Attenuation of Compensation of Endogenous Cardiac Natriuretic Peptide System in Chronic Heart Failure
Prognostic Role of Plasma Brain Natriuretic Peptide Concentration in Patients With Chronic Symptomatic Left Ventricular Dysfunction
Background Patients with congestive heart failure (CHF) have high plasma levels of atrial natriuretic peptide (ANP), mainly from the atrium, and brain natriuretic peptide (BNP), mainly from the ventricle. We examined the prognostic role of plasma BNP in chronic CHF patients in comparison with plasma ANP and other variables previously known to be associated with high mortality. We also evaluated the relationship between mortality and plasma cGMP, a biological marker of ANP and BNP.
Methods and Results The study subjects were 85 patients with chronic CHF (left ventricular ejection fraction <0.45) who were followed for 2 years. The plasma levels of ANP, BNP, cGMP, and norepinephrine increased with the severity of CHF. Among plasma levels of ANP, BNP, cGMP, and norepinephrine and clinical and hemodynamic parameters, only high levels of plasma BNP (P<.0001) and pulmonary capillary wedge pressure (P=.003) were significant independent predictors of the mortality in patients with CHF by Cox proportional hazard analysis. Although plasma levels of ANP and BNP were threefold or fivefold higher in nonsurvivors than in survivors, there was no difference in plasma cGMP level between nonsurvivors and survivors.
Conclusions These findings indicate that plasma BNP is more useful than ANP for assessing the mortality in patients with chronic CHF and that the plasma levels of BNP provide prognostic information independent of other variables previously associated with a poor prognosis. Our findings also suggest that the compensatory activity of the cardiac natriuretic peptide system is attenuated as mortality increases in chronic CHF patients with high plasma levels of ANP and BNP.
Increased levels of various vasoconstrictor neurohumoral factors have been found in patients with chronic CHF,1 2 3 4 5 6 7 and the high plasma levels of NE, renin, and endothelin-1 have been reported to be significant prognostic predictors,4 8 9 10 suggesting the important role of vasoconstrictors in the pathogenesis of CHF. High levels of vasodilator neurohumoral factors have also been found in patients with CHF, and a high plasma level of ANP, mainly from the atrium, has been reported to be a significant prognostic predictor.8 11 12 13 BNP levels are also increased, and the main origin is thought to be the ventricular myocytes in patients with acute and chronic CHF.14 15 16 17 Both plasma cardiac natriuretic peptides, ANP and BNP, are increased with the severity of CHF due to left ventricular dysfunction, and these increases are correlated to the hemodynamic parameters such as PCWP and LVEF.14 16 17 18 19 20 21 The plasma BNP has been reported to increase with the severity of CHF, but its relationship to the mortality in patients with chronic CHF remains unknown. Moreover, since the biological receptors of natriuretic peptides may be downregulated in patients with severe CHF22 23 and the compensatory activity of these endogenous peptides may be attenuated, the relationship between plasma cGMP level, a biological marker of natriuretic peptides,24 25 26 27 28 and mortality in patients with chronic CHF also must be determined.
Therefore, in the present study we examined whether the plasma level of BNP is superior to the plasma ANP for the assessment of the severity and mortality in chronic CHF patients with left ventricular dysfunction and whether the plasma BNP provides prognostic information additional to that obtained from clinical, hemodynamic, and biochemical variables previously known to be associated with high mortality in patients with CHF. In addition, we examined whether the attenuation of the compensatory activity of the cardiac natriuretic peptides system is related to the mortality of CHF patients with high plasma ANP and BNP levels.
