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Eur J Cardiothorac Surg 2001;20:140-146
© 2001 Elsevier Science NL

Plasma levels of atrial and brain natriuretic peptides as indicators of recovery of left ventricular systolic function after coronary artery bypass

M. Chelloa, P. Mastrorobertoa, F. Perticoneb, F. Cirilloa, E. Bevacquaa, S. Olivitoa, E. Covinoa

a Department of Clinical and Experimental Medicine, Division of Cardiac Surgery, University of Catanzaro, Catanzaro, Italy
b Department of Clinical and Experimental Medicine, Division of Cardiology, University of Catanzaro, Catanzaro, Italy

Received 12 October 2000; received in revised form 21 March 2001; accepted 11 April 2001.

Corresponding author. Via S. Giacomo dei Capri 29, 80128 Naples, Italy. Tel.: +39-0961-712309; fax: +39-0961-775337
e-mail: chello{at}unicz.it


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Objective: The purpose of this study was to investigate the effectiveness of atrial and brain natriuretic peptides (ANP and BNP, respectively) as indicators of recovery of left ventricular (LV) function after coronary surgery. Methods: We measured the concentrations of these peptides in 31 patients with poor LV function (ejection fraction, EF<35%) undergoing coronary artery bypass, and evaluated their correlation with the echocardiographic indexes of LV function. Results: Pre-operatively, the plasma levels of both ANP and BNP were markedly higher in coronary patients than in normal control subjects, and strongly correlated with both EF (BNP: r=-0.8, P<0.001; ANP: r=-0.6, P<0.001) and wall motion score index (WMSI). At post-operative follow up, plasma levels of both natriuretic peptides were markedly reduced compared with pre-operative values in 21 patients. In addition, the post-operative–pre-operative differences of BNP ({Delta}BNP) and ANP ({Delta}ANP) plasma levels strongly correlated with the differences of both EF (r=-0.7, P<0.0001 vs. {Delta}BNP; r=-0.6, P=0.0003 vs. {Delta}ANP) and WMSI (r=0.6, P=0.002 vs. {Delta}BNP; r=0.6, P=0.04 vs. {Delta}ANP). Finally, by logistic regression analysis, BNP appeared a significant predictor of LVEF recovery after surgery. Conclusion: Plasma levels of ANP and BNP might be used in routine clinical practice as a support to echocardiography in detecting recovery of the LV function after coronary surgery.

Key Words: Atrial natriuretic peptides • Brain natriuretic peptides • Left ventricular dysfunction • Coronary bypass


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Coronary artery bypass grafting (CABG) in patients with severe left ventricular (LV) dysfunction (ejection fraction, EF<30%) is nowadays performed with increasing frequency, due to the encouraging results of recent clinical reports [1,2]. In fact, in many patients with coronary artery disease (CAD), impairment of LV function is not always irreversible, resulting from the presence of viable, hibernating myocardium, rather than of irreversible fibrosis [3].The important characteristic of hibernating myocardium is its ability to improve its contractile function after myocardial revascularization [4]. As a consequence, patients with extensive areas of hibernating myocardium can be expected to obtain the greatest benefits from revascularization in terms of improvement of LV function, heart failure symptoms, and survival. The assessment of myocardial function is therefore critical for the comparable interpretation of the results of surgical revascularization. Several different methods are available to detect LV dysfunction, and among them, radionuclide ventriculography and echocardiography are the most frequently adopted by clinical investigators. Nevertheless, the first presents some limitations in terms of availability, cost, and the need to administer a radioactive dose, while echocardiography, although widely available and less expensive, is less objective and requires experienced personnel.

