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European Journal of Heart Failure 2007 9(9):892-896; doi:10.1016/j.ejheart.2007.05.015
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© 2007 European Society of Cardiology

Independent effects of both right and left ventricular function on plasma brain natriuretic peptide

Thomas Wiis Vogelsanga,b,*, Ruben J. Jensena, Astrid L. Monradb, Kaspar Russb, Uffe H. Olesenb, Birger Hessea,b and Andreas Kjæra,b

a Department of Clinical Physiology, Nuclear Medicine and PET Rigshospitalet, Copenhagen, Denmark
b Cluster of Molecular Imaging, Department of Biomedicine The Panum Institute, University of Copenhagen, Denmark

* Corresponding author. Cluster for Molecular Imaging, Department of Biomedical Sciences, University of Copenhagen, The Panum Institute, Building 12.3, Blegdamsvej 3, DK-2200 Copenhagen. Tel.: +45 35 32 75 33; fax: +45 35 32 75 55. E-mail address: tvogelsang{at}mfi.ku.dk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Brain natriuretic peptide (BNP) is increased in heart failure; however, the relative contribution of the right and left ventricles is largely unknown.

Aim: To investigate if right ventricular function has an independent influence on plasma BNP concentration.

Methods: Right (RVEF), left ventricular ejection fraction (LVEF), and left ventricular end-diastolic volume index (LVEDVI) were determined in 105 consecutive patients by first-pass radionuclide ventriculography (FP-RNV) and multiple ECG-gated equilibrium radionuclide ventriculography (ERNV), respectively. BNP was analyzed by immunoassay.

Results: Mean LVEF was 0.51 (range 0.10–0.83) with 36% having a reduced LVEF (<0.50). Mean RVEF was 0.50 (range 0.26–0.78) with 43% having a reduced RVEF (<0.50). The mean LVEDVI was 92 ml/m2 with 22% above the upper normal limit (117 ml/m2). Mean BNP was 239 pg/ml range (0.63–2523). In univariate linear regression analysis LVEF, LVEDVI and RVEF all correlated significantly with log BNP (p<0.0001). In a multivariate analysis only RVEF and LVEF remained significant. The parameter estimates of the final adjusted model indicated that RVEF and LVEF influence on log BNP were of the same magnitude.

Conclusion: BNP, which is a strong prognostic marker in heart failure, independently depends on both left and right ventricular systolic function. This might, at least in part, explain why BNP holds stronger prognostic value than LVEF alone.

Key Words: BNP • Ejection fraction • Heart failure • Right ventricle • Left ventricle

Received August 3, 2006; Revised March 5, 2007; Accepted May 24, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Heart failure is a clinical syndrome, characterized by output failure relative to the metabolic needs of the tissue, with or without compensatory increased filling pressure [1]. In response to an increased filling pressure, the ventricles of the heart secrete brain natriuretic peptide (BNP) [2,3], increasing natriuresis and vasodilation. BNP is primarily secreted from the ventricles [2] and is a well-established biochemical marker of left ventricular function [4]. In patients with left ventricular dysfunction, regardless of its cause, the BNP concentration is increased [3]. BNP is related to the degree of impairment of LVEF in patients with congestive heart failure [5]. Since BNP is released from both ventricles [6], although usually mainly from the left ventricle, the right ventricle might also contribute to the increase in BNP plasma concentration seen in patients with cardiac dysfunction. In patients with right-sided cardiac enlargement, with hypertrophy and impaired ventricular function caused by e.g. pulmonary hypertension or pulmonary embolism, the right side of the heart may in the initial phase be affected, without any dysfunction of the left side [7]. Some small studies have shown elevated BNP in isolated right-sided cardiac dysfunction [8,9].

Therefore, we hypothesized that the plasma concentration of BNP could correlate, not only with left ventricular dysfunction, but also with right ventricular dysfunction. To test this hypothesis, we investigated the relationship between plasma levels of BNP and the functional parameters of both the right and left ventricles in patients with ventricular dysfunction of different causes, affecting the right and/or left ventricles.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
A total of 105 consecutive patients aged 18-78 (mean 49) years, referred to the department of Clinical Physiology, Nuclear Medicine and PET at Rigshospitalet, Copenhagen, Denmark for combined determination of left and right ventricular ejection fraction by radionuclide ventriculography, were included. The examinations were routine clinical examinations since we measure BNP as a standard procedure in connection with all radionuclide ventriculographies. Accordingly no examinations were excluded. Table 1 summarizes the different diagnoses of the patients. Data management was handled in accordance with the guidelines set out by The Danish Data Protection Agency, i.e. each patient was anonymised by using a random number.