The subjects were 85 patients with chronic CHF (61 men and 24 women between 22 and 84 years old [mean age, 60 years]) who were hospitalized at our institution. Informed consent was obtained from all patients for participation in the study according to a protocol approved by the Committee on Human Investigation at our institution. The cause of heart failure was dilated cardiomyopathy in 41 patients, ischemic heart disease (>3 months since myocardial infarction) in 41 patients, and hypertensive heart disease in 3 patients. All patients had an LVEF of <45% on the basis of left ventriculography with radionuclide or contrast medium. Patients who had an infection, chronic inflammatory disease, malignancy, or renal failure were excluded. Forty-six patients were in NYHA functional class II, 18 were in class III, and 21 were in class IV. All patients were clinically stable on constant doses of diuretics; 75 patients were treated with digoxin, 68 patients were treated with ACE inhibitors, 50 patients were treated with vasodilators, and 25 patients were treated with β-blockers. All drugs had been administered for ≥4 weeks (most for >3 months).
Right-sided cardiac catheterization was performed with a 7F Swan-Ganz catheter, and right heart pressure, such as right atrial pressure, mean pulmonary arterial pressure, and PCWP, were measured after ≥30 minutes of bed rest with the patient in the supine position. Cardiac output was measured according to the thermodilution technique, and blood samples were drawn from the pulmonary artery for measurement of plasma ANP, BNP, cGMP, and NE concentrations. Left ventriculography was performed with contrast medium or radioisotope at least before or 1 week after the hemodynamic measurements and blood sampling. All patients were followed for >1 year (mean follow-up period, 24 months). Twenty-five patients died from a cardiac cause during the follow-up period.
Measurement of Plasma Levels of ANP, BNP, and NE
Samples for the assay of plasma ANP and BNP concentrations were transferred to chilled disposable tubes containing aprotinin (500 kallikrein inactivator units/mL). The blood samples were immediately placed on ice and centrifuged at 4°C as previously reported.21 Plasma ANP concentrations were measured with a specific immunoradiometric assay for α-human ANP using a commercial kit (Shionoria). Briefly, this assay uses two monoclonal antibodies against α-human ANP, one recognizing a carboxyl-terminal sequence and the other the ring structure of ANP, and measures α-human ANP by sandwiching it between the two antibodies without the plasma extraction. The minimal detectable quantity of α-human ANP is 5 pg/mL. The intra-assay and interassay coefficients of variation were 5.1% and 5.8%, respectively. This assay system did not cross-react with angiotensin I or II, vasopressin, or human BNP. The cross-reactivity with human BNP was <0.001% on a molar basis. Plasma BNP concentrations were measured with a specific immunoradiometric assay for human BNP using a commercial kit (Shionoria). Briefly, this assay uses two monoclonal antibodies against human BNP, one recognizing a carboxyl-terminal sequence and the other the ring structure of BNP, respectively, and measures BNP by sandwiching it between the two antibodies without the plasma extraction. The minimal detectable quantity of human BNP is 2 pg/mL. The intra-assay and interassay coefficients of variation were 5.2% and 6.1%, respectively. This assay system did not cross-react with angiotensin I or II, vasopressin, or human ANP. The cross-reactivity with human ANP was <0.001% on a molar basis. Blood specimens for the assay of plasma cGMP concentrations were transferred to a chilled disposable tube containing 5 mmol/L EDTA. The blood specimens were immediately placed in ice and centrifuged at 4°C. Aliquots of plasma were measured by radioimmunoassay with a commercial kit (Yamasa Shoyu Co Ltd) as previously reported.22 The minimal detectable concentration was 0.5 pmol/mL. The intra-assay and interassay coefficients of variation were 2.4% (n=6) and 6.1% (n=6), respectively. Plasma NE concentrations were measured with high-performance liquid chromatography as previously reported.7
All values were expressed as mean±SEM. Univariate analyses were performed using the Student’s t test. Comparisons between multiple groups were determined by one-way ANOVA with Scheffé’s test. Categoric data were compared against a χ2 distribution. The prognostic value of the variables was tested in a Cox proportional hazards regression analysis. Kaplan-Meier analysis was performed on the cumulative rates of survival in patients with CHF stratified into two groups on the basis of median plasma levels of BNP, and the differences between survival curves were analyzed by log-rank test. To determine whether the plasma BNP concentration seen in our CHF patients was an independent prognostic factor or only reflected the importance of other factors, 14 variables, as listed below, were entered into a Cox proportional hazard analysis. Linear regression analysis was used to determine the relationship between continuous variables. The difference of the slope of the linear regression line was tested by an ANCOVA. A value of P<.05 was considered statistically significant.
