Elevated B-type natriuretic peptide despite normal left ventricular function on rest and exercise stress echocardiography in mitral regurgitation

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1 European Heart Journal (2008) 29, doi: /eurheartj/ehm553 CLINICAL RESEARCH Valvular heart disease Elevated B-type natriuretic peptide despite normal left ventricular function on rest and exercise stress echocardiography in mitral regurgitation Andrew J. Kerr 1,2 *, O. Christopher Raffel 1,3, Gillian A. Whalley 2, Irene Zeng 3, and Ralph A. Stewart 2,3 1 Department of Cardiology, Middlemore Hospital, Hospital Road, Private Bag 93311, Otahuhu, Auckland, New Zealand; 2 Department of Medicine, The University of Auckland, Auckland, New Zealand; 3 Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand Received 24 June 2007; revised 19 October 2007; accepted 25 October 2007 See page 290 for the editorial comment on this article (doi: /eurheartj/ehm593) Aims To determine whether elevated B-type natriuretic peptide (BNP) predicts left ventricular (LV) contractile dysfunction on exercise stress echocardiography in patients with severe mitral regurgitation (MR).... Methods Thirty three patients with moderate-to-severe or severe MR, a LV ejection fraction 60% and New York Heart and results Association Class I or II symptoms, and 12 controls underwent resting and exercise stress echocardiography. In 20 MR patients, BNP was within the normal range (mean + SD, pmol/l), and in 13 MR patients, BNP was.12 pmol/l ( pmol/l). LV end-systolic volume index after exercise was lower in controls than patients with MR (P, ), but similar in MR patients with normal and elevated BNP, respectively (controls , MR vs cm 2 /m 2, P. 0.05). However, pulmonary artery systolic pressure (PAP) after exercise was higher in MR with high BNP ( vs mmhg,,0.0001) and controls (38+11 mmhg). A two-fold increase in plasma BNP was associated with an average increase in resting PAP of 7.6 (95% CI 2.9, 12.2) mmhg, an increase in post-exercise PAP of 14.4 (95% CI 9.0, 19.9) mmhg and increase in left atrial area index of 2.1 (95% CI 0.5, 3.8) cm 2 /m 2. However, there was no significant association between the plasma level of BNP and any rest or post-exercise measure of LV systolic function (r, 0.25, P for all).... Conclusion The plasma level of BNP may be within the normal range in patients with moderate-to-severe or severe MR despite significant increases in LV end-systolic volume. Increase in BNP is associated with pulmonary artery hypertension on exercise and left atrial enlargement even when LV systolic function on exercise stress echocardiography is normal Keywords Mitral regurgitation B-type natriuretic peptide Exercise stress echocardiography Introduction Optimal timing of surgery in asymptomatic patients with severe MR and preserved left ventricular (LV) function is controversial. One approach is to recommend surgery for patients with severe regurgitation whenever valve repair is likely to be successful. 1 This recommendation is based on excellent surgical outcomes in experienced units, and from large observational studies in which the majority of patients need surgery during long-term follow-up. 2 The alternative is to undertake surgery when there is evidence that cardiac compensatory mechanisms to the volume load are failing this includes onset of symptoms, evidence of LV dysfunction, atrial fibrillation, and pulmonary hypertension. 3,4 This approach avoids the up-front risks of surgery and possible valve replacement, but good outcomes depend on regular follow-up, reliable assessment of symptoms, and detection of early LV dysfunction. 5 * Corresponding author. Tel: þ ext. 8061, Fax: þ , andrewkerr@middlemore.co.nz Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oxfordjournals.org.

