Echocardiography. Measurement of BNP plasma levels. Statistical analysis. Echocardiographic classifications. 368 Maisel et al

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1 Utility of B-natriuretic peptide as a rapid, point-ofcare test for screening patients undergoing echocardiography to determine left ventricular dysfunction Alan S. Maisel, MD, FACC, Jen Koon, BSN, Padma Krishnaswamy, MD, Radmila Kazenegra, MD, Paul Clopton, BSN, Nancy Gardetto, NC, Robin Morrisey, NC, Alex Garcia, BS, Albert Chiu, BS, and Anthony De Maria, MD, FACC San Diego, Calif Background Although echocardiography is an important tool for making the diagnosis of left ventricular (LV) dysfunction, the cost of this procedure limits its use as a routine screening tool for this purpose. Brain natriuretic peptide (BNP) accurately reflects ventricular pressure, and preliminary studies have found it to be highly sensitive and highly specific in diagnosing congestive heart failure in the emergency department. We hypothesized that BNP might therefore be useful as a screening tool before echocardiography in patients with suspected LV dysfunction. Methods Subjects included patients referred for echocardiography to evaluate the presence or absence of LV dysfunction. Patients with known LV dysfunction were excluded from analysis. BNP was measured by a point-of-care immunoassay (Biosite Diagnostics, San Diego, Calif). The results of BNP levels were blinded from cardiologists making the assessment of LV function. Patients were divided into those with normal ventricular function, abnormal systolic ventricular function, abnormal diastolic function, and evidence of both systolic and diastolic dysfunction. Results Two hundred patients in whom LV function was unknown were studied. In the 105 patients (53%) whose ventricular function was subsequently determined to be normal by echocardiography, BNP levels averaged 37 ± 6 pg/ml. This was significantly less than in those patients with either ultimate diastolic dysfunction (BNP 391 ± 89 pg/ml (P <.001) or systolic dysfunction (BNP 572 ± 115 pg/ml (P <.001). A receiver-operator characteristic curve showing the sensitivity and specificity of BNP against the echocardiography diagnosis revealed the area under the curve (accuracy) was At a BNP level of 75 pg/ml was 98% specific for detecting the presence or absence of LV dysfunction by echocardiography. Conclusions A simple, rapid test for BNP, which can be performed at the bedside or in the clinic, can reliably predict the presence or absence of LV dysfunction on echocardiogram. The data indicate that BNP may be an excellent screening tool for LV dysfunction and may, in fact, preclude the need for echocardiography in many patients. (Am Heart J 2001; 141: ) Although patients with left ventricular (LV) dysfunction have improved survival on medications such as angiotensin-converting enzyme inhibitors and β-blockers, 1,2 this may be a difficult diagnosis to make by conventional criteria. 3,4 No blood test can rapidly determine whether a patient has LV dysfunction, 5 and echocardiography may not always be cost-effective as a screening device, especially From the Division of Cardiology and the Department of Medicine, Veteran s Affairs Medical Center and University of California, San Diego. Submitted August 16, 2000; accepted November 29, Reprint requests: Alan Maisel, MD, VAMC Cardiology 111-A, 3350 La Jolla Village Dr, San Diego, CA amaisel@ucsd.edu 4/1/ doi: /mhj in those patients who have a low probability of cardiac dysfunction. 6,7 B-natriuretic peptide (BNP) is a cardiac neurohormone secreted from the cardiac ventricles as a response to ventricular volume expansion and pressure overload BNP levels are elevated in patients with symptomatic LV dysfunction and correlate with New York Heart Association (NYHA) class as well as with prognosis However, the utility of plasma BNP as a screening test has been limited by the same standard assay issues common to other hormones or cytokines also elevated in heart failure By use of a rapid immunoassay for BNP, we sought to determine whether BNP levels could serve as a screen to patients referred for echocardiography at the San Diego Veteran s Health Care System.