Patient Characteristics and Clinical Data
Twenty-five patients died from a cardiac cause during the follow-up period. NYHA functional class differed significantly between survivors and nonsurvivors (Table 1⇓); there was no difference between survivors and nonsurvivors in age, gender, etiology of heart failure, or treatment. The basal plasma ANP levels in patients who were treated with ACE inhibitors were significantly higher than those in patients who were not treated with ACE inhibitors (192±20 versus 89±28 pg/mL, P<.05), but there was no significant difference in plasma BNP levels between patients who were treated with ACE inhibitors and those who were not treated with ACE inhibitors (208±36 versus 174±68 pg/mL).
Neurohumoral Plasma Concentrations According to Severity of Heart Failure
The plasma levels of NE, ANP, BNP, and cGMP increased with the severity of CHF (Fig 1⇓). The plasma level of ANP differed significantly between functional classes II and III and between classes II and IV but not between classes III and IV. The plasma levels of NE, BNP, and cGMP differed significantly between classes II and IV and between classes III and IV but not between classes II and III.
Hemodynamic and Neurohumoral Data According to Survival
The mean LVEF was 31±1.1% in 85 patients with CHF. All hemodynamic data except mean arterial pressure and cardiac index differed significantly between survivors and nonsurvivors (Table 2⇓). The plasma level of NE was significantly higher in nonsurvivors than in survivors. Plasma levels of ANP and BNP were also significantly higher in nonsurvivors than in survivors, but there was no significant difference in plasma cGMP level (Table 2⇓).
Correlation Between Plasma Cardiac Natriuretic Peptide Concentrations and Clinical, Hemodynamic, and Neurohumoral Data
Among the hemodynamic variables, plasma ANP levels significantly correlated with right atrial pressure, PCWP (r=.54, P<.0001), mean pulmonary arterial pressure (r=.46, P<.0001), cardiac index, and LVEF (r=−.47, P<.0001) (Table 3⇓). Among other neurohumoral factors, plasma ANP levels significantly correlated with plasma cGMP (r=.58, P<.0001) and NE (r=.47, P<.0001).
Plasma BNP concentrations significantly correlated with age (r=.46, P<.0001). Among the hemodynamic variables, plasma BNP concentrations significantly correlated with heart rate, right atrial pressure, PCWP (r=.47, P<.0001), mean pulmonary arterial pressure (r=.45, P<.0001), and LVEF (r=−.38, P=.0003) (Table 3⇑). Among other neurohumoral factors, plasma BNP concentrations significantly correlated with plasma ANP (r=.53, P<.0001), cGMP (r=.40, P=.0002), and NE (r=.67, P<.0001).
Relationship Between Plasma ANP and BNP and Plasma cGMP Level in Survivors and Nonsurvivors
Plasma BNP concentration was approximately fivefold higher in nonsurvivors than in survivors, but there was no significant difference in the plasma level of cGMP (Table 2⇑). There was a significant positive correlation between the plasma levels of ANP and cGMP in both survivors and nonsurvivors. The slope of the linear regression line between the two parameters in nonsurvivors was approximately one third of that in survivors, showing a significant difference (Fig 2⇓, P<.001). There also was a significant positive correlation between the plasma levels of BNP and cGMP level in survivors (r=.53, P<.0001). In contrast, there was no significant correlation between the two parameters in nonsurvivors (Fig 3⇓). Moreover, the majority of the cases were on the right side of the linear regression line of the survivors. The slope of the linear regression line between the plasma levels of BNP and cGMP level in nonsurvivors was approximately one fifth of that in survivors, showing a significant difference (Fig 3⇓, P<.001).
