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(Hypertension. 1996;28:988-994.)
© 1996 American Heart Association, Inc.

Articles

Superiority of Brain Natriuretic Peptide as a Hormonal Marker of Ventricular Systolic and Diastolic Dysfunction and Ventricular Hypertrophy

Kazuhiro Yamamoto; John C. Burnett, Jr; Michihisa Jougasaki; Rick A. Nishimura; Kent R. Bailey; Yoshihiko Saito; Kazuwa Nakao; Margaret M. Redfield

The Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minn (K.Y., J.C.B., M.J., R.A.N., K.R.B., M.M.R.), and the Department of Medicine and Clinical Science, Kyoto (Japan) University Graduate School of Medicine (Y.S., K.N.).

Correspondence to Margaret M. Redfield, MD, The Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail redfield.margaret@mayo.edu.

	Abstract

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Atrial and brain natriuretic peptides (ANP and BNP) are produced by the heart, and their plasma concentrations are increased in human chronic congestive heart failure. Although separate studies have suggested that circulating levels of the biologically active C-terminal ANP, the biologically inactive N-terminal ANP, and BNP may have diagnostic utility in the detection of left ventricular systolic dysfunction or left ventricular hypertrophy, no studies have directly assessed the relative value of these peptides prospectively. We therefore designed this study to compare the relative ability of the different natriuretic peptides to detect abnormal left ventricular systolic and diastolic function and left ventricular hypertrophy. Using a prospective study design, we investigated 94 patients referred for cardiac catheterization and 15 age-matched normal subjects. The diagnostic abilities of elevated plasma C-terminal ANP, N-terminal ANP-(1-30), and BNP concentrations to identify systolic dysfunction (ejection fraction <45%), diastolic dysfunction (time constant of left ventricular relaxation >55 milliseconds, left ventricular end-diastolic pressure >18 mm Hg), and left ventricular hypertrophy (left ventricular mass index >120 g/m²) were objectively compared by receiver operating characteristic analysis. The areas under the receiver operating characteristic curve of BNP for detecting each of these abnormalities ranged from 0.715 to 0.908 and were significantly greater than those of C-terminal ANP or N-terminal ANP-(1-30). The sensitivity and specificity of an elevated plasma BNP, which we defined as greater than the mean+3 SD of the 15 age-matched normal subjects, were 0.83 and 0.77, respectively, for detecting ejection fraction less than 45%, 0.85 and 0.70 for detecting the time constant of left ventricular relaxation greater than 55 milliseconds, 0.63 and 0.76 for detecting left ventricular end-diastolic pressure greater than 18 mm Hg, and 0.81 and 0.85 for detecting left ventricular mass index greater than 120 g/m². The use of BNP and one other peptide increased sensitivity (0.90 to 0.96), albeit with lower specificity (0.56 to 0.71). An elevated plasma BNP was a more powerful marker of left ventricular systolic dysfunction, left ventricular diastolic dysfunction, and left ventricular hypertrophy than C-terminal ANP or N-terminal ANP-(1-30) in this population of patients with suspected cardiac disease. Measurement of BNP alone or in combination with C-terminal ANP or N-terminal ANP-(1-30) has potential utility for the detection of altered left ventricular structure and function in a patient population at risk for cardiovascular disease.

Key Words: natriuretic hormone • ventricular function • hypertrophy, left ventricular • hemodynamics