2 364 A.J. Kerr et al Failure to recognize impaired LV function is a major concern because of its association with increased surgical risk and adverse clinical outcomes including late after mitral valve surgery. Current ESC guidelines recommend surgery in symptomatic patients or asymptomatic patients with severe mitral regurgitation (MR) when LV ejection is below 60% and/or the LV end-systolic dimension by echocardiography is greater than 45 mm. 4 Reliable attribution of symptoms to the valve lesion is often problematic when the patient is mildly symptomatic, and reliable assessment of LV function is difficult when there is a large regurgitant volume and low resistance to flow into the left atrium. Alternative measures including tissue Doppler measurements of long axis LV function and contractile reserve on stress echocardiography may better predict LV impairment in patients with severe MR. 6 8 The plasma level of B-type natriuretic peptide (BNP) is known to increase with LV dysfunction from many causes. In observational studies, the plasma level of BNP is higher in symptomatic compared with asymptomatic patients with MR. 9 In addition, patients with MR who have an elevated BNP may be more likely to have adverse clinical events during follow-up. 10 These studies suggest that measuring the plasma level of BNP may provide a simple accessible low cost method for monitoring patients with moderate-to-severe MR. However, it is currently not clear whether BNP reliably identifies early or latent LV dysfunction in patients with severe MR. The aim of this study is to determine whether a higher plasma level of BNP predicts early LV dysfunction at rest or on stress echocardiography in asymptomatic or mildly symptomatic patients with moderate-tosevere or severe MR and preserved resting LV ejection fraction (EF). Methods Study population Patients with moderate-to-severe or severe MR with preserved LV systolic function were enrolled. Patients were excluded if they had New York Heart Association (NYHA) Class III or IV symptoms, EF,60% on screening echocardiogram, history of myocardial infarction, angina or heart failure, atrial fibrillation, significant renal disease (creatinine.0.16 mmol/l), respiratory disease, or other significant valvular disease. Consecutive patients who presented to the cardiology service who met study inclusion criteria were invited to participate. Control subjects were volunteers from the local community. They were recruited by advertisement and had no clinical evidence of cardiovascular or respiratory disease. To ensure a similar age distribution in the two groups MR patients were ranked in 10 year age bands, and control patients were chosen for each age band in proportion to the number of MR patients in each band. The study protocol was approved by the regional ethics committee, and all subjects gave written informed consent. All subjects who enrolled in the study completed the study protocol and are included in the analysis. Symptom assessment and exercise testing Symptomatic status was assessed by a study cardiologist at enrolment. Dyspnoea was graded according to the NYHA classification. All subjects underwent a symptom limited exercise treadmill test. A standard Bruce protocol was used. Blood pressure was recorded at the end of each stage. Exercise was stopped for marked dyspnoea, fatigue, chest discomfort, 2 mm ST depression, significant arrhythmia or slowing of heart rate, on patient request, or on completion of the treadmill protocol after 15 min or 17.2 metabolic equivalents (METs). Resting and stress echocardiography All patients underwent cardiac echocardiography using a standard protocol on commercially available systems (Vivid 5 or Vivid 7 System, GE Vingmed Ultrasound, Horten, Norway). The LV end-systolic and enddiastolic volumes and EF were measured from the apical four-chamber view using the modified Simpson s single-plane method. 8 This method was chosen to allow comparison with the post-exercise volumes. The left atrial area was measured in the apical four-chamber view. 11 The severity of MR was assessed by quantitative Doppler with mitral and aortic stroke volumes 12 and by the proximal isovelocity surface area (PISA) method. 13 The stroke volumes obtained from the two methods were averaged to give a mean regurgitant volume. 10 MR severity was also semi-quantitatively assessed by two methods, the vena contracta width, 14 and the MR score described by Thomas et al. 15 The MR score is calculated from visual assessment of MR jet penetration, mitral continuous-wave Doppler characteristics, left atrial size, pulmonary venous flow pattern, tricuspid regurgitation velocity, and PISA radius. 