Univariate and Multivariate Predictors of Mortality
During the follow-up period, 25 patients died of cardiac causes. Fourteen clinical, neurohumoral, and hemodynamic variables were analyzed using univariate and stepwise multivariate Cox proportional hazards regression analyses (Table 4⇓). By univariate analyses, 10 clinical, neurohumoral, and hemodynamic variables (except heart rate, cardiac index, mean arterial pressure, and gender) were significant predictors of mortality. According to stepwise multivariate analyses, only high levels of the plasma BNP (P<.0001) and PCWP (P=.003) were significant independent predictors (Table 4⇓). Once these variables were entered into the model, other variables, including LVEF, ANP, and cGMP, failed to contribute to prediction of survival. In the present study, the relative risk ratio of BNP was 1.003 (95% confidence interval, 1.001 to 1.004), and that of PCWP was 1.083 (95% confidence interval, 1.027 to 1.143).
Kaplan-Meier Lifetime Analysis
The patients were stratified into two groups on the basis of median plasma concentration of BNP (73 pg/mL, Fig 4⇓), and cumulative survival curves were constructed according to Kaplan-Meier survival methods. Survival rates, as evaluated by Kaplan-Meier survival analysis, were significantly lower in patients with plasma BNP concentration of >73 pg/mL (P<.0001).
Various circulating neurohumoral factors that increase in patients with heart failure are thought to play important roles in the pathogenesis of heart failure.1 2 3 4 5 6 7 8 9 10 11 12 13 We demonstrated for the first time that high plasma levels of BNP, mainly derived from the ventricle, may be an important prognostic predictor in chronic CHF patients with left ventricular dysfunction. Moreover, the plasma BNP level is a better predictor than the plasma ANP level, mainly from the atrium, and the plasma BNP level is an independent significant predictor if used with hemodynamic parameters, such as PCWP and LVEF, to assess mortality in chronic CHF patients with left ventricular dysfunction. These findings suggest that the plasma BNP concentration is a sensitive marker of the left ventricular damage or dysfunction because BNP is ventricular in origin.15 17
We also demonstrated for the first time the role of plasma level of cGMP, a biological marker of natriuretic peptide,24 25 26 27 28 as a predictor of prognosis of chronic CHF patients. Although plasma levels of ANP and BNP were threefold and fivefold higher, respectively, in nonsurvivors than in survivors, there was no difference in plasma level of cGMP between nonsurvivors and survivors, and the relations between plasma ANP and BNP and plasma cGMP differed between survivors and nonsurvivors (Figs 2⇑ and 3⇑), suggesting the downregulation of natriuretic peptide receptor coupled to guanylate cyclase in the nonsurvivors of the present study as previously shown in patients with severe CHF.22 23 The plasma level of cGMP was a significant prognostic predictor as a result of a univariate analysis but was no longer an independent prognostic predictor among 14 clinical, hemodynamic, and neurohumoral variables, including plasma levels of ANP and BNP. These findings suggest that the attenuation of the compensatory activity of cardiac natriuretic peptide system may increase the mortality of CHF patients with high levels of plasma cardiac natriuretic peptides.
Possible Downregulation of BNP Receptors Coupled to Guanylate Cyclase
At least two mechanisms are known to increase intracellular cGMP; one is the particulate guanylate cyclase, such as the GC-A receptor to which both ANP and BNP bind with high affinity, and the other is soluble guanylate cyclase. The plasma arteriovenous cGMP difference increased after intravenous nitroglycerin infusion, as previously reported.29 Therefore, we cannot deny the possibility that the increase in plasma cGMP in CHF patients treated with nitrates may have derived in part from soluble guanylate cyclase. Studies with HS-142-1, a natriuretic peptide receptor antagonist, in dogs with pacing-induced heart failure, indicated that most of the elevated plasma cGMP level may have derived from the particulate guanylate cyclase.30 The plasma levels of BNP were approximately fivefold higher in nonsurvivors than in survivors, but there was no significant difference in the plasma level of cGMP. The slope of the linear regression line between the plasma levels of BNP and cGMP level in nonsurvivors was approximately one fifth of that in survivors. Therefore, our findings suggest that the downregulation of cardiac natriuretic peptide receptors coupled to guanylate cyclase occurs with BNP as well as with ANP22 23 31 and contributes to the progression of CHF.