2 368 Maisel et al American Heart Journal March 2001 Methods Study population The study was approved by the University of California Institutional Review Board and conducted at the San Diego Veteran s Health care System between June and October Two hundred consecutive patients referred for echocardiography to evaluate LV function and consented to be studied were included from a total of 262 patients referred for LV function during this time period. The 62 patients with known LV dysfunction were excluded from analysis. Patients referred for echocardiography to assess valve disease, the presence of a vegetation, or to rule out a cardiac cause of stroke were not included in this database. Both outpatients and inpatients were included in this study, and approximately 24% of the sampling population consisted of inpatients. Echocardiography Two-dimensional, M-Mode, spectral, and color flow Doppler echocardiograms were obtained with commercially available instruments operating at 2.0 to 3.5 mhz. Two-dimensional imaging examinations were performed in the standard fashion in parasternal long- and short-axis views and apical 4- and 2- chamber views. 23 Pulsed Doppler spectral recordings were obtained from a 4 4 mm sample volume placed at the tips of the mitral leaflets and in the pulmonary vein and that was adjusted to yield the maximal amplitude velocity signals. All data were copied to 0.5-inch VHS videotape for subsequent playback, analysis, and measurement. Two-dimensional echocardiograms were subjected to careful visual analysis to detect regional contractile abnormalities. LV systolic and diastolic volumes and ejection fractions were derived from biplane apical (2- and 4-chamber) views with use of a modified Simpson s rule algorithm. 24 The transmitral pulsed Doppler velocity recordings from three consecutive cardiac cycles were used to derive measurements as follows: E and A velocities as the peak values reached in early diastole and after atrial contraction, respectively, and deceleration time as the interval from the E wave to the decline of the velocity to baseline. In addition, pulmonary venous systolic and diastolic flow velocities were obtained as the maximal values reached during the respective phase of the cardiac cycle, and the pulmonary venous A reversal as the maximal velocity of retrograde flow into the vein after the P wave of the electrocardiogram (ECG). Finally, the LV isovolumetric relaxation time (IVRT) was obtained from the apical 5-chamber view with a continuous wave cursor or, if possible, a pulsed Doppler sample volume positioned to straddle the LV outflow tract and mitral orifice to obtain signals from aortic valve closure or the termination of ejection and mitral valve opening or the onset of transmitral flow. IVRT was taken as the time in milliseconds from the end of ejection to the onset of LV filling. All echocardiograms were interpreted by experienced cardiologists who were blinded to the BNP levels. Echocardiographic classifications Normal ventricular function. Normal ventricular function was defined by normal LV end-diastolic ( ) and endsystolic dimensions ( ), no major wall motion abnormalities, an ejection fraction of >50%, and no evidence of impaired or restrictive relaxation abnormalities. Systolic dysfunction. Systolic dysfunction was defined by an ejection fraction less than 50% or either global hypokinesis or discrete wall motion abnormalities. Diastolic dysfunction. Diastolic dysfunction was defined as impaired relaxation, restrictive pattern, and pseudonormal pattern on the basis of the definitions below. 1. Impaired relaxation: E/A ratio <1 and deceleration time >240 ms in patients <55 years old and E/A ratio <0.8 plus deceleration time >240 ms in patients 55 years old. IVRT measurements, which were available in approximately one half of the patients, was >90 ms in 90% or more of patients were abnormal E/A ratio changes or deceleration time >240 ms. 2. Restrictive: E/A ratio >1.5 and deceleration time <150 ms. Confirming evidence included pulmonary vein diastolic > pulmonary vein systolic, pulmonary A reversal > forward mitral A wave duration, pulmonary vein diastolic flow reversal, IVRT < 70 ms. Confirming evidence by one or more of the above was seen in >50% of patients. 3. Pseudonormal E/A ratio >1 and deceleration time >240 ms. Confirmation by Valsalva maneuver when possible. Systolic plus diastolic-restrictive. Systolic plus diastolicrestrictive was defined as ejection fraction less than 50% with global hypokinesis or discrete wall motion abnormalities and deceleration time <150 ms. Measurement of BNP plasma levels During initial evaluations, a small sample (5 ml) was collected into tubes containing potassium EDTA (1 mg/ml blood). BNP was measured with the Triage B-Type Natriuretic Peptide test (Biosite Diagnostics, San Diego, Calif). The Triage BNP Test is a fluorescence immunoassay for the quantitative determination of BNP in whole blood and plasma specimens. The concentration of BNP in the specimen is proportional to the fluorescence bound in the detection lane of the device and was quantified by the portable Triage meter. When possible, BNP levels were measured in whole blood and processed within 4 hours. Otherwise, samples were spun down and the plasma frozen until the sample was analyzed (1-2 days). Figure 1 shows a high correlation between the assay used in this study (Biosite Diagnostics) and the Shiono radioimmunoassay (RIA) (Shionogi, Osaka, Japan). The range of detectable levels are 1 to 1300 pg/ml. The average 95% confidence limit of the analytical sensitivity of the test is less than 5 pg/ml (95% confidence interval pg/ml). The average total imprecision is 10.1% at mean values of 28 pg/ml and 16.2% at mean levels of pg/ml. There is no significant cross-reactivity with endothelin-1, α-atrial natriuretic peptide, or aldosterone. Statistical analysis Group comparisons of BNP values were made with t tests for independent samples and analyses of variance. In all cases these were computed with raw BNP values and repeated with logtransformed BNP values because the BNP distribution was positively skewed. Both versions yielded the same conclusions. Sensitivity, specificity, and accuracy were computed for BNP with a selection of possible cut points. The diagnostic utility of BNP alone was compared with the echocardiographic probability of LV dysfunction with receiver-operator characteristic (ROC) curves.