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  		Table 1 Referral diagnoses of the study group (n=105)

 
2.2. Determination of left and right ventricular ejection fraction
With a small field-of-view gamma camera positioned in a right anterior oblique 30° angle view and a bolus of 700 to 900 MBq of 99mTc-labeled human serum albumin, RVEF was measured by a first-pass radionuclide study (FP-RNV). Thereafter, LVEF was measured in all 105 patients by using multiple ECG-gated equilibrium radionuclide study (ERNV) in which the gamma camera was positioned in a left anterior oblique 30° angle view, with a caudal tilt of 5° to 10° and adjusted for optimal separation of the left ventricle. LV end-diastolic volume (LVED) was calculated according to a previously described method [10] and was normalized to body surface area (LVEDVI). RVEF and LVEF were calculated using GE software (eNTEGRA version 1.5, General Electric, Milwaukee, WI, USA). The 95% confidence limits has previously been shown to be ±0.03 on a single measurement of LVEF and ±0.06 on a single measurement of RVEF [11].

2.3. Blood sample analysis
Blood samples were obtained in the supine resting position after 10 min of rest during the preparation of the scanning. Blood was drawn into tubes containing EDTA and aprotinin (Trasylol®, Bayer, Germany) and immediately transferred to ice-cold water. The samples were centrifuged at 10,000 rpm for 10 min; then plasma was transferred to polyethylene tubes and immediately frozen and kept at –80 °C until analyzed.

BNP was measured by an automated two-site sandwich immunoassay technique using chemiluminescence (Bayer, ADVIA Centaur, Leverkusen, Germany). The assay measures the physiologically active C-terminal peptide (77-108). The sensitivity of the assay was 2 pg/ml and the intra- and interassay coefficients of variation were 1.2% and 2.3%, respectively.

2.4. Statistical analysis
Data are presented as mean±SEM (range). Correlation between hormones and cardiac parameters was tested by means of linear regression. A one-sample Kolmogorov-Smirnov procedure was performed on the BNP values and they were found not to be normally distributed. A log10 transformation was then performed and BNP values were then normally distributed, which is in accordance with previous data [12,13]. We used a univariate regression analysis to predict the individual correlation between RVEF, LVEF, LVEDVI and log10 BNP. For determination of independent effects of RVEF, LVEF and LVEDVI on log10 BNP a multiple regression analysis was used with backward elimination of parameters. For evaluation of relative contribution of parameters, the parameter estimates in the final adjusted model were used. All statistical analyses were performed by SPSS statistical software package version 13.0 (SPSS, Chicago, IL, USA). p<0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Ventricular function and volume
One hundred and five subjects had their LVEF measured. By equilibrium radionuclide ventriculography (ERNV) LVEF was found to be 0.51 (range 0.10-0.83). In the present investigation 36% of the patients had an LVEF below 0.50, the lower reference value in our department for left ventricular dysfunction.

Left ventricular end-diastolic volume index (LVEDVI), measured in 100 of the patients, had an average value of 92 (range 35-263). Twenty-two percent of the patients had an LVEDVI above 117 ml/m2 (upper reference limit using our methodology), [11].

The mean RVEF, measured in the 105 patients by FP-RNV, was 0.50 (range 0.26-0.78), with 43% below the normal limit of 0.50. Thirty-one of the patients (30%) had combined reduction in LVEF and RVEF (both below 0.50).

3.2. BNP measurement
In the 105 patients the average plasma BNP concentration was 239±44 pg/ml (range 1-2521). Dividing the patients into sub-groups based on ejection fraction, we found that in the group of patients with LVEF below or above the 0.50 limit, the BNP concentration was 373±80 and 165±53 pg/ml, respectively. The sub-groups with RVEF below or above 0.50 had an average BNP concentration of 332±70 and 170±56 pg/ml, respectively.

In the sub-group of patients with both RVEF and LVEF below 0.50 the average BNP concentration was 413±95 pg/ml, and the sub-group with both RVEF and LVEF at or above the 0.50 limit had an average BNP concentration of 168±65 pg/ml. Log BNP concentrations in the different EF groups are shown in Fig. 1.


Figure 01
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  		Fig. 1 BNP values (log10 BNP) in the different EF groupings, i.e. in patients with RVEF and/or LVEF above or below 0.50. Values are mean±SEM. ##p<0.01 and ###p<0.001 vs. combined RV/LV dysfunction. *p<0.05 and ***p<0.01 vs. normal.