Why Is Plasma BNP a Stronger Prognostic Predictor Than ANP or LVEF?
Because there is a positive correlation between the plasma ANP and atrial pressure,17 18 19 20 21 atrial pressure or stretch plays an important role in regulating secretion of ANP. BNP is another novel cardiac natriuretic peptide, which was first isolated from the porcine brain32 and subsequently from the hearts of humans as well as of pigs and rats, that forms a peptide family with ANP and may be involved in the regulation of blood pressure and fluid volume.33 34 Previous studies have shown that plasma levels of ANP and BNP are increased in patients with CHF7 9 10 14 15 16 17 ; in the present study, the plasma levels of BNP and ANP were markedly increased in patients with CHF. Generally, plasma levels of ANP and BNP are significantly correlated with hemodynamic parameters such as right atrial pressure, PCWP, and left ventricular end-diastolic pressure. Therefore, these hormones have been considered to be noninvasive hemodynamic markers.14 17 18 19 20 21 Recently, Yasue et al17 reported that ANP is secreted mainly from atria and that BNP is secreted mainly from the left ventricle in proportion to the degree of the left ventricular dysfunction in patients with CHF. BNP DNA has an AT-rich sequence in the 3′-untranslated region that is known to destabilize mRNA and is not found in ANP DNA; in addition, BNP mRNA is strongly induced during, for example, ventricular wall tension or stretch.35 36 37 These findings suggest that BNP plays a role as an emergency aid for ANP in patients with heart failure and that the synthesis and secretion of BNP are stimulated with the degree of myocardial ischemia, necrosis, damage, and local mechanical stress on ventricular myocytes even when the global hemodynamic parameters are the same. These possibilities may account for our finding that the plasma BNP level is a strong prognostic predictor and a sensitive marker of the ventricular damage in multivariate analyses that included hemodynamics such as LVEF and PCWP.
Prognostic Role of LVEF and NE in the Present Study
In the present study, LVEF was a prognostic predictor in univariate analysis but not an independent factor in multivariate analysis. We selected patients with a low LVEF (<45%) and the other variables such as ANP and BNP were not restricted by that criterion, the severity varied among patients with the same LVEF, and there was also a significant correlation between the LVEF and plasma levels of ANP and BNP. Therefore, LVEF was not an independent factor in multivariate analysis. In the present study, plasma NE levels also were not independent predictors of mortality when the ANP level was measured concomitantly as shown previously,9 11 but a positive correlation between the plasma levels of NE and BNP suggests sympathetic nervous activation, which is well known to stimulate the myocardial damage, increases the secretion of BNP directly and/or indirectly.
Prognostic Role of Cardiac Natriuretic Peptides in Myocardial Infarction
The prognostic role of ANP, mainly secreted from the atrium, has been well established in patients with CHF.8 11 In the case of myocardial infarction, the plasma level of ANP is a powerful indicator of prognosis among various neurohumoral factors, including plasma NE and the renin-angiotensin-aldosterone system. However, in both the SAVE and CONSENSUS II trials,9 38 plasma ANP was also significantly associated with the severity of left ventricular dysfunction, and the independent predictive value of plasma ANP levels was markedly reduced or eliminated in multivariate analyses that included LVEF, which is firmly established as a powerful determinant of prognosis after myocardial infarction. BNP is secreted predominantly from the ventricle in response to ventricular damage or dilatation, although smaller amounts are also released from atrial myocytes. Circulating levels of BNP levels increase in patients with myocardial infarction in proportion to the severity of the disease, so BNP may be a sensitive marker of left ventricular remodeling.15 16 Very recently, Omland et al39 reported the important prognostic role of plasma BNP on day 3 after symptom onset in patients with acute myocardial infarction showing a wide range of LVEF (range, 14.5% to 71%). The prognostic role of BNP remains unknown in patients with an old myocardial infarction with a low LVEF (<45%). In the present study, the plasma BNP level was an independent prognostic predictor in multivariate analysis that included hemodynamics, such as LVEF and PCWP, in 85 patients with symptomatic left ventricular dysfunction, including 41 patients with old myocardial infarction. Our findings as well as those of Omland et al39 indicate that knowledge of BNP levels not only at the acute but also at the chronic phase of the disease might be valuable to evaluate the severity of the disease and predict the mortality of the patients with myocardial infarction regardless of whether assessment of LVEF is available.