3 American Heart Journal Volume 141, Number 3 Maisel et al 369 Figure 1 Figure 2 Correlation between two assays for BNP: Triage Cardiac assay (Biosite Diagnostics, and Shiono RIA, Shionogi), n = 42 patients. Measurements done in parallel, same day. Mean and SEM for normal and abnormal LV dysfunction. Table I. Patient characteristics No. 200 Age (y) ± 0.9 Sex (male/female) 189/11 All normal 53% All abnormal 48% History of hypertension 65% History of diabetes 34% History of coronary artery disease 46% History of shortness of breath 52% History of edema 28% Figure 3 Characteristics of all 200 patients recruited into the study. History included presence or absence of diabetes, hypertension, or coronary artery disease and symptoms included presence or absence of shortness of breath or edema when referred for echocardiogram. BNP values for the different subclasses of LV dysfunction, namely, all systolic, all diastolic, and all systolic plus diastolic dysfunction. The group systolic plus diastolic dysfunction is a subgroup of all systolic dysfunction. Data are expressed as mean ± SEM. Results The characteristics of the 200 patients are shown in Table I. Fifty-two percent of patients had unsubstantiated complaints of dyspnea, whereas the remaining were essentially asymptomatic. Nearly all patients had risk factors for heart disease, including 46% with a history of coronary artery disease. Figure 2 presents BNP values (mean and SE) for patients classified as either normal LV function or abnormal LV function groups. Patients diagnosed with abnormal LV function (n = 95) had a mean BNP concentration of 489 ± 75 pg/ml, whereas the normal LV function group (n = 105) had a mean BNP concentration of 29.5 ± 62.4 pg/ml. The group difference was significant in raw (P <.001) and log (P <.001) form. Figure 3 shows the breakdown of patients with abnormal LV function into purely systolic (n = 53), purely diastolic (n = 42), and the combination of systolic plus diastolic (n = 14) on the basis of echocardiography. Values for all abnormal LV function groups are significantly higher than for the normal LV function group (P <.001). Patients with systolic plus diastolicrestrictive dysfunction had significantly higher BNP values (1077 ± 272 pg/ml) than pure systolic (567 ± 113 pg/ml) or pure diastolic function alone (391 ± 89 pg/ml) (P <.0001). The ejection fraction of the systolic plus diastolic-restrictive group was 34% versus 45% for the pure systolic patients.

4 370 Maisel et al American Heart Journal March 2001 Table II. BNP levels: normal versus abnormal Positive Negative BNP levels predictive predictive (pg/ml) Sensitivity (%) Specificity (%) value (%) value (%) Accuracy (%) (88-98) 66 (56-74) 71 (63-79) 93 (85-97) (85-97) 80 (71-97) 81 (72-87) 81 (72-87) (84-96) 86 (76-91) 85 (77-91) 92 (84-96) (80-94) 91 (84-96) 90 (82-95) 90 (82-94) (78-92) 98 (93-100) 98 (92-100) 89 (82-94) 93 Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of various BNP levels. The various cut points were obtained from ROC curve analysis. Figure 4 Table III. Normal LV function versus abnormal LV function Normal Abnormal LV function LV function (n = 105) (n = 95) Age >55 y 71% 90% Clinical presentation History of hypertension 56% 75% History of diabetes 28% 40% History of coronary artery disease 33% 60% History of shortness of breath 42% 63% History of edema 24% 32% BNP levels (pg/ml) >80 1% 85% >100 1% 83% >120 1% 80% ROC curve comparing the sensitivity and specificity of BNP and echocardiography diagnosis of LV dysfunction. Selected BNP values are indicated in picograms per milliliter. An ROC curve showing the sensitivity and specificity of BNP against the echocardiography diagnosis for LV function in all 200 patients is shown in Figure 4. The area under the curve (accuracy) was ( ). Table II represents the sensitivity, specificity, positive and negative predictive values, and accuracy of various BNP levels in determining LV function with use of echocardiography as the gold standard. The different cut points were picked from the ROC curve. As can be seen, a BNP level cutoff value at 38.5 pg/ml was 95% sensitive for the detection of LV dysfunction and 66% specific. Levels at or below 38.5 pg/ml had a negative predictive value of 93%. A BNP cut point of 75 pg/ml exhibited the best specificity (98%), best positive predictive value (98%), and the highest accuracy (93%). Table III shows characteristics of patients belonging to the two groups (normal and abnormal LV function). As can be seen, histories of hypertension, diabetes, and Clinical presentation and BNP levels among the two groups of patients normal and abnormal LV function, by echocardiography. Abnormal group included either systolic dysfunction, diastolic dysfunction, or both systolic and diastolic dysfunction. coronary disease are frequently seen in both groups of patients. Yet BNP levels >100 pg/ml were seen in only 1% of patients with normal ventricular function compared with 80% of patients with abnormal ventricular function (P <.001). Figure 5 shows a depiction of all cardiac referrals for assessment of LV function. Twenty-four percent of patients in the referral group had known LV dysfunction. The mean BNP in this group was 798 ± 106 pg/ml. Sixty percent of patients referred had unknown LV function. Breakdowns of BNP levels in these groups are discussed above. Discussion Early detection of LV dysfunction enables administration of treatment that can improve survival and increase well-being. 2,6 But ventricular dysfunction may be difficult to diagnose because patients may be asymptomatic, and abnormal findings on physical examination are often absent. 3,4 Echocardiography, the most commonly used method to diagnose LV dysfunction, is one of the fastest growing procedures in cardiology. 25 However,