Several recent studies have demonstrated that cardiac natriuretic hormones are a reliable index of LV dysfunction [5–8]. The atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are homeostatic hormones secreted from the human heart, which protect both the cardiac and the renal function through their natriuretic, diuretic, and vasodilative properties. BNP, first isolated from the porcine brain [9], presents a high degree of structural homology with ANP and is primarily synthesized in and secreted from the ventricle [10], whereas ANP is primarily synthesized in and secreted from the atrium [11]. The plasma half-life of BNP is longer, and BNP has greater natriuretic and arterial pressure-lowering effects than ANP [12]. It is well known that these hormones increase in patients along with increases in the severity of congestive heart failure or acute myocardial infarction, and their levels are strongly correlated with indicators of LV systolic and diastolic dysfunction [5–8,13,14]. The aim of our study is to determine: (1) whether plasma natriuretic cardiac peptide concentrations might be helpful in the follow-up monitoring of the LV function in patients undergoing coronary artery bypass, by comparing their plasma levels with the echocardiographic indexes of LV dysfunction; and (2) what the predictive power of these hormones on the recovery of the LV function is.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
Between May 1996 and October 1997, patients with CAD who were accepted for CABG were prospectively enrolled in this study if they fulfilled the following criteria: (1) LVEF<35% as assessed by echocardiography; and (2) detection of contractile reserve in dysfunctional myocardial segments by dobutamine stress echocardiography. Exclusion criteria were: (1) significant valvular heart disease; (2) acute myocardial infarction or unstable angina within 3 months; (3) LV aneurysm; (4) decompensation of heart failure within 3 months; (5) perioperative myocardial infarction; (6) angina during the echocardiographic study; and (7) suboptimal echocardiographic images. Thirty-one consecutive patients met the entry criteria.

2.1. Clinical characteristics
The clinical characteristics of the patients are summarized in Table 1. The mean duration of symptoms in the 31 patients was 20 months (range 8–44 months). All patients had an LVEF of <35% at entry (range 21–34%, mean 28.6±3.6%), determined visually by two-dimensional echocardiography. Renal function, as assessed by plasma creatinine concentrations, was normal in all patients.


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  		Table 1. Demographic and cardiac dataa

 
Forty control subjects were also studied. They were considered eligible if there were no historical or physical findings of heart disease or hypertension. Men composed 65% of the control group. The average age was 56±12 years and ranged from 28 to 78 years.

The study protocol was approved by the University of Catanzaro Committee for investigation involving human subjects. All patients gave their informed consent.

2.2. Echocardiography
All patients underwent dobutamine echocardiography by use of a Hewlett–Packard 77030A phased-array ultrasonoscope and a 2.5 or 3.5 MHz transducer; images were digitized on-line with an electrocardiogram (ECG) R wave-triggered mechanism and recorded on a 0.75 inches (1.9 cm) video recorder for subsequent analysis. Images were acquired from parasternal long- and short-axis views and from apical four- and two-chamber views, with the patient in the left lateral recumbent position.

After a rest ECG and echocardiogram were acquired, intravenous access was secured, and dobutamine was infused by an infusion pump, starting from 5 µg kg-1 min-1 with increments of 10 µg kg-1 min-1 every 3 min until a maximum of 40 µg kg-1. When 85% of the predicted maximal heart rate was not reached, atropine (up to 1 mg) was added to the continuing 40 µg kg-1 dobutamine infusion. LV wall motion score, volumes, and LVEF were calculated at each stage of dobutamine infusion.

2.3. Regional wall motion
Regional wall motion was assessed according to the recommendations of the American Society of Echocardiography with a 16-segment model [15]. In all studies, each segment was graded using a semiquantitative four-point scoring system, as follows: normal=1; hypokinetic=2, marked reduction of endocardial excursion and wall thickening; akinetic=3, near or total absence of inward motion and thickening; and dyskinetic=4, systolic outward motion with thinning. The wall motion score index (WMSI) was calculated by dividing the sum of individual segment scores by the number of evaluated segments.

2.4. Myocardial viability
A response was considered normal when segments with normal wall thickening at rest had a persistent hyperdynamic response to dobutamine. The presence of myocardial viability was defined as a functional improvement of at least one grade at low-dose dobutamine infusion (up to 10 µg kg-1 min-1) in at least two contiguous segments with abnormal rest regional function.

The echo images were interpreted by two independent investigators who adopted the same assessment criteria and were blinded to patients' data. In case of disagreement, a third observer reviewed the study. Agreement of interobserver analysis for segmental dyssynergy occurred in 96% of the segments visualized.