	Introduction

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Enhanced production of the natriuretic peptides by the heart is a hallmark of congestive heart failure, and the pathophysiological significance of these peptides in the regulation of renal, humoral, and cardiovascular function in heart failure is well recognized. The reinduction of the embryonic genome with expression of the ANP gene and subsequent peptide production is a highly conserved and cardinal feature of ventricular hypertrophy,¹ and there is similar evidence that BNP production is upregulated early in the hypertrophic process.^{2 3 4} The enhanced production of these peptides in the presence of altered LV function and structure is now recognized, and interest is growing in their potential diagnostic use. Plasma concentrations of the natriuretic peptides have emerged as potential noninvasive markers for the detection of abnormal LV structure and function.^{5 6 7 8 9} The proform of ANP is produced predominantly in the atrium¹⁰ and is released in two molecular forms: the biologically active C-ANP, which has a short half-life, and the biologically inactive N-ANP, which has a longer half-life.^{11 12} ANP is released by atrial myocytes in response to stretch associated with increased atrial pressure.¹³ Ventricular production of ANP occurs only in the presence of ventricular hypertrophy.¹ BNP is predominantly of ventricular origin,¹⁰ and its production is enhanced in the presence of chronic congestive heart failure or LV hypertrophy.^{10 14 15} Although several studies have examined the utility of a single natriuretic peptide in the detection of LV systolic dysfunction or LV hypertrophy and have reported favorable findings, especially with regard to the detection of asymptomatic LV systolic dysfunction, no study has compared C-ANP, N-ANP, and BNP to determine which assay may best detect the presence of LV systolic dysfunction and LV hypertrophy. Furthermore, no study has focused on the ability of the peptides to detect LV diastolic dysfunction, which occurs frequently in individuals with hypertension and other types of cardiac disease.^{16 17}

We designed this study to prospectively determine whether one of the natriuretic peptides—C-ANP, N-ANP, or BNP—is superior to the others for the detection of LV systolic dysfunction, LV diastolic dysfunction, or LV hypertrophy in patients with suspected cardiac disease referred for cardiac catheterization. We also examined the role of combined analysis of the natriuretic peptides. We used echocardiography to assess LV systolic function and LV mass. We analyzed LV pressure tracings to characterize LV diastolic function. Normal values for the peptides were determined in age-matched subjects without cardiovascular disease, and an elevated value used as a partition value of each peptide was prospectively defined as greater than the mean value in normal subjects plus 3 SD. To avoid effects of the definition of an elevated value on the comparison of the abilities of these peptides, we also performed ROC analysis, which can compare the combined sensitivity and specificity of the natriuretic peptides for the detection of altered LV structure and function independently of partition values.

	Methods

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Study Population
Ninety-four consecutive patients referred for cardiac catheterization were studied. Patients with acute myocardial infarction, active ischemia, or renal failure (plasma creatinine concentration >201 µmol/L) were not included. The clinical record of each patient was reviewed for determination of their New York Heart Association (NYHA) class regarding symptoms of heart failure. All studies were done electively, and nearly all were outpatient procedures. This protocol was approved by the Mayo Clinic Institutional Review Board, and all patients provided written informed consent.

Echocardiography
Transthoracic echocardiographic examinations¹⁸ were conducted within 3 hours before catheterization. All patients were in the fasting state, and medications were not withheld before the study for ethical reasons.

Cardiac Catheterization
Blood samples for humoral assay were obtained from the side arm of the sheath in the femoral artery. LV pressure was recorded with a 7F high-fidelity manometer-tipped catheter in 63 patients or a 6F pigtail catheter connected to a fluid-filled transducer in the other 31 patients. The high-fidelity LV pressure was calibrated to the fluid-filled LV pressure measured by the lumen of the catheter just before the recording.¹⁹ LV pressure was digitized at 5-millisecond intervals onto an off-line computer.

Data Analysis
From the LV pressure tracing, LVEDP was measured.¹⁹ In the patients with high-fidelity pressure recordings, the time constant of LV relaxation () was calculated for assessment of LV relaxation rate by the method of Weiss et al²⁰ using zero asymptote from peak -dP/dt to 5 mm Hg above LVEDP.^{19 21} From the echocardiographic recordings, EF and LV mass were calculated. EF was assessed in all patients by a modification of the method of Quinones et al²² as previously described.^{18 23} Measurements that allowed the calculation of LV mass with the formula derived from the data of the American Society of Echocardiography²⁴ were possible in 74 patients. LV mass index was calculated as the ratio of LV mass to body surface area as previously described.²⁵ Averaged values of echocardiographic and pressure-derived parameters of more than three consecutive beats were used for statistical analysis.