5 American Heart Journal Volume 141, Number 3 Maisel et al 371 Figure 5 A pie chart representing all referrals for echocardiography to evaluate LV function at San Diego Veterans Administration Medical Center between June and October This group includes both outpatients and inpatients. both the limited availability of echocardiography in community settings and its expense may not make it the best screening test for patients with low probability of LV dysfunction. Although studies using logistic regression models with features of the history, physical examination, chest x-ray film, and ECG have been used to predict the probability of an abnormal echocardiogram, 7,26 a simple, rapid blood test that is both sensitive and specific for LV dysfunction would be of significant clinical benefit. The test should reliably rule out LV dysfunction with an adequate positive predictive value. The fact that increased levels of neurohumoral factors such as norepinephrine, renin, and endothelin-1 have been found to be significant prognostic predictors in congestive heart failure (CHF) suggests an important role of these vasoconstrictors in the pathogenesis of CHF However, the use of these neurohumoral factors to diagnose LV dysfunction is impractical, in large part because of difficult assay characteristics, general instability of the compounds, and wide-ranging, often overlapping values. 35,36 BNP is a 32 amino acid polypeptide containing a 17 amino acid ring structure common to all natriuretic peptides. 37 The source of plasma BNP is cardiac ventricles, which suggests that it may be a more specific indicator of ventricular disorders than other natriuretic peptides. 5,8,32 The nucleic acid sequence of the BNP gene contains the destabilizing sequence tatttat, which suggests that turnover of BNP messenger RNA is high and that BNP is synthesized in bursts. 8 This release appears to be directly proportional to ventricular volume expansion and pressure overload. 8-11,32 BNP is an independent predictor of high LV pressure 10 and correlates to NYHA classification. 11 BNP as a screen for LV dysfunction BNP appears to be a useful addition in the evaluation of possible CHF ,18 In a community-based study where 1653 subjects underwent cardiac screening, the negative predictive value of BNP of 18 pg/ml was 97% for LV systolic dysfunction. 14 In a study of 122 consecutive patients with suspected new heart failure referred by general practitioners to a rapid-access heart failure clinic for diagnostic confirmation, a BNP level of 76 pg/ml, chosen for its negative predictive value of 98% for heart failure and similar to the cutoff value in the current study, had a sensitivity of 97%, a specificity of 84%, and a positive predictive value of 70%. 13 Finally, Davis et al 15 measured the natriuretic hormones atrial natriuretic peptide and BNP in 52 patients with acute dyspnea and found that admission plasma BNP concentrations more accurately reflected the final diagnosis than did ejection fraction or concentration of plasma atrial natriuretic peptide. Point-of-care testing of BNP This is the first study that examines the utility of a rapid, point-of-care test for BNP to predict LV dysfunction as determined by echocardiography. This immuno-

6 372 Maisel et al American Heart Journal March 2001 assay is automatic, uses 5 ml of whole blood, and is small enough to use at the bedside or the echocardiography clinic. Our findings suggest that BNP may be a useful screen for patients with LV dysfunction and yields an ROC curve of compared to echocardiography. This accuracy is similar to that of the prostatespecific antigen for prostate cancer detection, which had an area under the curve (AUC) of 0.94 and is superior to those of Papanicolaou smears and mammography (AUC 0.70 and 0.85, respectively) We found that BNP levels were elevated in both systolic and diastolic dysfunction, with the highest values being reported in patients with systolic dysfunction plus a decreased mitral valve deceleration time. Interestingly, this group of patients has also been shown to have the worst prognosis of all echocardiogram classifications of LV dysfunction. 12,17 The European Society of Cardiology recently published its recommendations regarding the diagnosis of isolated diastolic heart failure, which included the presence of symptoms, presence of normal or mildly reduced systolic function, and evidence of abnormal LV relaxation and filling, diastolic distensibility, and diastolic stiffness. 