Eur J Echocardiography (2007) 8, 30e36

Brain natriuretic peptide plasma level is a reliable indicator of advanced diastolic dysfunction in patients with chronic heart failure
Angela Beatrice Scardovi a,*, Claudio Coletta a, Nadia Aspromonte a, Silvia Perna b, Manuela Greggi a, Paola DErrigo c, Augusto Sestili a, Vincenzo Ceci a
a

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Cardiology Department, S. Spirito Hospital, Lungotevere in Sassia 1, 00196 Rome, Italy Cardiology Department, S. Andrea Hospital, Rome, Italy c `, Istituto Superiore di Sanita Rome, Italy
b

Received 6 August 2005; received in revised form 13 October 2005; accepted 15 December 2005 Available online 14 February 2006

KEYWORDS
Brain natriuretic peptide; Heart failure; Doppler echocardiography; Diastole

Abstract The aim of the study was to determine the value of brain natriuretic peptide for the identication of diastolic dysfunction status in congestive heart failure. We studied 204 patients with stable heart failure. Brain natriuretic peptide plasma levels were correlated with echocardiographic parameters of diastolic dysfunction. Diastolic dysfunction was classied as mild (abnormal echocardiographic relaxation pattern) and severe (pseudo-normal or restrictive pattern). A signicant correlation between brain natriuretic peptide levels and the other parameters was detected. Brain natriuretic peptide dosage, then, seems to be a reliable tool for the assessment of diastolic dysfunction status in patients with congestive heart failure. 2005 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.

Introduction
Congestive heart failure is one of the main causes of hospitalization in industrialized countries, with
* Corresponding author. Tel.: 39 06 68352264; fax: 39 06 68354880. E-mail address: ab.scardovi@libero.it (A.B. Scardovi).

a ve-year survival rate as low as 50%. The clinical syndrome of congestive heart failure occurs over a broad range of underlying left ventricular systolic functional status.1,2 Conversely, diastolic dysfunction plays a primary role in determining individual prognosis.3,4 Although Doppler echocardiography is widely used to determine left ventricular diastolic lling, this method has several

1525-2167/$32 2005 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.euje.2005.12.009

Brain natriuretic peptide plasma level is a reliable indicator of advanced diastolic dysfunction limitations and pitfalls, related to the clinical status of the patient and to the unavoidable technical difculties. In this setting an alternative marker, whenever related to the diastolic functional status, could give useful information for a rst-step outcome assessment of congestive heart failure patients. Brain natriuretic peptide, a marker of neurohormonal activation secreted by cardiomyocytes in response to ventricular wall stretch, has a basic role in cardiovascular remodelling and volume homeostasis. High plasma brain natriuretic peptide levels in resting conditions act as sensitive and specic markers for the diagnosis of heart failure from other causes of dyspnea.5 Moreover, their levels are closely related to the NYHA functional class and the individual prognosis6e10 and seem to reect diastolic functional status,11 but no definite data exist about the relationship between BNP levels and severe diastolic dysfunction. Indeed, the aim of our study was to investigate the relationship between brain natriuretic peptide levels and the severity of diastolic dysfunction as assessed by Doppler echocardiography in stable outpatients with congestive heart failure.