Blood for humoral analysis was placed in tubes containing EDTA, which were immediately placed on ice. After centrifugation at 2500 rpm and 3°C, the plasma was decanted and stored at -80°C until analysis. Plasma concentration of C-ANP was measured by radioimmunoassay with the use of antibody to preproANP-(124-151) (Peninsula Laboratories)^{26 27} ; interassay and intra-assay variabilities were 9% and 6%, respectively. Plasma concentration of N-ANP was determined by radioimmunoassay with the use of antibody to preproANP-(26-55), which is also known as proANP-(1-30) [N-ANP-(1-30)] (Phoenix Pharmaceuticals Inc). For the assay, 1 mL of plasma was preacidified with 1 mL of 0.5% trifluoroacetic acid. C8 cartridges (Analytichem) were washed with 4 mL of 100% methanol and 4 mL water. Plasma was applied to the cartridge, washed with 2 mL normal saline and 6 mL water, and eluted with 2 mL of 90% methanol and 1% trifluoroacetic acid. This antibody does not cross-react with higher molecular weight forms of N-ANP or C-ANP. Recovery is 78% to 85% and is determined with the use of synthetic preproANP-(26-55) at 0.003, 0.023, and 0.091 pmol per tube (Phoenix Pharmaceuticals Inc). Plasma concentration of BNP was determined by immunoradiometric assay with antibody to human BNP (Shionogi Co Ltd)^{10 28} ; the interassay and intra-assay variabilities were both 8%. There was no cross-reactivity among these assays.

Echocardiographic and catheterization data were interpreted blindly with respect to natriuretic peptide levels.

Plasma was also collected from 15 age-matched control subjects (mean age, 67 years) for measurement of C-ANP, N-ANP-(1-30), and BNP and calculation of the mean and SD of these peptides in normal individuals. These subjects were vigorously screened by the Mayo Clinic Department of Laboratory Medicine, Normal Values Laboratory, to be without cardiac or other systemic disease. For the purpose of this study, an elevated value was defined as greater than the mean normal value plus 3 SD. Normal values were determined from venous samples, and arterial samples were collected in patients referred for cardiac catheterization. As previously shown,¹⁰ the difference between arterial and venous plasma concentrations of C-ANP is slightly larger compared with that of BNP or N-ANP. Thus, the partition value for C-ANP may differ between arterial and venous sampling and may affect sensitivity and specificity. However, ROC analysis compares the diagnostic value of the peptides independently of the partition value.

Statistical Analysis
Values are expressed as mean±SD. The linear association of each peptide with physiological variables was assessed by simple linear regression and correlation as well as by Spearman rank correlation. Correlations were compared by Williams' modification of Hotelling's statistics.²⁹ For the correlation analysis, we used the natural logarithm (ln) of BNP, C-ANP, and N-ANP-(1-30) to normalize the distribution of their plasma concentrations.

We assessed the relative ability of natriuretic peptides to identify EF less than 45%, LV mass index greater than 120 g/m², LVEDP greater than 18 mm Hg, and greater than 55 milliseconds by ROC analysis. To assess whether natriuretic peptide assays have any information content, we compared the areas under the ROC curves with 0.5 (area under the line of no information) using the Wilcoxon rank sum statistics.³⁰ We compared the areas under the ROC curves for detecting each abnormality between peptides by the method of Delong et al.³¹ We explored the question of whether measuring two peptides enhances the ability to detect abnormal physiological variables by determining the sensitivity and specificity of the combined analysis of two peptides for the detection of each abnormality. Statistical significance was judged at the .05 level of significance.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Patient Characteristics
Table 1 reports the clinical characteristics of the patient population. Table 2 reports LV function, LV mass, and natriuretic peptides in the patient population and the natriuretic peptides in the age-matched normal control population. Ten of the 24 patients with EF less than 45%, 8 of the 20 patients with greater than 55 milliseconds, 18 of the 35 patients with LVEDP greater than 18 mm Hg, and 11 of the 26 patients with LV mass index greater than 120 g/m² had mild or no (NYHA class II or less) symptoms of dyspnea. Thus, significant structural and functional abnormalities were frequently unassociated with frank clinical evidence of heart failure.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of the Patient Population