41 Our results are similar to those of Redfield et al, 42 who studied 657 subjects with normal systolic function and found that BNP levels were higher in those with isolated diastolic dysfunction. Although BNP levels cannot differentiate between systolic and diastolic dysfunction, elevated BNP levels likely represent true diastolic dysfunction when systolic function is normal by echocardiography. The results of this study can be extended to other venues where rapid screening for left ventricular dysfunction is important. 12,17,18 We recently evaluated point-of-care testing of 250 patients seen in the emergency department for acute dyspnea. At the cut point for BNP of 80 pg/ml, the negative predictive value was 98%. BNP levels added significantly to variables found in the history, physical examination, and the laboratory. Patients whose dyspnea was subsequently found to be the result of pulmonary disease had BNP levels 10-fold less than those of patients with CHF. Twenty-nine of 30 cases of acute dyspnea misdiagnosed by emergency department physicians would have been correctly identified had BNP levels been available. 43 Role of BNP in asymptomatic or minimally symptomatic LV dysfunction It is estimated that 3% of the population above the age of 45 years may have ventricular dysfunction and that 50% of them may be asymptomatic. 44 The National Institutes of Health sponsored Studies of Left Ventricular Dysfunction (SOLVD) in patients with asymptomatic LV dysfunction, demonstrated humoral activation characterized by increases in the natriuretic peptides without activation of the circulating renin-angiotensin system. 45 In the current study we found that nearly half the patients were asymptomatic, yet BNP levels were elevated in the majority of patients. Our data amplify the suggestion of Mair et al, 46 who concluded that there is sufficient evidence to encourage physicians to gain experience with BNP as a supplement in the diagnosis of patients suspected of having heart failure. The current study demonstrates the usefulness of BNP for selecting patients for further cardiac evaluation. It is clear that BNP should not replace imaging techniques in the diagnosis of CHF because these methods provide complementary information. An increase in BNP is serious enough to warrant follow-up echocardiography. Because BNP also provides information on neurohormonal activation in CHF, which is independent and of additive prognostic value to hemodynamic variables, BNP might also be helpful for the cardiologist to monitor therapy and disease course in patients with CHF and for estimating prognosis in these patients. 47,48 Limitations This was an observational study done at a single Veteran s hospital, so one must be careful about generalizing the results to the entire population. Both the AUC from an ROC, as well as the negative predictive values are dependent on the patient population studied. Our population represents generally older, predominantly male, veterans. Echocardiographic recordings form the basis of the diagnosis of systolic and diastolic dysfunction in the current study. Numerous previous reports have validated the ability of cardiac ultrasonography to detect abnormalities of contractile function and to quantitate LV volumes and ejection fraction. 23,24 All patients in this study so designated had clear-cut evidence of LV systolic dysfunction. Although diastolic dysfunction implies an abnormal relationship between LV volume and pressure, echocardiography is capable of assessing only parameters related to volume. Therefore transmural and pulmonary venous flow velocities provide only indirect measurements of diastolic performance. Nevertheless, these parameters have been shown to provide reliable markers of impaired diastolic function and are applied for this purpose in clinical practice. Finally, in this study BNP is being used to identify any impairment of ventricular function rather than significant impairment. Thus symptoms in such patients are not necessarily of cardiac origin and could challenge the value of labeling those patients as abnormal with BNP. Conclusion An easy, rapid test for BNP, which can be performed at the bedside or clinic, with a whole blood sample,

7 American Heart Journal Volume 141, Number 3 Maisel et al 373 can reliably predict the presence or absence of LV dysfunction on echocardiography. We believe that BNP may be an excellent screening tool for LV dysfunction, especially in the community where the greatest burden of disease exists and where there is limited access to echocardiography. In this setting it is likely that BNP analysis would greatly assist in appropriateness of patient referral and in the optimization of drug therapy. References 1. Sander GE, McKinnie JJ, Greenberg SS, et al. Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in the treatment of heart failure caused by left ventricular systolic dysfunction. Prog Cardiovasc Dis 1999;41: Pfeifer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement trial: the SAVE Investigators. 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