Although the plasma cGMP level is a well known biological marker of ANP and BNP,24 25 26 27 28 30 we cannot deny that other mechanisms regulate plasma cGMP levels in patients with CHF, including soluble guanylate cyclase.29 We also cannot deny the possibility of more rapid degradation of the plasma cGMP in severe CHF patients with high plasma natriuretic peptides. Generally, high plasma levels of ANP and BNP in CHF patients with normal renal function are thought to increase the secretion of ANP and BNP with no remarkable change in the clearance of these peptides. Therefore, we believe that the plasma level of cGMP in CHF patients with normal renal function is mainly regulated by production from the target cells of the natriuretic peptides.
Treatments were not randomized in the present study, so it may be difficult to evaluate the effects of the drugs on mortality. We did not evaluate drug treatments using Cox multivariate analysis. If we entered drug treatments in addition to 14 variables in the Cox multivariate analyses, none of the drugs, including digitalis and ACE inhibitors, would have been independently significant predictors of mortality in the present study. Further studies are needed to clarify the role of repetitive measurement of BNP before and after treatments with drugs such as ACE inhibitors in determining the prognosis of CHF patients.
Conclusions and Clinical Implications
High plasma levels of BNP, mainly derived from the ventricle, can be an important prognostic predictor in chronic CHF patients with left ventricular dysfunction. Moreover, we demonstrated that the plasma level of BNP is more useful than the plasma level of ANP, mainly derived from the atrium, and that the plasma BNP level provides important prognostic information independent of hemodynamic parameters, such as PCWP and LVEF, for predicting mortality in chronic CHF patients with left ventricular dysfunction. These findings suggest that the plasma BNP concentration is a sensitive biochemical marker of left ventricular damage or dysfunction because BNP is ventricular in origin. To clarify our hypothesis, further studies are needed to evaluate the relationship between the repetitive measurement of plasma BNP level and the treatment effects of therapy, such as with ACE inhibitors, on the mortality and morbidity of patients with left ventricular dysfunction. On the basis of the relationship between the plasma levels of natriuretic peptides and cGMP, the attenuation of the compensatory activity of cardiac natriuretic peptide system may increase the mortality of CHF patients with high plasma cardiac natriuretic peptides. These findings indicate that the effects of neutral endopeptidase inhibitors and/or exogenous natriuretic peptides may be attenuated in patients with chronic severe CHF accompanied by high endogenous natriuretic peptides levels.
Selected Abbreviations and Acronyms
|ANP||=||atrial natriuretic peptide|
|BNP||=||brain natriuretic peptide|
|CHF||=||congestive heart failure|
|LVEF||=||left ventricular ejection fraction|
|NYHA||=||New York Heart Association|
|PCWP||=||pulmonary capillary wedge pressure|
This study was supported by a Grant-in-Aid for Scientific Research (C) in Japan. We wish to thank Ikuko Sakaguchi for excellent technical assistance.
- Received November 18, 1996.
- Revision received January 31, 1997.
- Accepted February 7, 1997.
- Copyright © 1997 by American Heart Association
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