View this table: [in this window] [in a new window]   Table 2. LV Function and Mass and Natriuretic Peptides in the Patient Population and Natriuretic Peptides in Normal Subjects

Correlation Study
The pairwise linear associations between each peptide and each physiological variable were significant with the exception of the association between ln N-ANP-(1-30) and EF (Table 3). For each physiological variable, the strongest correlate was ln BNP. Spearman rank correlation provided identical findings.

View this table: [in this window] [in a new window]   Table 3. Correlation Coefficients Between Natriuretic Peptides and Ejection Fraction, LV Mass Index, , or LV End-Diastolic Pressure

ROC Analysis
The Figure presents the findings of the ROC analysis. The areas under the ROC curves were significantly greater than 0.5, with the exception of that of C-ANP for detecting greater than 55 milliseconds or LVEDP greater than 18 mm Hg and that of N-ANP-(1-30) for detecting EF less than 45%. The areas for BNP detecting abnormal EF, LV mass index, and were significantly larger than those for C-ANP and N-ANP-(1-30). The area for BNP detecting abnormal LVEDP was significantly larger than that for C-ANP and tended to be larger, but not significantly, than that for N-ANP-(1-30).

View larger version (34K): [in this window] [in a new window]   Figure 1. ROC curves for natriuretic peptide concentrations in predicting EF <45% (top left), LV mass index >120 g/m2 (top right), the time constant of isovolumic LV pressure fall () >55 milliseconds (bottom left), and LVEDP >18 mm Hg (bottom right). Area under the ROC curve for each peptide is described below each diagram. *P<.05 vs area under the ROC curve of C-ANP; P<.05 vs area under the ROC curve of N-ANP-(1-30).

Table 4 shows the sensitivity and specificity and their 95% confidence intervals of an elevated value of each peptide as prospectively defined for the identification of each parameter. Table 5 shows the plasma peptide concentration at the point closest to that of perfect separation on each ROC curve and the sensitivity and specificity of each peptide with that partition value. The optimal BNP levels shown in Table 5 are close to the prospectively determined partition value (mean+3 SD of the normal values), and the use of the optimal BNP levels as partition values slightly improved specificity.

View this table: [in this window] [in a new window]   Table 4. Sensitivity and Specificity of an Abnormal Peptide Level as Prospectively Determined

View this table: [in this window] [in a new window]   Table 5. Sensitivity and Specificity of an Abnormal Peptide Level as Determined Retrospectively by ROC Curves

In our patient population, the sensitivity and specificity of BNP greater than 14.7 pmol/L (mean+3 SD of the normal control value) for detecting any abnormality of LV structure or function (ie, the presence of EF <45%, >55 milliseconds, or LV mass index >120 g/m²) were 0.73 and 0.83, respectively.

Combined Analysis of Natriuretic Peptides
Table 6 shows the sensitivity and specificity when another peptide was analyzed along with BNP. The optimal peptide concentrations as determined by the ROC analysis (shown in Table 5) were used as partition values in this analysis. Proper combination of BNP and another peptide allowed the detection of abnormal EF, , and LV mass index with very high sensitivity (0.90 to 0.96) while retaining moderate specificity (0.56 to 0.71).