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Doppler echocardiography
Comprehensive transthoracic Doppler echocardiography was performed on the standard left parasternal and apical views by experienced operators (CC, AS) in blind conditions. The pulsed-wave Doppler approach was used for the transmitral ow velocity analysis using a 2e4 mm sample volume placed at the mitral leaet tip level in the apical four-chamber view. The transmitral pulsed-wave Doppler blood ow velocities were calculated off-line from ve consecutive cardiac cycles and the following measurements were performed: early diastolic ow (E) peak velocity (cm/s), late diastolic ow (A) peak velocity (cm/s), E/A velocity ratio and E-velocity deceleration time (ms). In patients without return of E velocity slope to baseline, extrapolation of the deceleration signal to the zero line was accepted. Diastolic function, as determined from the pattern of transmitral and pulmonary venous blood ow, was classied into three categories: Type I: identied by the abnormal relaxation pattern (E/A velocity ratio < 0.75); Type II: identied by the pseudo-normal pattern (E/A velocity ratio ! 0.75 and <1.5; Evelocity deceleration time > 140 ms and pulmonary vein peak diastolic velocity > peak systolic velocity); Type III: identied by the restrictive pattern (E/A velocity ! 1.5, E-velocity deceleration time 140 ms). For the purposes of the study, types II and III were classied as severe diastolic dysfunction. In our laboratory, interobserver reproducibility data for transmitral early- and late peak diastolic velocity have been detected in 20 consecutive patients with symptoms of congestive heart failure and demonstrated to be 5 4% and 4 4%, respectively. In the same setting, interobserver variability of E-velocity deceleration time was 6 7%. Left ventricular ejection fraction (%) was measured off-line using the modied Simpsons biplane method by the apical four and two chambers views as recommended by the American Society of Echocardiography.12 All images and clips were stored on a magnetooptical disc. Finally, peak systolic pulmonary arterial pressure (mmHg) was empirically calculated using the formula: right ventricle right atrium peak systolic gradient (mmHg) 10 mmHg.

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Methods
Patients
Two hundred and seventy-six consecutive outpatients referred to our tertiary cardiology centre between February 2002 and January 2003 were considered for the study. All patients were in clinically stable conditions since at least four weeks before admission. For the purpose of the study, the following exclusion criteria were dened: (a) renal insufciency (serum creatinine ! 2 mg/dl), (b) any mitral stenosis or previous mitral valve surgery, (c) signicant aortic stenosis (peak systolic velocity ! 4 m/s) and/or insufciency, (d) signicant pulmonary or liver disease, (e) recent ( 3 months) myocardial infarction or unstable angina, (f) New York Heart Association (NYHA) functional class IV, (g) atrial brillation or utter at the moment of the study or documented paroxysmal atrial brillation in the last three months, (h) Moreover, 24 patients (9%) were excluded from the study due to a low technical quality of Doppler echocardiography with unavailability of reliable pulmonary artery pressure or pulmonary venous ow velocity assessment. The study was approved by the local Ethical Committee and all patients gave written consent.

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Table 1 (n 204) Clinical data of the study population

Brain natriuretic peptide plasma levels

In all patients blood was collected by venipuncture from antecubital vein after 10 min of sitting rest, in tubes containing ethylene diamine tetracetic acid before echocardiography examination. The blood samples were kept at room temperature and analyzed within 4 h of the draw time. Before analysis, each tube was inverted several times to ensure homogeneity. A point-of-care test for determination of brain natriuretic peptide (Triage BNP test, Biosite Diagnostics) based on immunouorometric assay in whole blood or plasma was used in our study. The range of detectable levels, at the time of the study, was 1e1.300 pg/mL. The average 95% condence limit of the analytical sensitivity of the test is less than 5 pg/mL (95% condence interval 0.2e4.8 pg/mL). The average total error is 10% at mean values of 28 pg/mL and 16.2% at mean levels of 1080.4 pg/mL. No signicant cross-reactivity with endothelin-1, atrial natriuretic peptide or aldosterone is present.13 Brain natriuretic peptide concentrations were determined by nurses who were blinded to echocardiography results.

Therapy Ace-inhibitors Non-potassium sparing diuretics Nitrates b-blockers Potassium sparing diuretics Angiotensin II receptor blockers Anticoagulant Digitalis Etiology Ischemic Hypertensive Idiopathic Alcoholic NYHA functional class I II III Mean NYHA functional class Left bundle branch block

184 163 122 117 43 20 20 10 122 45 26 10

(90%) (80%) (60%) (57%) (21%) (10%) (10%) (5%) (60%) (22%) (13%) (5%)
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20 (10%) 140 (69%) 43 (21%) 2.13 0.52 54 (24%)

ACE: angiotensin converting enzyme; NYHA: New York Heart Association.