2.5. Measurement of plasma levels of ANP and BNP
Pre-operative and post-operative blood sampling were done from the antecubital vein after the patient had rested supine for 20 min. All blood samples were placed in chilled plastic tubes containing 1 mg ml-1 ethylenediaminetetraacetic acid (EDTA) and 1000 kallikrein inhibitory units ml-1 aprotinine and immediately placed on ice. Thereafter, the blood was centrifuged at 4°C, and the plasma was stored at -70°C until assay. Plasma concentrations of BNP and ANP were measured by radioimmunoassay using a commercially available kit (Peninsula Laboratories).

2.6. Statistic
Data are expressed as mean±1 SD unless otherwise indicated. Data were analyzed using Student's test for paired and unpaired data where appropriate. Because ANP and BNP values were not normally distributed, hormone plasma levels were logarithmically transformed for statistical analysis, but are presented in the study as non-transformed mean±SEM. Linear regression analysis was used to assess the relation between plasma levels of natriuretic peptides and hemodynamic variables. To assess the predictive power of plasma levels of natriuretic peptides on the recovery of the LV function, we used a logistic regression, with improved LVEF (post-operative increment >5%) as the dependent variable and the plasma levels of ANP and BNP, age, sex, previous myocardial infarction, and number of viable myocardial segments as independent variables. A value of P<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1. Surgery
Two of 31 patients (6.5%) had a single coronary graft, 11 had two grafts (35.5%), and 18 had three grafts (58%). The mean number of grafts per patient was 2.5. There was one hospital death (6 days post-operatively) because of congestive heart failure. All surviving patients were followed up to a mean of 13 months (range 12–20 months). The number of patients in NYHA classes III and IV decreased from 25 (80%) to 9 (30%). Of the 30 surviving patients, recurrent angina occurred in two patients during the follow-up period. In both patients, the LVEF remained unchanged compared with pre-operative values. Digoxin and diuretics were gradually suspended in 14 out of 21 patients with post-operative improvement of LVEF (>5%).

3.2. Echocardiography
Follow-up echocardiograms (mean 10±3 months) were compared with the corresponding pre-operative rest images. The observers had no knowledge of the pre-operative dobutamine results. A total of 496 myocardial segments was analyzed in the 31 patients pre-operatively. Resting pre-operative echo examinations detected 129 normal (26%), 164 hypokinetic (33%), 168 akinetic (34%), and 35 dyskinetic segments (7%). After revascularization, the percentage of normal segments increased to 226 (from 26 to 49%, P=0.0008), whereas a significant decrease in the percentage of akinetic segments was observed (from 34 to 14%, P=0.0005). The regional WMSI improved greatly after CABG, from 2.2±0.1 to 1.7±0.2 (P<0.0001).

3.3. ANP–BNP plasma levels
Pre-operatively, the mean plasma concentration of both ANP and BNP was markedly higher in the patients with CAD than the mean for control (n=40) in our assay (ANP: 46±14.3 pmol l-1 in CAD vs. 9±6 pmol l-1 in control, P<0.0001; BNP: 38.5±17.2 pmol l-1 in CAD vs. 4±3 pmol l-1 in control, P<0.0001). The plasma BNP and ANP values strongly correlated in patients with LV dysfunction (r=0.8, P<0.0001). When calculated on a separate linear regression analysis, there was a significant negative correlation between LVEF and plasma concentrations of BNP (r=-0.8, P<0.0001) and ANP (r=-0.6, P<0.0001) in patients with LV dysfunction (Fig. 1 ).



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  		Fig. 1. Correlation between left ventricular ejection fraction (EF) and plasma concentrations of ANP (upper panel) and BNP (lower panel). Pre-operative values are reported.