13 Early (E) and late (A) mitral inflow velocities were measured by pulsed-wave Doppler ultrasound at the mitral leaflet tips. Doppler tissue imaging was performed at the medial mitral annulus from the apical four-chamber view, and the peak systolic (S 0 ) and diastolic (E 0 ) mitral annular velocities and E/E 0 measured. 16 An intravenous injection of agitated saline was used to enhance the tricuspid regurgitant jet for estimation of right ventricular (RV) systolic pressure using continuous-wave Doppler both at rest and after exercise. 17 Right atrial pressure was estimated from the resting inferior vena cava diameter with changes during respiration. 18 Resting RV function was assessed from the peak systolic tricuspid annular velocity (S 0 ) and from RV fractional area change [¼(RV end-diastolic area 2 RV end-systolic area)/rv end-diastolic area] in the apical four-chamber view. 19 Immediately after exercise echocardiographic images were obtained in the apical four-chamber view, first for LV volumes then for tricuspid regurgitant jet velocity with agitated saline enhancement. In most patients, data were obtained within 1 min of peak exercise. Images were stored digitally and analysed later off-line using a commercial analysis system (EchoPac PC version 3.0 GE Medical, Milwaukee, WI, USA) by an investigator who was blind to clinical, exercise, and natriuretic peptide data. All measurements were averaged from three to five cardiac cycles. Measurement of natriuretic peptides A venous blood sample was collected from an indwelling intravenous catheter with the subject supine before exercise. Samples were collected in an EDTA tube and immediately placed on ice and centrifuged within 2 h at 248C. Plasma was stored at 2808C before being assayed for ANP and BNP using an established radioimmunoassay. 20 The normal range for BNP is 3 12 pmol/l and the within assay coefficient of variation is 5.2%. 20,21 To convert BNP measured in pmol/l to pg/ml divide by Statistical analysis A sample size of 30 MR patients was estimated to have 80% power (at the 0.05 level of significance) for a difference in post-exercise LV end-systolic volume index of 10 cm 3 /m 2 between MR patients with a normal BNP compared with patients with a raised plasma level of BNP (.12 mol/l). This assumes a common standard deviation for LV end-systolic volume index (LVESVI) of 9 cm 3 /m 2 based on the study by Leung et al., 8 and at least 10 patients in the high BNP group. 9 ANCOVA was used to compare normal controls, and patients with BNP within and above the normal reference range (12 pmol/l).

3 Elevated B-type natriuretic peptide in mitral regurgitation 365 Comparisons were adjusted for age and beta-blocker usage. Bonferroni corrections were used to control for type I error in multiple tests. Spearman correlation coefficients were reported for the associations between continuous variables. Multivariable linear regression analysis was conducted to examine the association of BNP with various cardiovascular outcome measures adjusting for known covariates age and gender. 22,23 Receiver Operating Characteristics analysis was conducted to assess the predictive value of BNP. The 95% confidence interval of sensitivity and specificity were estimated using SAS macro (% senspe) released by the Biostatistics Unit of Mayo Clinic Education and Research Institute. About 1000 bootstrap replicates were generated to derive the standard error of area under the receiver operating characteristics curves. Peptide levels, post-exercise pulmonary pressure, and E/E 0 underwent natural log transformation due to right skew distribution in all analyses. Two sided tests were used in all analysis and a P-value,0.05 was considered statistically significant. SAS institute released SAS 9.1 and R were used. Results Sixteen MR patients had NYHA Class I and 17 NYHA Class II symptoms. All patients were in sinus rhythm. MR was due to mitral valve prolapse in 26 and rheumatic mitral valve disease in seven patients. Five patients were taking a beta-blocker. Baseline clinical characteristics and resting echocardiographic measures are summarized for 12 normal controls and patients with MR who had a plasma level of BNP within (n ¼ 20) and above (n ¼ 13) the normal reference range (12 pmol/l) in Table 1. The mean age for patients and controls was 53 and 51 years, respectively. There was a small but not significant