Statistical analysis
Categorical variables are presented as mean values standard deviation (SD). Mean values and their SD were compared by the Students t test or by ANOVA with Bonferroni post-hoc test for multiple groups. Analysis of correlation among the parameters of the study was performed using a Pearsons correlation and results are presented by the r coefcient of correlation. The receiveroperating characteristic curves were also calculated for determining the best diagnostic accuracy of brain natriuretic peptide levels. The results are expressed in terms of the areas under the curve with their 95% condence intervals. Sensitivity, specicity and accuracy for identication of severe diastolic dysfunction were computed using a selection of multiple cut-off points of brain natriuretic peptide level. All statistical tests were based on a two-tailed models and a p value < 0.05 was considered statistically signicant. Data were analyzed using the SPSS 11 for Microsoft Windows package (SPSS Inc., Chicago).

Results
The nal population of the study was constituted by 204 patients. Mean age was 70 11 years, most subjects were males (135/204, 66%) (Table 1).

Average left ventricular ejection fraction and systolic pulmonary arterial pressure, in our study population, were 41 13% and 47 14 mmHg, respectively. One-hundred and twenty-four (61%) patients had a diastolic function type I, 33 patients (16%) had type II and 47 patients (23%) had type III, so that a severe diastolic dysfunction was detected in 80 out of 204 patients (39%). The prevalence of severe diastolic dysfunction was lower in patients on beta-blocker therapy (23% vs 36%, p 0.061). Mean ejection fraction was lower and the E-velocity deceleration time was shorter in patients with severe diastolic dysfunction than in those without (35 11% vs 44 11%, p < 0.001, and 152 41 vs 236 63 ms, p < 0.001, respectively) (Table 2). Average brain natriuretic peptide plasma level was 266 351 pg/mL (median value: 122 pg/mL). Plasma levels were within the standardized normal limit (40 pg/mL) in 37 out of 204 patients (18%). Conversely, a level < 100 pg/mL was detected in 83 patients (41%). Fourteen (17%) patients had preserved systolic function and severe diastolic dysfunction (types II and III). In this subgroup mean ejection fraction was 54 6% and average brain natriuretic peptide level was 168 97 pg/mL (median: 166 pg/mL, range: 16e361). Ejection fraction and diastolic dysfunction were signicantly correlated (r 413; p < 0.01).

Brain natriuretic peptide plasma level is a reliable indicator of advanced diastolic dysfunction
Table 2 BNP values and echocardiography e Doppler results in the study population Pts (%) DD I DD II DD III DD II DD III All patients 124 33 47 80 204 (61) (16) (23) (39) (100) BNP (pg/mL) (SD) 142 257 604 503 265 (166) (323) (494) (341) (350) BNP (pg/mL) Median (range) 90 142 486 291 122 (3e915) (16e1.300) (48e2360) (16e2360) (3e2360) EF% (SD) 44 40 31 35 41 (11) (12) (9) (11) (11) EDT (ms) (SD) 236 189 125 152 203 (63) (37) (14) (41) (69) E (cm/s) (SD) 56 95 95 95 71 (16) (35) (25) (28) (29) A (cm/s) (SD) 88 59 38 47 72 (22) (20) (20) (22) (30) E/A ratio (SD) 0.69 1.79 2.86 2.41 1.40

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(0.57) (1.03) (1.51) (1.43) (1.3)

A: transmitral A velocity; BNP: brain natriuretic peptide; DD I: diastolic dysfunction type I; DD II: diastolic dysfunction type II; DD III: diastolic dysfunction type III; E: transmitral E-velocity; EDT: E-velocity deceleration time; EF: left ventricular ejection fraction; LAD: left atrial dimensions; Pts: patients.

Diastolic function and brain natriuretic peptide

Brain natriuretic peptide was signicantly higher in patients with severe diastolic dysfunction than in those without (459 462 pg/mL vs 142 166 pg/mL, p < 0.001). A signicant correlation between brain natriuretic peptide and left atrium (r 0.311; p < 0.01), E velocity (r 0.369; p < 0.01), E/A velocity ratio (r 0.515; p < 0.01) and pulmonary systolic arterial pressure (r 0.509; p < 0.001) was found. The relationship between brain natriuretic peptide and systolic pulmonary pressure appeared particularly evident in symptom-free patients (r 0.934; p < 0.001). Moreover, a reverse correlation between brain natriuretic peptide level and ejection fraction (r 0.445; p < 0.01), A velocity (r 0.358; p < 0.01) and E velocity deceleration time (r 0.389; p < 0.01) (Fig. 2) was present (Table 3).