 
At follow up (mean 10±3 months), plasma levels of both ANP and BNP decreased greatly compared with pre-operative values (ANP: 34.5±10.4 pg ml-1, P=0.01; BNP: 22.4±9.6 pmol l-1, P=0.0003). The correlation between the difference of the plasma levels of BNP and ANP and the differences of the LVEF and WMSI between the post-operative period and the pre-operative periods were also evaluated. Figs. 2 and 3 show that the difference of the mean plasma levels of BNP ({Delta}BNP) and that of ANP ({Delta}ANP) closely correlated with the differences of EF ({Delta}EF) (r=-0.7, P<0.0001 vs. {Delta}BNP, r=-0.6, P=0.0003 vs. {Delta}ANP) and of WMSI ({Delta}WMSI) (r=0.6, P=0.002 vs. {Delta}BNP, r=0.6, P=0.004 vs. {Delta}ANP), respectively.



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  		Fig. 2. Correlation between post-operative–pre-operative differences of plasma levels of ANP ({Delta}ANP, upper panel) and BNP ({Delta}BNP, lower panel) and post-operative–pre-operative difference of left ventricular ejection fraction ({Delta}EF).

 


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  		Fig. 3. Correlation between post-operative–pre-operative difference of plasma levels of ANP ({Delta}ANP, upper panel) and BNP ({Delta}BNP, lower panel) and post-operative–pre-operative difference of wall motion score index.

 
3.4. Ejection fraction
Compared with pre-revascularization assessment, LVEF increased greatly in 21 patients (post-operative 38.7±3.4% vs. pre-operative 29±3.9%, P<0.0001), and remained essentially unchanged (within five EF points of the pre-operative value) in nine patients. Table 2 shows the plasma levels of the two natriuretic hormones in the two groups of patients. In patients with unchanged post-operative LVEF, both the pre-operative and the post-operative plasma levels of BNP were higher than in patients with improved LVEF, whereas only post-operative plasma ANP levels showed a significant difference between the two groups. When analyzed by logistic regression, plasma BNP levels and the number of viable myocardial segments were found to be the only variables with predictive power regarding recovery of the LV function.


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  		Table 2. ANP and BNP levels in LVEF groupsa

 
3.5. NYHA classes
The plasma levels of both ANP and BNP increased markedly in proportion to the severity of the NYHA class, and they were considerably higher in classes III and IV compared with class II (ANP: 49.4±14.4 vs. 34.10±11.6 pg ml-1, P=0.02; BNP: 41±16.9 vs. 21.1±8.3 pg ml-1, P=0.01). When analyzed by linear correlation, a significant correlation was found between plasma levels of both BNP and ANP and NYHA class (BNP: r=0.7, P<0.001 and ANP: r=0.7, P=0.002).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
The incidence of congestive heart failure is increasing despite an observed decline in CAD mortality [16]. The prevalence of heart failure, in particular, is increasing owing to the aging population, the more patients surviving acute myocardial infarction, and the improved non-surgical treatment of coronary disease.

In many recent studies good results have been obtained with CABG in patients with CAD and severe LV dysfunction [1,2] and a direct correlation between the amount of viable myocardium and functional improvement after revascularization has been demonstrated [17,18]. In the present study, we found that both the pre-operative plasma levels of BNP and the number of viable myocardial segments were good predictors of the recovery of the LV function after coronary artery bypass surgery in patients with severe LV dysfunction. On the whole, these results suggest that a proper selection of patients with severe CAD and LV dysfunction is advisable to identify those patients who will likely benefit from surgical revascularization in terms of low operative risk and long-term outcomes.

4.1. Comparison with previous studies
The results of this study are in agreement with the above-cited reports, and show that patients with compromised LV function have good in-hospital outcomes and good medium-term survival. An increase in LVEF of 5% or more after operation is usually chosen to overcome any potential variation in its measurement. In the present study, only 21 patients (70%) achieved such a favorable outcome. Patients with this finding also had more frequent improvement in heart failure symptoms 1 year post-operatively. The improvement in contractile status during stress with dobutamine paralleled the observed reduction of the WMSI. Nevertheless, in most zones, the amount of contractile recovery was less than that anticipated by contractile reserve. The possible explanation for these findings has already been discussed in other studies [17,18] and could be explained by some inherent limitations of the dobutamine echocardiography test, such as tethering, which may lead to possible overestimation of myocardial viability.