excess of men in the MR group (55% vs. 33%, P ¼ 0.21). The 20 subjects with MR and a plasma level of BNP 12 pmol/l had higher average BNP than normal controls indicating mild elevation of BNP within the normal range. In these MR patients, both LVESVI and LV enddiastolic volume index (LVEDVI) at rest were markedly increased compared to normal controls. In addition, mitral annular tissue velocities during both systole (S 0 ) and diastole (E 0 ) were higher than controls and the peak mitral E velocity was increased. Peak pulmonary artery systolic pressure (PAP) at rest and after exercise was higher than normal controls and exercise capacity was slightly decreased. Compared with MR patients with BNP,12 pmol/l, those with MR and elevated BNP were older and more likely to have a lower treadmill exercise capacity, a smaller increase in exercise systolic blood pressure during exercise, and a higher pulmonary artery pressure both at rest and after exercise. However, there was no statistically significant difference in any rest measure of LV function for subjects with a raised compared with normal plasma level of BNP. There was a trend towards lower augmentation of LVEF with exercise in the patients with elevated BNP (increase in EF ¼ 5.7% vs. 0.5%, P ¼ 0.07), but after adjustment for age and beta-blocker status this was not significant (P ¼ 0.49). All other results were similar after adjusting for age and beta-blocker status. For patients with NYHA Class 2 symptoms compared with asymptomatic patients with MR, the plasma level of BNP was higher (15.0 vs. 9.6 pmol/l, P ¼ 0.02), rest PAP was greater (42 vs. 32 mmhg, P, ) and exercise duration was less (5.9 vs. 9.6 min, P, ). However, there were no statistically significant differences in any resting or post-exercise measure of LV function between symptomatic and asymptomatic patients with MR. For MR patients, associations between different echocardiographic measures at rest and after exercise, and both the plasma level of BNP and exercise capacity are presented in Table 2. There were strong correlations between the plasma level of BNP and PAP both at rest and after exercise (Figure 1). There were also moderate correlations between the plasma level of BNP and septal E/E 0, left atrial area index, and an inverse correlation with treadmill exercise capacity (Figure 2). In contrast, there was no significant correlation between the plasma level of BNP and any resting or post-exercise measurement of LV function, including LVEF, indexed LV volumes or change in EF after exercise (Figure 1). There was also no statistically significant association between the plasma level of BNP and any echocardiographic measures of severity of MR or RV function assessed using tricuspid annular tissue velocities and change in RV fractional area at rest. The echocardiographic measures most strongly associated with treadmill exercise capacity were resting and post-exercise pulmonary pressure. There was a weak association between exercise capacity and post-exercise LV end-diastolic volume index but no clear association with other resting or post-exercise measures of LV function. After adjusting for age and gender, the association between natural log scaled BNP and both post-exercise pulmonary artery pressure (partial r 2 ¼ 0.49, P, ) and resting pulmonary artery pressure (partial r 2 ¼ 0.30, P ¼ 0.001) remained strong. There was a more modest association between BNP and with exercise capacity (partial r 2 ¼ 0.21, P ¼ 0.01) and with left atrial area index (partial r 2 ¼ 0.16, P ¼ 0.02). The association of BNP with resting septal E/E 0 (partial r 2 ¼ 0.16, P ¼ 0.04) was of borderline statistical significance. A two-fold increase in plasma BNP was associated with an average increase in resting PAP of 7.6 (95% CI 2.9, 12.2) mmhg, an increase in post-exercise PAP of 14.4 (95% CI 9.0, 19.9) mmhg and 2.1 (95% CI 0.5, 3.8) cm 2 / m 2 increase in left atrial area index. The sensitivity and specificity of BNP for predicting guideline based abnormal resting and post-exercise pulmonary pressures thresholds, 3 and impaired exercise capacity 24 are presented in Table 3 and Figure 3. BNP above the upper limit of normal (.12 pmol/l) was a good predictor of PAP.60 mmhg after exercise and rest PAP.50 mmhg, and a weaker predictor of reduced exercise capacity defined as failure to complete 6 min of the Bruce protocol (equivalent to,7 METs). Discussion In this study of asymptomatic or mildly symptomatic patients with moderate-to-severe or severe MR and a preserved LVEF at rest, a higher plasma level of BNP was associated with higher pulmonary pressures at rest and after exercise, increased left atrial volume and lower exercise capacity on functional testing. However, there were no clear association between BNP and measures of LV function at rest or after exercise. These results suggest that increase in the