View this table: [in this window] [in a new window]   Table 6. Sensitivity and Specificity of Combinations of BNP and Another Peptide for Detection of Abnormal LV Function or LV Hypertrophy

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study compared the ability of plasma concentrations of C-ANP, N-ANP-(1-30), and BNP to detect LV systolic dysfunction (decreased EF), LV diastolic dysfunction (prolonged , increased LVEDP), and LV hypertrophy (increased LV mass index) in patients with suspected cardiac disease. When the relative diagnostic utility of the three peptides was determined by either comparative ROC analysis or comparative correlation analysis, BNP emerged as the single best marker of LV systolic dysfunction, LV diastolic dysfunction, and LV hypertrophy compared with C-ANP and N-ANP-(1-30). Measurement of BNP and another peptide provided better sensitivity, with moderate specificity.

Congestive heart failure is caused by LV systolic or diastolic dysfunction.^{16 17} It is an extremely common condition, especially in the elderly, where the prevalence approaches 10%,³² and is very costly as it is the most common discharge diagnosis for hospitalized patients in the United States.³³ Thus, new strategies must be developed to identify and treat patients with or at risk for the development of congestive heart failure in a more cost-effective way.³⁴ These new strategies must include an emphasis on early treatment to delay and hopefully prevent the progression to end-stage heart failure.^{34 35} Such an emphasis requires the ability to identify patients with LV dysfunction before the development of severe symptoms. Considering the large number of patients suspected of having cardiac disease who are at risk for LV dysfunction, interest is growing in the use of the natriuretic peptides as diagnostic, potentially cost-effective, markers of altered LV structure and function.^{9 36}

Plasma C-ANP concentration is elevated in patients with overt heart failure^{26 37} and in some patients with LV dysfunction without overt heart failure.³⁸ However, the biologically inactive N-ANP has reduced clearance compared with C-ANP and circulates at a concentration 10- to 20-fold higher than that of C-ANP,³⁹ and previous studies have reported that N-ANP is superior to C-ANP in the detection of asymptomatic LV systolic dysfunction in selected cardiac populations^{8 40} and as a prognostic factor after acute myocardial infarction.⁵ The current study did not demonstrate that N-ANP-(1-30) was superior to C-ANP in detecting LV systolic dysfunction. A previous study by Lerman et al⁸ focused on the ability of N-ANP-(1-30) to detect asymptomatic LV dysfunction, whereas the current study included patients with and without symptoms. Lerman et al used a different technique to assess EF and a different definition of LV systolic dysfunction that included patients with a resting EF of greater than 50% if they had a peak exercise EF of less than 55%. Indeed, the mean EF in the patients with asymptomatic LV dysfunction was 49%, and the population of patients with exercise-induced but not resting LV systolic dysfunction may be unique. The current study was confined to patients referred for cardiac catheterization, and this population may differ in other respects from one consisting of patients referred for radionuclide angiography. These differences may be responsible for the discrepancy between our results and previous results. Also, the current study measured proANP-(1-30), not proANP-(1-98), as N-ANP, and thus, the measurement of proANP-(1-98)^{5 12} might have provided different results.

Plasma BNP concentration is also elevated in patients with chronic congestive heart failure.^{14 37} As BNP is produced primarily in ventricular myocytes, elevated BNP concentrations may more accurately reflect alterations in the structure and function of the ventricle. Previous studies have reported that BNP can detect systolic dysfunction after acute myocardial infarction with more sensitivity than C-ANP or clinical history and examination.^{6 7} Davis et al⁹ found that the presence of an elevated BNP concentration was an excellent discriminator of cardiac and noncardiac dyspneas. The present study examined the relative abilities of C-ANP, N-ANP-(1-30), and BNP to detect LV systolic dysfunction and demonstrated that BNP is a better marker than C-ANP or N-ANP-(1-30) in patients with suspected cardiac disease.