4.2. Correlation between BNP–ANP and left ventricular dysfunction
Assessment of the benefits obtained by revascularization procedures is an important clinical issue in patients with chronic ischemic heart disease and global LV dysfunction. As stressed by McDonagh et al. [7], differences between studies in the methods used to assess LV function (e.g. echocardiography, radionuclide ventriculography, or angiography, which have known discrepancies in the normal range of EF) lessen the value of comparison of absolute sensitivity and specificity. Moreover, changes in LVEF alone may not reflect the benefits obtained by revascularization and clinical evaluation is inadequate in detecting LV dysfunction. EF, like all diagnostic indexes, has an optimal range and is less accurate at the upper and lower ends of the spectrum [19], and at this latter edge are patients with heart failure. Finally, the New York Association classification of symptoms in patients with heart failure has been the subject of criticism in recent years [20,21]: besides a subjective interpretation of symptoms, a placebo effect could potentially influence the subjective clinical status of patients as assessed by this classification after a coronary operation.

Studies by several investigators demonstrated that BNP and ANP are raised in people with LV systolic dysfunction, whether symptomatic or asymptomatic [5–8]. However, to the best of our knowledge, our study is the first to report a relation between plasma BNP and ANP and recovery of the LV function after coronary bypass surgery. Our data confirm that plasma BNP and ANP concentrations are raised in cardiac disease in proportion to the severity of LV dysfunction, and that pre-operative plasma levels of BNP are valuable predictors of the post-operative recovery of the LV function.

This information complements the powerful body of published evidence linking BNP concentrations to hemodynamic state in heart disease [5–8,13,14]. In the present study, in which hemodynamic data were available only pre-operatively, plasma BNP and ANP correlated significantly with pulmonary capillary wedge pressure, cardiac index, and LV end diastolic pressure (data not shown), which is consistent with the data reported by other investigators [22–24]. On the whole, our data seem to support an association of plasma natriuretic hormones with LV function. Although some studies suggest that BNP may be more closely related to LV dysfunction than ANP [5,25], the close relationship between plasma ANP and BNP levels observed in this study indicates that both hormones are equally accurate in the detection of LV dysfunction. Finally, in the present study, both digoxin and diuretics have been gradually discontinued in 14 patients with improved LVEF; however, to the best of our knowledge, neither diuretics nor digoxin seem to be directly related to plasma levels of cardiac natriuretic peptides.

4.3. Study limitations
The aim of our study was to determine whether plasma BNP and ANP concentrations could serve as a marker for early recovery of LV dysfunction after coronary artery bypass. Because our study covered a short time interval, we did not evaluate the role of these hormones in predicting long-term prognosis and the overall impact of the procedure on mortality, for which longitudinal studies are advisable in a larger group of patients.

The major limitations of this study are the relatively small patient cohort. Moreover, some intrinsic limitations of dobutamine echocardiography must be addressed: at first, the evaluation of regional wall motion may be influenced by tethering and post-operative paradoxical septal motion [10,11]. Finally, the echocardiograms were interpreted locally by three independent readers and, although they were examined without knowledge of the intervention, post-surgical abnormal septal wall motion could have biased the analysis. However, follow-up echocardiography was performed a mean of 10 months post-operatively, thereby limiting the confounding effect of paradoxical septal dyssynergy.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
In this study, in a group of patients with coronary obstructive disease and LV dysfunction, plasma BNP and ANP concentrations were raised above normal in proportion to the degree of hemodynamic impairment, whereas a significant decrement was observed after coronary revascularization, which paralleled improvement of LV function. BNP and plasma ANP concentrations were closely correlated and the two peptides may complement each other in the overall neurohumoral response to cardiac dysfunction. Hormonal assays such as ANP and BNP are not widely available at present but technology and expertise are available to perform these assays in all hospital laboratories. In conclusion, both natriuretic peptides are suitable as indicators of improved LV function after coronary revascularization and might be used in routine clinical practice as a support to echocardiography.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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