In the receiver-operating curve analysis, the identication of severe diastolic dysfunction by brain natriuretic peptide levels showed overall area under the curve to be 0.764 (95% CI: 0.68e 0.84), and a level ! 138 pg/mL appeared to be the best limit for severe diastolic dysfunction, with accuracy, 70%, sensitivity, 72%, and specicity, 70% (Fig. 1). Alternatively, a brain natriuretic peptide level ! 402 pg/mL had the highest sensitivity (93%) and positive predictive value (85%), but the specicity was low (38%). Finally, a 46 pg/ml level, with a 93% negative predictive value, reliably identied patients free of severe diastolic dysfunction (Fig. 3).

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Discussion
The results of our study conrm the moderate relationship between plasma brain natriuretic peptide values and severe diastolic dysfunction

Figure 1 Scatter plots of brain natriuretic peptide (BNP) concentrations versus E/A ratio. BNP: brain natriuretic peptide; E/A ratio: early diastolic ow (E), peak velocity late diastolic ow (A), velocity ratio.

Figure 2 Scatter plots of brain natriuretic peptide (BNP) concentrations versus E-velocity deceleration time (EDT). BNP: brain natriuretic peptide; EDT: E-velocity deceleration time.

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Table 3

A.B. Scardovi et al.

Correlation coefcient between brain natriuretic peptide levels and echocardiographic parameters LAD E 0.369 <0.0001 A 0.358 <0.001 E/A ratio 0.515 <0.01 PAPS 0.445 <0.01 EF 0.445 <0.01 EDT 0.389 <0.01 0.311 <0.0001

Correlation coefcient p Value

A: transmitral A velocity; BNP: brain natriuretic peptide; E: transmitral E velocity; EF: ejection fraction; EDT: E velocity deceleration time; LAD: left atrial dimensions; PAPS: pulmonary artery systolic pressure.

as dened by Doppler echocardiography in patients with established congestive heart failure. In this clinical setting, the selection of different cutoff values of brain natriuretic peptide allowed a reasonable identication of patients at higher and at lower risk of severe diastolic dysfunction. Although diastolic dysfunction plays an important role in the risk stratication of CHF-patients, the ideal approach requires invasive measurement of left ventricular pressures and volumes, resulting in a time-consuming, high-cost and unpractical approach for the daily practice. As a consequence, non-invasive determination of left ventricular lling by Doppler blood ow velocity encoding has become a routine clinical tool for identifying diastolic function and predicting mortality in patients with clinically evident heart failure. However Doppler echocardiography, due to the well-known technical limitations, cannot provide unequivocal evidence of left ventricular diastolic functional status in any patient.14 As a consequence, alternative low-cost markers for identifying patients at higher risk of advanced diastolic dysfunction might be very useful in the rst-step screening of large populations with congestive heart failure. Brain natriuretic peptide is a cardiac neurohormone secreted from the ventricle walls as a response to chamber volume expansion and pressure overload, easily dosable by point-of-care systems15 and strictly correlated to prognosis16e18; high brain natriuretic peptide levels are detectable in symptomatic patients and, similarly, an activated neurohormonal status is present in patients with diastolic dysfunction19,20 and high pulmonary systolic pressure.21,22 The link among these variables is probably multifactorial. It is possible that brain natriuretic peptide levels act as a non-selective index of cardiac performance, reecting the combined effects of left ventricular systolic and diastolic function as well as the severity of global cardiopulmonary exercise impairment. The results of our study demonstrate a correlation among brain natriuretic peptide levels, diastolic dysfunction and pulmonary artery pressure, suggesting the possible role of the neurohormone as a window on the hemodynamic status of