Although recent studies examining the diagnostic utility of the natriuretic peptides have focused on the detection of systolic dysfunction, the stimulus for the enhanced production of these peptides partly reflects the structural changes (hypertrophy) and hemodynamic consequences (elevated intracardiac pressures) usually associated with systolic dysfunction. Kohno et al¹⁵ have reported that plasma BNP concentration is correlated with LV mass index in patients with hypertension. LV hypertrophy is a potent risk factor for cardiovascular morbidity and mortality.⁴¹ As LV hypertrophy cannot be reliably predicted from blood pressure level,⁴² a noninvasive and inexpensive method for the detection of LV hypertrophy would be clinically useful. The current study examined the utility of the natriuretic peptides in detecting LV hypertrophy and demonstrated that BNP concentration correlated well with LV mass index and that the sensitivity and specificity for the detection of LV hypertrophy were excellent and exceeded those for C-ANP and N-ANP-(1-30).

Patients with cardiac disease often have diastolic dysfunction, which can result in elevated filling pressures and symptoms of overt heart failure, sometimes in the absence of systolic dysfunction.^{43 44} Although studies have demonstrated that the concentrations of the natriuretic peptides correlate with filling pressures, the strength of these correlations vary,^{45 46} perhaps because filling pressures are determined by both LV diastolic function and loading conditions.⁴⁷ LV relaxation is an important component of diastolic function⁴⁷ and can be assessed invasively by but is difficult to assess noninvasively.^{19 48 49} Impaired relaxation precedes reduced EF in most cardiac diseases.⁵⁰ In the present study, elevated BNP concentrations detected impaired relaxation with good sensitivity and specificity. However, although the area under the ROC curve of BNP for detecting elevated LVEDP was greater than those of C-ANP and N-ANP-(1-30), the overall sensitivity and specificity of BNP as a marker of elevated LVEDP was relatively poor compared with its ability to detect abnormal EF, , or LV mass index. These data suggest that BNP best reflects LV structural and functional abnormalities rather than abnormal loading conditions. The current study significantly extends previous studies and exhibits the utility of the natriuretic peptides in the detection of diastolic dysfunction.

Although BNP is the single best marker in the detection of LV functional and structural abnormalities and preload augmentation, the combined analysis of BNP and either C-ANP or N-ANP-(1-30) increased sensitivity. In some clinical situations, higher sensitivity may be desirable, and in this study, the combined use of BNP and another peptide increased sensitivity, particularly to more than 0.90 in detecting LV systolic dysfunction, LV diastolic dysfunction, and LV hypertrophy, with a moderate reduction in specificity. Although previous studies have focused on the utility of a single peptide, our study suggests the potential utility of a combination analysis.

Conclusions
The current study reports that elevated plasma BNP is a more powerful marker of LV systolic dysfunction, LV diastolic dysfunction, and LV hypertrophy than C-ANP or N-ANP-(1-30) in this population of patients with suspected cardiac disease. The combined use of BNP and another peptide increases the sensitivity while decreasing specificity moderately. These findings suggest that plasma BNP alone or together with C-ANP or N-ANP-(1-30) may have diagnostic utility for the detection of altered LV function or structure in patients with or at risk for cardiac disease. The subjects of this study were referred for cardiac catheterization and thus have a high prevalence of altered LV structure and function. Further studies in broader populations at risk for altered LV structure and function are needed for determination of the potential role of these peptides in clinical practice.

	Selected Abbreviations and Acronyms

 

ANP = atrial natriuretic peptide BNP = brain natriuretic peptide C-ANP = C-terminal atrial natriuretic peptide EF = ejection fraction LV = left ventricular LVEDP = left ventricular end-diastolic pressure N-ANP = N-terminal atrial natriuretic peptide ROC = receiver operating characteristic

	Acknowledgments

 
This study was supported in part by grants from the Joseph P. and Jeanne M. Sullivan Foundation, Chicago, Ill; the National Heart, Lung, and Blood Institute, Bethesda, Md (HL-033643); the Miami Heart Research Institute; and the Mayo Foundation. Dr Yamamoto was supported by the Fellowship of the Uehara Memorial Foundation.

Received April 8, 1996; first decision May 8, 1996; accepted July 22, 1996.

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