Clinical Utility of B-Type Natriuretic Peptide (Full Title Below)

ABSTRACT: Background. B-type natriuretic peptide (BNP) and echocardiographic tissue Doppler indices (TDI) predict elevated filling pressures, but few data exist comparing these methods while adjusting for clinical variables. We hypothesized that BNP would provide incremental value for estimating left ventricular end-diastolic pressure (LVEDP). Methods. Clinical data, echocardiograms, and BNP levels were obtained in 182 geriatric patients undergoing diagnostic left-heart catheterization. Patients with severe valvular disease or acute myocardial infarction were excluded. LVEDP and standard echocardiographic measurements, including early (E) and late (A) mitral inflow velocities and early (Em) mitral annular velocities by TDI, were measured in blinded fashion. Results. Mean age was 71 years, 51% were female, and 19% were nonwhite. Univariate correlations with LVEDP (p ≤ 0.05) included functional class, beta-blocker use, body-mass index (BMI), heart rate, blood urea nitrogen (BUN), hemoglobin, peak tricuspid regurgitation velocity, left atrial volume index, E/A ratio, deceleration time, septal E/Em ratio and BNP. Linear regression analysis revealed independent correlations of LVEDP with BMI (p = 0.002), BUN (p = 0.011), and E/A ratio (p 15 (p = 0.023). BNP was an independent predictor of LVEDP ≥ 20 mmHg after adjustment for these variables (p = 0.037, c-statistic 0.663). Conclusions. Standard clinical variables offer only modest utility for predicting LV filling pressures. BNP provides incremental value for estimating LVEDP, and elevated BNP is an independent predictor of increased LVEDP among older patients undergoing diagnostic cardiac catheterization. J INVASIVE CARDIOL 2010;22:107–112 Heart failure (HF) is the most common Medicare diagnosis for hospitalized older Americans, and it is the most costly diagnosis-related group by a factor of almost two.1 In addition, close to 50% of HF admissions in the geriatric population occur in the setting of preserved left ventricular (LV) systolic function. Elevations in LV pressures are best diagnosed at cardiac catheterization, but older patients experience higher complication rates from invasive diagnostic and therapeutic procedures.2-5 Noninvasive assessment of these individuals has been hampered by a lack of consensus about the definitions and diagnostic tools for “diastolic HF” when evaluated by noninvasive techniques, plus the inability to predict impending HF exacerbations using LV systolic function parameters alone. B-type natriuretic peptide (BNP) is released from ventricular myocardium in response to myocyte stretch, and multiple studies have demonstrated its correlation with LV filling pressures in select patient populations.6–12 Echocardiographic tissue Doppler imaging (TDI) has helped identify individuals with elevated LV filling pressures in the setting of acute illness or known HF.13,14 However, the value of BNP in conjunction with TDI for predicting LV end-diastolic pressure (LVEDP) has not previously been described in patients referred for elective cardiac catheterization, and both noninvasive modalities remain poorly studied in subjects without heart failure or outside of the intensive care unit setting. We therefore hypothesized that BNP would provide incremental value beyond clinical and echocardiographic predictors of LVEDP among patients referred for diagnostic left heart catheterization.

Methods

Study population. Consecutive patients 60 years of age or older referred for diagnostic left heart catheterization at Barnes-Jewish Hospital in St. Louis, Missouri were eligible for this investigation. Subjects were excluded if they experienced an acute myocardial infarction (MI) or percutaneous coronary intervention (PCI) within the prior 6 months (or during the index hospitalization), or if they had known severe valvular heart disease, hypertrophic cardiomyopathy, prior cardiac surgery or end-stage renal or hepatic disease. Data collection. All subjects participating in the study provided informed consent, and the study was approved by the Human Studies Committee at Washington University. Patient demographics, medical history, medications, cardiovascular symptoms, indications for catheterization, vital signs, baseline laboratory data, electrocardiographic findings and stress-test results (when available) were recorded on standardized data forms. Blood samples were drawn in the pre-catheterization holding area, and were hand-delivered to the hospital’s clinical laboratory to determine plasma BNP levels (chemiluminescence immunoassay, Bayer Advia Centaur, reference range 0–100 pg/mL). Standard echocardiographic views were obtained concurrently using a Hewlett-Packard 5500 Sonos machine, including mitral inflow at the mitral leaflet tips in the apical 4-chamber view, plus TDI assessments of mitral annular velocity15 using Philips “Revision D.0 Ultraperformance” software. Diagnostic catheterization was then performed in accordance with standard protocol, including LV pressure measurements using commercially available pressure transducers and fluid-filled catheters.16 Measurements. Echocardiographic assessment of valvular disease, LV systolic function and mitral inflow patterns was performed using standard techniques.17–19 Velocities of early (E) and late (A) mitral inflow, as well as early and late mitral annular velocities by TDI (Em and Am), were assessed offline by evaluating 2–4 consecutive cardiac cycles using ProSolv analysis software (Problem Solving Concepts, Indianapolis, Indiana). Other measurements included left atrial volume (LAV), E-wave deceleration time (DT), E/A ratio, and both septal and lateral E/Em ratios by TDI. Coronary score was defined as the number of major coronary arteries or branches with ≥ 70% diameter stenosis (≥ 50% for left main disease). LVEDP also was obtained offline by manually averaging the LV pressure just prior to the onset of electrical systole from 4–8 consecutive cardiac cycles. All echocardiographic and catheterization measurements were performed in blinded fashion without knowledge of other clinical, laboratory or imaging results. Statistical analysis. A correlation matrix was constructed to evaluate the relationship between LVEDP and the major variables collected in this study. Based on these findings, a multivariable model was constructed from demographic, clinical, laboratory and echocardiographic factors utilizing linear regression analysis. In order to test the hypothesis that BNP would provide greater utility for estimating LVEDP than clinical variables alone, BNP was added incrementally to the best clinical model. Given the clinical importance of a markedly elevated LVEDP, an additional model was constructed using logistic regression for predicting LVEDP ≥ 20 mmHg. As with the prior analysis, BNP was added to the best clinical model to determine its potential incremental value for predicting increased filling pressure. Based on findings from the multivariable analyses, frequency analysis was utilized to determine cut-points for continuous variables. An LVEDP integer risk score was calculated for each subject (1 point per variable from the logistic regression model) to better estimate an individual’s risk of having a clinically relevant elevation in filling pressure.