 
3.3. Relation of BNP to cardiac dimensions and ejection fraction
By linear regression analysis, the logarithm of BNP significantly correlated with LVEF, RVEF and LVEDVI. The strongest correlation was found with LVEF (R=–0.56, p<0.0001), followed by RVEF (R=–0.48, p<0.0001) (Table 2, Fig. 2) and LVEDVI (0.37, p<0.0001) (Table 2). In a multivariate regression analysis the initial model including the parameters LVEF, RVEF and LVEDVI, only LVEF and RVEF independently affected BNP (Table 3). The model was therefore adjusted by backwards elimination, i.e. LVEDVI was omitted and the model then consisted of LVEF and RVEF. In this model both LVEF and RVEF independently affected BNP. The parameter estimates in this adjusted final model were –1.99±0.45 for LVEF and –1.80±0.75 for RVEF on log BNP, i.e. change in log10 BNP was –1.99 for an increase in LVEF of 1 (100%). Therefore, the effects of LVEF and RVEF were of comparable size and seem almost equally important (Table 4).


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  		Table 2 Univariate regression analyses of cardiac parameters and BNP

 


Figure 02
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  		Fig. 2 Correlations between the log BNP and LVEF (upper panel: R2=0.32, p<0.001) and RVEF (lower panel: R2=0.23, p<0.001). LVEF: left ventricular ejection fraction; RVEF: right ventricular ejection fraction.

 


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  		Table 3 Multivariate regression analysis of cardiac parameters and BNP

 


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  		Table 4 Multivariate regression analysis of cardiac parameters and BNP

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The present study investigated the relation between circulating levels of BNP and left and right ventricular function in consecutive patients referred for measurement of right and left ventricular function. The major finding of the present investigation was the independent effect of RVEF as well as LVEF on the plasma level of BNP.

It has previously been demonstrated that BNP reflects LVEF in patients with heart failure [4]. The data in the present study are in accordance with previous studies and with findings from our own laboratory, showing that BNP correlates negatively with LVEF and positively with LVEDVI [14] and supports the idea that BNP can be used in the screening of patients for suspected heart failure [4]. It should be noted, that the two parameters are not independent, which is probably the reason why LVEDI in the multivariate analysis did not reach significance when LVEF was also included in the statistical model.

The correlation between BNP and right ventricular function has not been studied extensively. We found a highly significant correlation between BNP and RVEF (p<0.0001). A relation between BNP and RVEF has been reported previously in selected patient groups [8,15,16]. In the initial state of, for example pulmonary diseases and pulmonary embolism, only the right side of the heart will be affected by impaired ventricular function and ventricular hypertrophy [7]. However, primary left ventricular dysfunction eventually leads to right ventricular dysfunction. Likewise, after long standing right heart failure the left side may also become affected. Therefore, since right and left ventricular dysfunction are often combined, it is important to know whether RVEF independently affects BNP. To our knowledge, this has not previously been addressed. Using a multivariate regression analysis we found that RVEF independently correlated with BNP. Thus, BNP levels are determined both by LVEF and RVEF. Since right and left ventricular dysfunction often coexist, especially in the later stages of heart failure, looking only at LVEF and correlation with BNP could be too simple. Different degrees of right ventricular involvement may explain the varying results found when comparing LVEF and BNP. This could also be part of the explanation why BNP holds stronger prognostic value than LVEF [5] since BNP also covers right-sided involvement. However, it should be noted that BNP is not only explained by RVEF and LVEF, since the final model including these parameters only had an R2 of 0.35 (R=0.59). The relative importance of RVEF and LVEF seems to be similar, since the parameter estimates in the final adjusted model were of the same magnitude. One possible explanation for the unexplained variation in log BNP, is that stable secretion of BNP from another source such as the brain, could be a stable and low BNP contributor thus "diluting" the cardiac effect on circulating BNP concentrations. However, in healthy subjects BNP can be very low indicating that the heart is probably the most important source. Furthermore, it has indeed been demonstrated from comparison of concentrations in the coronary sinus and the systemic circulation, that the heart is indeed the major source of BNP both in states where BNP is normal and in states where BNP is increased [17].

It could be argued that the relation between RVEF, LVEF and BNP is only true for certain study populations. However, we studied consecutive patients with a mixture of diagnoses indicating that the results are broadly applicable. Inclusion of HIV patients may seem unusual, however we have previously shown that HIV patients have the same relation between levels of BNP and LVEF as HIV negatives [11]. Therefore, HIV per se is most unlikely to have influenced the relation between cardiac function and BNP.

We conclude that both LVEF and RVEF independently affect the plasma concentration of BNP and thus BNP is also a marker of right ventricular dysfunction. This could, at least in part, explain the higher prognostic value of BNP compared to LVEF. These findings further support the use of BNP in diagnosing and monitoring of patients with right- and/or left-sided heart failure.


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

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P. Leszek and J. Korewicki
Independent effects of both right and left ventricular function on plasma brain natriuretic peptide levels
Eur J Heart Fail, March 1, 2008; 10(3): 328 - 328.
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