4 366 A.J. Kerr et al Table 1 Comparison of normal controls, and patients with mitral regurgitation with a plasma level of BNP above compared with below the normal reference range (12 pmol/l) Normal controls MR BNP MR BNP P-value Normal controls P-value MR 12 pmol/l >12 pmol/l vs. MR BNP 12 pmol/l BNP vs. >12 pmol/l Number of subjects Age (years) 51 (14) 48 (15) 61 (16) Natriuretic peptides BNP (pmol/l) 5.1 (1.3) 7.7 (2.7) 19.6 (7.2) 0.004, ANP (pmol/l) 13.5 (6.3) 26.8 (6.0) 52.9 (28.6), Symptoms NYHA Class 2 vs. 1 0 (0%) 9 (45%) 8 (62%) Echocardiography (rest) Regurgitant volume (ml) 85 (34) 73 (32) 0.33 Mitral regurgitation index 2.4 (0.5) 2.6 (0.2) 0.19 Vena contracta (mm) 6.1 (1.0) 6.4 (1.2) 0.45 Left atrial area index (ml/m 2 ) 10 (1.7) 17.1 (4.5) 18.1 (4.4), PAP (mmhg) 22 (4) 32 (7) 46 (15) S 0 tricuspid annulus (cm/s) 12.3 (2.2) 14.3 (3.0) 13.8 (1.8) RV fractional area change 0.41 (0.07) 0.32 (0.09) 0.27 (0.07) LV function (rest) LVEDVI (ml/m 2 ) 46 (9) 77 (14) 75 (14), LVESVI (ml/m 2 ) 16 (6) 27 (7) 26 (6), LVESD (cm) 3.2 (0.6) 3.3 (0.5) 3.4 (0.6) LVEF (%) 66 (8) 64 (7) 65 (7) E wave (m/s) 0.7 (0.2) 1.1 (0.3) 1.2 (0.4) a S 0 mitral annulus (cm/s) 8.3 (1.7) 8.7 (1.7) 9.0 (1.7) E 0 mitral annulus (cm/s) 9.4 (3.5) 10.4 (3.0) 10.0 (2.5) E/E 0 mitral annulus 7.7 (1.7) 11.7 (4.5) 13.4 (4.6) Stress echocardiography PAP (mmhg) 38 (8.2) 48 (11) 70 (20) LVEDVI (ml/m 2 ) 38 (9.0) 65 (17) 59 (17), LVESVI (ml/m 2 ) 8.5 (3.9) 20 (7) 20 (9), LVEF (%) 78 (8.5) 70 (6) 66 (9) EF (post pre exercise) 11.6 (4.7) 5.7 (8.2) 0.5 (9.6) Treadmill exercise Exercise time (min) 10.7 (2.9) 8.9 (2.0) 5.8 (2.2) Peak systolic BP (mmhg) 159 (24) 158 (28) 130 (28) Increase in sys. BP (mmhg) 47 (14) 37 (16) 23 (20) Peak heart rate 164 (10) 150 (20) 131 (20) a After adjusting for age and beta-blocker use P ¼ 0.06 for E wave. There was no important change in P-values for other parameters. PAP, peak pulmonary artery systolic pressure; LV, left ventricle; EDVI, end-diastolic volume index; ESVI, end-systolic volume index; EF, ejection fraction. plasma level of BNP does not necessarily indicate the presence of early or latent LV dysfunction in patients with severe MR. The lack of a clear association between plasma levels of BNP and measures of LV function in the current study contrasts with some previous reports. 10,25,26 In a large cohort study including NYHA Class 1 4 patients and mild-to-severe organic MR Detaint found a weak but statistically significant association between the plasma level of BNP and LV end-systolic volume index (r ¼ 0.26). In a separate report that included subjects with both organic and functional MR, Detaint et al., 25 reported that LV end-systolic volume index was the major determinant of the plasma level of BNP. However, in this study, most patients with a LV end-systolic volume 60 ml/m 2 and a high plasma BNP had primary LV dysfunction. Yusoff et al. 26 also reported statistically significant associations between the plasma level of N-terminal-BNP and several measures of LV remodelling including the LV sphericity index

5 Elevated B-type natriuretic peptide in mitral regurgitation 367 Table 2 Correlations (r) between (i) the plasma level of B-type natriuretic peptide and (ii) exercise capacity and selected resting and post-exercise echocardiographic measurements for mitral regurgitation patients Correlation with exercise Correlation with BNP (r) P-value capacity (r) P-value Rest echocardiography Regurgitant volume Left atrial area index Pulmonary artery pressure LVEDVI LVESVI LV ejection fraction S 0 septal E wave E 0 sep E/E 0 sep Stress echocardiography Pulmonary artery pressure 0.68, LVEDVI LVESVI LVEF EF (post pre exercise) Exercise time Figure 1 Association between the natural logarithm (Ln) of B-type natriuretic peptide and resting and post-exercise pulmonary pressure (upper panels), and left ventricular end-systolic volume index (LVESVI) (lower panels) for normal controls (open symbols) and patients with mitral regurgitation (closed symbols). The values of non-transformed values of B-type natriuretic peptide in pmol/l are shown in brackets. For patients with mitral regurgitation, there were clear associations between B-type natriuretic peptide and post-exercise pulmonary pressure measured at rest (r ¼ 0.53, P ¼ 0.002) and post-exercise (r ¼ 0.68, P, ). On average, both B-type natriuretic peptide and left ventricular end-systolic volume index are higher in patients with MR compared with normal controls. However, there is no clear association between B-type natriuretic peptide and either rest (r ¼ 20.19, P ¼ 0.31) or post-exercise (r ¼ 20.07, P ¼ 0.7) left ventricular end-systolic volume index for patients with mitral regurgitation