the single patient. The r values found in this study were quite low, but elevated brain natriuretic peptide levels reliably indicated severe diastolic abnormality, in spite of the well-known, potentially confounding variability of neurohormonal levels among heart failure patients. Elevated brain natriuretic peptide levels reliably indicate severe diastolic abnormality, but the well-known variability of neurohormonal levels among heart failure patients can still generate some confusion in interpreting the results. However, the correlation between brain natriuretic peptide level and severe diastolic dysfunction explains the independent prognostic value either in patients with normal or abnormal left ventricle systolic function.21 Although the isolated detection of abnormal brain natriuretic peptide levels cannot differentiate between systolic and diastolic dysfunction, a result within the range of normality in patients with preserved systolic function reliably rules out advanced diastolic dysfunction.19 Conversely, the combined and confounding effect of right ventricular performance, mitral and aortic functional status and pulmonary/systemic

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Figure 3 Receiver-operating characteristic curve comparing sensitivity and specicity of brain natriuretic peptide (BNP) and echocardiographic diagnosis of left ventricular diastolic dysfunction. AUROC: area under the receiver-operating characteristic curve; BNP: brain natriuretic peptide; DD II: diastolic dysfunction type II; DD III: diastolic dysfunction type III; DD II DD III: severe diastolic dysfunction.

Brain natriuretic peptide plasma level is a reliable indicator of advanced diastolic dysfunction hypertension explains the lower accuracy of brain natriuretic peptide for the identication of pure systolic dysfunction.22e25 One important feature of our study was the high prevalence (41%) of patients with a brain natriuretic peptide level < 100 pg/mL (the accepted cut-off value for diagnosing decompensated heart failure), and the large group of patients (18%) with normal (<40 pg/mL) levels. This seems due to the characteristics of our study population, constituted by clinically stable outpatients already receiving a point-of-care pharmacological treatment. In our population the high prevalence of long-term beta-blocker therapy probably played a role, reducing sympathetic inuence on heart rate, myocardial contractility and vascular tone, as indirectly conrmed by the lower prevalence of severe diastolic dysfunction in patients taking beta-blockers. The high correlation found between brain natriuretic peptide level and pulmonary artery pressure in asymptomatic patients remains an unexplained task. Possibly due to a casual distribution in this small group (n 20) of patients, it could also reect the ability of the neurohormone to identify abnormal tensive regimens of the pulmonary circulation, as conrmed by the established link between brain natriuretic peptide and pulmonary capillary wedge pressure.16,17 Based on the results of our study, brain natriuretic peptide dosage offers a simple and costsaving tool for assessing patients at high risk of severe diastolic dysfunction and, consequently, of worse outcome in the rst-step screening of large populations or in patients with technically inadequate Doppler echocardiography. Moreover, in the search of new strategies in patients with congestive heart failure, the combination of neurohormonal and echocardiographic parameters might represent a rational approach for a more accurate prognostic stratication, and further studies should be planned to assess this particular feature.

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patients with renal failure cannot be ascertained from our data. The link between diastolic function and brain natriuretic activity observed in our study was in part dependent on the strong relationship in the asymptomatic or mildly symptomatic patients. Consequently, in patients with more advanced NYHA functional class new prospective studies should better dene the accuracy of brain natriuretic peptide for the identication of severe diastolic dysfunction. We did not measure plasma N-terminal probrain natriuretic peptide, which has been recently suggested to be more accurate for predicting left ventricular function and prognosis after myocardial infarction. However, the assay utilized in this study represents the most widely accepted method for rapid determination of neurohormonal activity in congestive heart failure patients. Based on the design of our study, it remains unknown whether consecutive, multiple plasma brain natriuretic peptide levels, reducing the intrinsic variability of the method, would represent a more accurate approach for the identication of diastolic dysfunction in these patients. Finally, a relatively signicant proportion of patients were a priori excluded for technical limitations of Doppler echocardiography. The aim of the study was to analyze the possible role of brain natriuretic peptide level as an indirect marker of diastolic dysfunction, and this information appears particularly useful in patients without reliable Doppler information. Therefore, this unavoidable limitation should be considered in the clinical application of our data.