Results

Patient characteristics. We enrolled 200 consecutive patients, of whom 182 had complete LV pressure tracings and echocardiographic data recorded. Baseline characteristics of the 182 subjects are listed in Table 1. Mean age was 71 years, slightly more than half were female and 18% were non-Caucasian. Close to 50% had prior coronary artery disease, 21% had prior HF, and over 95% of subjects had at least one traditional cardiac risk factor and were being treated with antihypertensive or lipid-lowering therapies. Over two-thirds of individuals were referred for catheterization after stress testing was performed. Objective findings. During echocardiographic assessment (Table 2), over 85% of individuals demonstrated some degree of diastolic dysfunction by mitral inflow or TDI assessment. Nearly 75% had left atrial enlargement, 22 individuals (12%) were noted to have more than mild mitral regurgitation (MR), and 41 subjects (23%) met criteria for LV hypertrophy. While 44 subjects (24%) had less than normal LV systolic function by echocardiography, only 25 of the 137 interpretable ventriculograms (18%) had LV ejection fraction 15 (p = 0.023). After adjusting for these factors, BNP again provided incremental utility when added to the multivariable model for predicting high LVEDP (p = 0.037, regression model r = 0.359, c-statistic 0.663). The distribution of patients with LVEDP ≥ 20 mmHg according to LVEDP integer risk score is shown in Figure 2. Increasing risk score was strongly associated with a progressively greater likelihood of having LVEDP ≥ 20 mmHg in the study population (p Discussion BNP and LVEDP. This investigation demonstrates the utility of BNP for estimating LVEDP in older patients without acute myocardial infarction but with clinical indications for diagnostic coronary angiography. Specifically, our data indicate that BNP provides independent information to clinicians attempting to noninvasively estimate LV filling pressure, and in particular, for identifying individuals with LVEDP of 20 mmHg or higher. However, the best multivariable model had a c-statistic of only 0.663, implying only modest capability for identifying patients with elevated filling pressures using standard clinical, echocardiographic, and laboratory variables. In addition, the most striking finding from this analysis was the relatively weak association between any clinical variable (including BNP) and directly-measured LVEDP. The incremental utility of BNP for identifying patients with elevated LVEDP must therefore be tempered by the remarkably limited utility of standard clinical variables and existing noninvasive assessment techniques for predicting LVEDP in patients without established LV dysfunction or heart failure syndromes. Prior studies have shown associations between BNP and LV filling pressure in the setting of systolic HF.6–10 However, this relationship is weaker in critically ill patients in the intensive care unit,20,21 as well as in the setting of renal dysfunction21 or reversible coronary ischemia.22 Haug et al demonstrated a strong association between BNP and LVEDP in 85 patients undergoing diagnostic catheterization,11 but there was no adjustment for clinical variables known to affect BNP levels (age, weight, gender, renal function, etc.). In addition, despite the well-described elevation in BNP with advancing age,23–25 especially in women,24 to our knowledge this study is the first to specifically evaluate natriuretic peptide levels for estimating LV filling pressures in a geriatric patient population. TDI and filling pressures. The recent development of TDI has improved the noninvasive assessment of LV filling pressure and diastolic function by providing a relatively “load-independent” measure of ventricular diastolic performance.13,26,27 In particular, Ommen et al demonstrated the importance of the E/Em ratio for predicting LV diastolic pressure among 100 middle-aged subjects referred for diagnostic cardiac catheterization,14 with a ratio 15, suggesting elevated LVEDP (predictive accuracies of 70–75%). Importantly, the reliability of the E/Em ratio was substantially lower when LV ejection fraction was above 50% — a critical issue when evaluating the geriatric population, among whom nearly half of individuals with prevalent HF have preserved LV systolic function.28–33 Other investigators have reported similar findings,34,35 although Kim et al found equivalent associations between E/Em and filling pressure regardless of LV systolic function.36 In our study, E/Em was not an independent correlate of LVEDP, whether analyzing the septal or lateral E/Em ratio, the mean E/Em ratio derived from both septal and lateral wall measurements, or the estimated LVEDP from any of these ratios based on the formula by Nagueh and colleagues.13 Nonetheless, statistically significant correlations were noted between LVEDP and the dichotomized ratio (i.e., E/Em > 15) for the septal (r = 0.169; p = 0.047) and mean (r = 0.230; p = 0.007) E/Em values. This may explain the incremental utility of an elevated septal E/Em ratio for predicting a clinically-relevant elevation in LVEDP, as noted in Table 5. Also of note, septal E/Em ratio > 15 continued to independently predict LVEDP ≥ 20 mmHg regardless of LV ejection fraction. Comparative data. Several studies have demonstrated