6 368 A.J. Kerr et al Figure 2 Association between the natural log of B-type natriuretic peptide (LnBNP) and exercise capacity measured in minutes on the Bruce protocol for normal controls (open squares) and patients with severe mitral regurgitation (closed circles). The non-transformed values of B-type natriuretic peptide in pmol/l are shown in brackets. There is an inverse correlation between exercise capacity and natural log of B-type natriuretic peptide (r ¼ 20.6, P ¼ ) for patients with mitral regurgitation. However, some normal controls and individuals with mitral regurgitation have a low plasma level of B-type natriuretic peptide and a low exercise capacity Figure 3 Receiver operating characteristics curve for B-type natriuretic peptide for pulmonary hypertension after exercise.60 mmhg, and exercise capacity,7 metabolic equivalents (METs) (equivalent to,6 min on the Bruce protocol). The sensitivity and specificity of B-type natriuretic peptide.12 pmol/l (upper reference limit for laboratory) for these outcomes are presented in Table 3 Table 3 Sensitivity, specificity and area under the curve for B-type natriuretic peptide for pulmonary hypertension and exercise capacity Number of subjects Sensitivity a (95% CI) Specificity a (95% CI) AUC (95% CI) P-value Pulmonary pressure Rest.50 mmhg 4 100% (40%, 100%) 69% (49%, 85%) 0.93 (0.84, 1.0) 0.03 Post-exercise.60 mm Hg 12 75% (43%, 95%) 81% (58%, 95%) 0.87 (0.75, 1.0) Impaired exercise capacity METs achieved,7 7 86% (42%, 100%) 73% (52%, 88%) 0.82 (0.64, 1.0) % CI, 95% confidence interval; AUC, area under receiver-operating characteristic curve. a Sensitivity and specificity for BNP 12, the upper limit of normal range for laboratory. Cut levels for pulmonary artery pressure are thresholds used as an indication for surgery in current guideline of AHA/ACC. 3,Seven METs (metabolic equivalents) is failure to reach the end of the second stage (6 min) of the Bruce treadmill exercise protocol. 24 and LV end-systolic volume in 38 patients with severe MR with EF.55%. 26 However, unlike our study, the majority of patients had NYHA Class 2 or 3 symptoms and some patients had very high plasma levels of N-terminal-BNP. The variable association between BNP and LVESVI index observed in these studies probably reflect differing inclusion criteria. In the current study, the plasma level of BNP remained within the normal range for many MR patients despite significant increases in LV volumes. This suggests that compensatory changes in LV volume with MR are not necessarily associated with an increase in the plasma level of BNP above the normal range. Increase in E/E 0 is associated with higher LV end-diastolic pressure in patients with impaired LV systolic function 27, and there was a modest association between E/E 0 and BNP in the current study. However, in severe MR E increases because of the large regurgitant volume even though LV end-diastolic pressure may be normal, and the relationship between LV end-diastolic pressure and E/E may therefore be different. Natriuretic peptides are usually produced by ventricular myocytes in response to increases in LV wall stress and by atrial myocytes in response to increased atrial wall stress. 28 The predominant pressure load in MR is on the left atrium and, if pulmonary hypertension is present, on the RV. In the current study, the plasma level of BNP was not clearly associated with measures of early LV

