severe PH with a 100% sensitivity, however, with a low specificity (34%). Serial BNP testing in hemodynamically stable heart transplant candidates with MPAP≤40 mmHg allows reliable detection of development of severe PH, and may significantly reduce the need for repeated right-heart catheterizations in these patients.


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   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
* This study was funded by the grant of the Ministry of Health of the Czech republic No:VZ IKEM: CEZ L 17/98: 00023001. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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M. Kubanek, I. Malek, J. Bytesnik, P. Fridl, L. Riedlbauchova, L. Karasova, V. Lanska, and J. Kautzner
Decrease in plasma B-type natriuretic peptide early after initiation of cardiac resynchronization therapy predicts clinical improvement at 12 months
Eur J Heart Fail, December 1, 2006; 8(8): 832 - 840.
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