associations between BNP and indices of diastolic function by echocardiography, primarily in the setting of known HF,37–41 but to our knowledge, only one study has compared the two modalities in conjunction with directly-measured LV filling pressures. Among 50 critically ill patients admitted to the intensive care unit, Dokainish et al found that E/Em had a stronger correlation with the pulmonary capillary wedge pressure than did BNP.20 Nearly two-thirds of subjects had depressed LV ejection fraction, and multivariable analysis did not include adjustment for clinical factors other than BNP and echo parameters. By comparison, our sample size is substantially larger, the population is older, all patients were clinically stable, and three-fourths had preserved LV systolic function. In addition, we adjusted for clinical factors including age, medical history, vital signs, and other objective data such as BMI and renal function. As the only study to date specifically designed to compare BNP and echocardiography among ambulatory geriatric patients undergoing invasive hemodynamic assessment, we believe that our findings are directly relevant to the daily practice of clinical cardiologists caring for older patients with cardiovascular disease. Of note, the correlations between BNP and several TDI parameters in our study were only modest (r-values between 0.265–0.281 for septal, lateral, and mean E/Em ratios), suggesting that the roles of biomarkers and echocardiography for estimating LVEDP may be complementary but with limited predictive utility. In addition, the association between BMI and LVEDP observed in our patient population is consistent with the findings of recent studies, in which BMI and obesity were identified as independent predictors of incident heart failure.42,43 Similarly, increasing BMI appears to significantly affect BNP levels in patients with dyspnea and heart failure,44–48 and other factors such as genetic variation in BNP metabolism may impact estimation of LVEDP using this biomarker alone.49,50 These observations suggest that a multimarker approach should be considered for the clinical assessment of LV filling pressures, particularly given the difficulty predicting LVEDP in elderly patients with generally preserved LV systolic function, despite evaluating numerous clinical factors in multivariable analyses. Additional investigations that combine biomarkers, echocardiographic parameters, and clinical variables (such as BMI) for estimating LV filling pressure are clearly needed. Study limitations. The subjects evaluated in this study were moderate-risk patients, 60 years of age or older, referred for diagnostic left heart catheterization and coronary angiography at a single academic institution. Patients with recent acute myocardial infarction, percutaneous coronary intervention, or severe valvular disease or heart failure were excluded from our study. Therefore, the applicability of our findings to patients with acute cardiovascular or noncardiovascular medical illnesses is unknown. Prospective validation of the association between BNP and intravascular volume status should be performed in larger and more diverse populations, and future investigations of natriuretic peptides should incorporate clinical and echocardiographic variables which may modify the predictive accuracy of these biomarkers. In addition, the modest utility of both BNP and echocardiographic variables for assessing LVEDP suggests that unmeasured confounders affect LVEDP estimation. As a result, the value of noninvasive variables for predicting LVEDP remains limited. Finally, although we dichotomized BNP at 100 pg/mL using standard frequency analysis in conjunction with prior studies that used this cut-point, future studies should consider deriving more statistically rigorous cutoff values through spline or receiver-operator-curve analyses.

Conclusions

Among older patients undergoing diagnostic cardiac catheterization, BNP provides independent and incremental value for estimating LVEDP, and BNP provides information complementary to clinical variables and echocardiographic indices of LV systolic and diastolic function. However, the predictive utility of noninvasive parameters for estimating intravascular volume status — whether BNP is included or not — remains limited. Our findings require validation in larger, prospective studies using a multimarker approach before BNP or other noninvasive testing modalities can be incorporated into routine clinical practice as a means for estimating LV filling pressures.

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From the *Mid America Heart Institute of Saint Luke’s Hospital, Kansas City, Missouri; †University of Missouri-Kansas City, Kansas City, Missouri; and ‡Washington University Division of Cardiology, St. Louis, Missouri. Disclosure: The authors disclose that analyses for this study were funded by a Clinical Research Grant from the Society of Geriatric Cardiology. Manuscript submitted May 5, 2009, provisional acceptance given June 23, 2009, final version accepted September 21, 2009. Address for Correspondence: Joshua M. Stolker, MD, Mid America Heart Institute of Saint Luke’s Hospital, 4401 Wornall Road – Suite 5601, Kansas City, MO 64111. E-mail: jstolker@yahoo.com

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