7 Elevated B-type natriuretic peptide in mitral regurgitation 369 dysfunction. These observations are consistent with increased BNP production by the left atrium in response to the chronic increase in left atrial wall stress. Limited evidence suggests increased synthesis of BNP by atrial myocytes in response to chronic increases in wall stress 29 and co-storage of BNP with ANP in atrial granules. 28 The strong association between the plasma level of BNP and pulmonary artery pressure also raises the possibility of increased BNP secretion from the RV. However, in the current study, there was no association between the plasma level of BNP and measures of resting RV function. Previous studies of organic MR have reported an association between the presence and severity of symptoms and increase in plasma levels of BNP. 9,10,26 These observations are consistent with the strong correlation between BNP and functional capacity in the current study (r ¼ 0.6, P, ) and with maximum oxygen consumption in a previous study of severe organic MR. 30 However, resting and exercise stress measures of LV function were weak predictors of exercise capacity in this study and of maximum oxygen consumption in previous studies of severe MR. 26,30 Pulmonary artery pressure was the strongest echocardiographic predictor of functional capacity in the current study. These observations are consistent with severe MR leading to an increase in LA pressure and pulmonary hypertension during exercise even when LV contractility is normal or increased. The novel observation from the current study is that these effects of severe MR are associated with an increase in the plasma level of BNP. In patients with a LVEF.60%, the presence of symptoms attributable to MR, pulmonary hypertension at rest and/or after exercise, and decreased exercise capacity are ACC/AHA and ESC Class I or 2a indications for mitral valve surgery. Measuring the plasma level of BNP may therefore be useful for evaluating asymptomatic patients, and those with equivocal symptoms, even though an increase in BNP does not necessarily indicate the onset of LV dysfunction. Further studies are needed to reliably assess the value of BNP for this purpose. A limitation of this study is that it does not include follow-up for clinical outcomes or reassessment of LV function after mitral surgery. We are therefore unable to determine which patients, if any, would develop LV dysfunction. The presence of latent LV dysfunction was assessed using resting and post-exercise measures of LV size and performance previously published by Leung et al. 8 Decrease in the peak systolic mitral annular velocity is also associated with a lower LVEF after surgery and with decreased contractile reserve on exercise stress. 7 However, there was no evidence for an association between the plasma level of BNP and this measure in the current study. The peak systolic mitral annular velocity after exercise may be a more sensitive measure of early LV dysfunction 6,21 but was not measured in the current study. This study was limited to a subset of patients with clinically important MR in whom indications for surgery were at most equivocal. As discussed previously, we excluded patients with Class III or IV symptoms or LV impairment. Prior studies suggest a relationship between BNP and LV dilatation and dysfunction when such patients are included. The primary focus of this study was to assess the relationship of BNP to exercise LV parameters and pulmonary pressures. Because we used treadmill exercise there was a limited time window on cessation of exercise to obtain echo data and we were therefore unable to assess other variables of interest including exercise RV function and change in MR severity with exercise. Although the relationships between BNP and both pulmonary pressures and exercise capacity are statistically robust, the predictive value of BNP for individual patients requires further study in a larger cohort. In conclusion, in this study, many patients with moderate-to-severe or severe MR and a resting EF.60% had significant increases in LV end-systolic volumes, whereas BNP remained within the normal range. Elevated BNP predicted the presence of pulmonary hypertension and left atrial enlargement even when LV systolic function was normal at rest and on stress echocardiography. Acknowledgements We thank Margaret Oldfield who performed the exercise stress echocardiograms. Conflict of interest: none declared. Funding This study was supported by the Middlemore Cardiac Trust and a grant from the National Heart Foundation of New Zealand. Dr R.A.S. was supported by the Green Lane Research and Education Trust. G.A.W. is currently the National Heart Foundation of New Zealand Senior Fellow. References 1. Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, Detaint D, Capps M, Nkomo V, Scott C, Schaff HV, Tajik AJ. Quantitative determinants of the outcome of asymptomatic mitral regurgitation. N Engl J Med 2005;352: Ling LH, Enriquez-Sarano M, Seward JB, Tajik AJ, Schaff HV, Bailey KR, Frye RL. Clinical outcome of mitral regurgitation due to flail leaflet. 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