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Conclusion
In clinically stable heart failure patients plasma brain natriuretic peptide values are closely related to the diastolic functional status and pulmonary systolic pressure, both reliable markers of poor prognosis. Based on the results of our study, brain natriuretic peptide dosage could be considered a lowcost, widely available tool for the rst-step screening of patients at higher risk of severe diastolic dysfunction, particularly in the presence of normal or mildly abnormal functional status. In this era of cost-saving management of chronic heart disease, brain natriuretic peptide determination, eventually combined with Doppler echocardiography in a sequential approach, could represent a reliable strategy for the screening of asymptomatic or mildly symptomatic patients with congestive heart failure.

Study limitation
Our study acknowledges several limitations. First, the study population included only outpatients in stable clinical conditions, presumably not representative of the clinical status of more general populations referred for clinical management of congestive heart failure. Patients with renal insufciency were excluded from the study because of the non-specic elevation of plasma BNP in this clinical condition.26 Thus, whether different plasma BNP levels predict functional capacity and ventilatory response to exercise in HF

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14. Yamamoto K, Redeld MM, Nishimura RA. Analysis of left ventricular diastolic function: a common and costly clinical entity. Heart 1996;75(Suppl. 2):27e35. 15. Cheng V, Kazanagra R, Garcia A, Lenert L, Krishnaswamy P, Gardetto N, et al. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study. J Am Coll Cardiol 2001;37:386e91. 16. Silver MA, Maisel A, Yancy CW, McCullough PA, Burnett JC, Francis GS, et al. BNP consensus panel 2004: a clinical approach for the diagnostic, prognostic, screening, treatment monitoring, and therapeutic roles of natriuretic peptides in cardiovascular diseases. Congest Heart Fail 2004;10(Suppl. 3): S1e30. 17. Kazanegra R, Cheng V, Garcia A, Krishnaswamy P, Gardetto N, Clopton P, et al. A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study. J Card Fail 2001;7:21e9. 18. Troughton RW, Prior DL, Pereira JJ, Martin M, Fogarty A, Morehead A, et al. Plasma B-type natriuretic peptide levels in systolic heart failure. J Am Coll Cardiol 2004;43:416e22. 19. Lubien E, DeMaria A, Krishnaswamy P, Clopton P, Koon J, Kazanegra R, et al. Utility of Bnatriuretic peptide in detecting diastolic dysfunction. Comparison with Doppler velocity recordings. Circulation 2002;105:595e601. 20. Dokainish H, Zoghbi WA, Lakkis NM, Quinones MA, Nagueh SF. Comparative accuracy of B-type natriuretic peptide and tissue Doppler echocardiography in the diagnosis of congestive heart failure. Am J Cardiol May 1, 2004;93(9): 1130e5. 21. Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R, et al. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 2001;37:183e8. 22. Nagaya N, Nishikimi T, Okano Y, Uematsu M, Satoh T, Kyotani S, et al. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol 1998;31:202e8. 23. Mayer SA, De Lemos JA, Murphy SA, Brooks S, Roberts BJ, Grayburn PA. Comparison of Btype natriuretic peptide levels in patients with heart failure with versus without mitral regurgitation. Am J Cardiol Apr 15, 2004;93(8):1002e6. 24. Sutton TM, Stewart RA, Gerber IL, West TM, Richards AM, Yandle TG, et al. Plasma natriuretic peptide levels increase with symptoms and severity of mitral regurgitation. J Am Coll Cardiol Jun 18, 2003;41(12):2280e7. 25. Troughton RW, Prior DL, Pereira JJ, Martin M, Fogarty A, Morehead A, et al. Plasma B-type natriuretic peptide levels in systolic heart failure: importance of left ventricular diastolic function and right ventricular systolic function. J Am Coll Cardiol Feb 4, 2004;43(3):416e22. 26. Ishizaka Y, Yamamoto Y, Fukanaga T, Yokota N, Kida O, Kitamura K, et al. Plasma concentration of human brain natriuretic peptide in patients on haemodialysis. Am J Kidney Dis 1994;24:461e72.

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