Natriuretic Peptides in Common Valvular Heart Disease

Journal of the American College of Cardiology © 2010 by the American College of Cardiology Foundation Published by Elsevier Inc.

Vol. 55, No. 19, 2010 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2010.02.021

FOCUS ISSUE: BIOMARKERS IN CARDIOVASCULAR DISEASE

Natriuretic Peptides in Common Valvular Heart Disease Christopher D. Steadman, MB, CHB,* Simon Ray, MD,† Leong L. Ng, MD,* Gerry P. McCann, MD* Leicester and Manchester, United Kingdom Valvular heart disease, particularly aortic stenosis and mitral regurgitation, accounts for a large proportion of cardiology practice, and their prevalence is predicted to increase. Management of the asymptomatic patient remains controversial. Biomarkers have been shown to have utility in the management of cardiovascular disease such as heart failure and acute coronary syndromes. In this state-of-the-art review, we examine the current evidence relating to natriuretic peptides as potential biomarkers in aortic stenosis and mitral regurgitation. The natriuretic peptides correlate with measures of disease severity and symptomatic status and also can be used to predict outcome. This review shows that natriuretic peptides have much promise as biomarkers in common valvular heart disease, but the impact of their measurement on clinical practice and outcomes needs to be further assessed in prospective studies before routine clinical use becomes a reality. (J Am Coll Cardiol 2010;55: 2034–48) © 2010 by the American College of Cardiology Foundation

Surveillance of valvular heart disease accounts for a significant proportion of outpatient attendances in cardiology. The predicted prevalence may double within 20 years due to an aging population (1). Patient management usually involves monitoring for clinical symptoms or functional deterioration usually assessed by imaging studies, of which transthoracic echocardiography is the mainstay. A biomarker is defined as a biological molecule that can be identified in a particular disease and additionally may be able to assess the severity and prognosis or monitor the response to treatment of that disease state. This is an attractive prospect in valvular heart disease. A robust biomarker could potentially eliminate the need for some costly imaging studies during routine surveillance and aid in management decisions, particularly with regard to the optimum timing for surgical or percutaneous intervention. Natriuretic peptides are endogenous cardiac hormones and have shown utility as biomarkers in heart failure, both for diagnosis (2) and to monitor and guide therapy (3,4), and, in ischemic heart disease, as a predictor of outcome (5–7). This review examines natriuretic peptides as potential biomarkers in the most commonly managed valvular heart diseases, aortic stenosis (AS) and mitral regurgitation (MR).

From the *Department of Cardiovascular Sciences, University Hospitals of Leicester, Leicester, United Kingdom; and the †Manchester Academic Health Sciences Centre, Manchester, United Kingdom. Dr. Steadman is supported by the British Heart Foundation Project Grant 07/068/2334. Prof. Ng has received grants in aid from BRAHMS AG for biomarker research. Prof. Ng and Dr. McCann are supported by the Leicester National Institute for Health Research Cardiovascular Biomedical Research Unit. Manuscript received September 14, 2009; revised manuscript received January 19, 2010, accepted February 9, 2010.

Natriuretic Peptides Three types of natriuretic peptides have been identified: B-type natriuretic peptide (BNP), atrial natriuretic peptide (ANP), and C-type natriuretic peptide (CNP). Their physiology has been reviewed in detail elsewhere (8 –11). Briefly, CNP is structurally distinct from ANP and BNP. CNP is expressed to a much greater extent in the central nervous system and vascular tissues than in the heart (12), acting as a potent vasorelaxant and inhibitor of vascular smooth muscle proliferation and endothelial cell migration (11). BNP and ANP exist as pro-hormones that are cleaved into inactive N-terminal fragments (N-terminal proBNP [NTproBNP], N-terminal proANP [NT-proANP]) and biologically active hormones (BNP, ANP) before release into the circulation. The N-terminal fragments are more stable in vivo and are often used as surrogate markers for the biologically active hormone (8). The predominant cardiac source of ANP is the atria and the ventricles are the main cardiac source of BNP, although both can be synthesized in either chamber. ANP is stored in granules, whereas BNP is released in bursts regulated by gene transcription (13–15) The stimulus for ANP and BNP release is primarily myocyte stretch, but endothelin-I, nitric oxide, and angiotensin II may all have a role. ANP concentrations are more closely related to left atrial (LA) pressure and BNP to left ventricular (LV) pressure (16,17). Three natriuretic peptide receptors (NPRs) have been identified; NPR-A and NPR-B, which mediate their biological action, and NPR-C, which is a clearance receptor (18). Natriuretic peptides cause natriuresis, diuresis, and vasorelaxation, reducing blood pressure and preload (11). BNP has direct lusitropic (relaxing) properties in the myocardium (19). ANP and BNP have been shown in vitro to have the effect

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of inhibiting the synthesis of collagen by cardiac fibroblasts (20,21). Additionally, natriuretic peptides, their processing enzymes, and their receptors are expressed in the cardiac valves themselves (22). The close links between natriuretic peptides and cardiovascular structure, function, and hemodynamics are clear; however, current understanding of the molecular biology is far from complete (8). Methods A systematic search of peer-reviewed literature until September 2009 using PubMed was performed. The search terms “biomarkers,” “natriuretic peptide,” “BNP,” “NTproBNP,” “ANP,” and “CNP” were combined and then coupled with each of “aortic stenosis” and “mitral regurgitation.” Predefined limits were: 1) the main body of text of the article needed to be in English; 2) human adult subjects; 3) prospective, retrospective, and randomized studies were included; 4) reviews and case reports or studies with ⬍10 patients were excluded; and 5) only studies in which a group containing at least mild isolated AS or isolated MR, which had been well characterized and specifically analyzed (primarily or as a substudy), were included. Studies including patients with mixed valve disease or severe valvular lesions in addition to the valve lesion of interest were excluded. Studies were included irrespective of the presence of other comorbidities including coronary artery disease (CAD) and symptoms. Results In AS, 41 studies of natriuretic peptides were appropriate for review. Details of the important studies are presented in Tables 1 through 3 for baseline correlations, unoperated, and post-operative outcome, respectively. In MR, 9 studies of natriuretic peptides were appropriate for review. Details of baseline correlations are given in Table 4, and predictors of outcome are shown in Table 5. For both valvular diseases, the studies reviewed have significant clinical and methodological diversity, particularly with regard to measures of outcome. This heterogeneity does not lend itself to a meaningful meta-analysis, and therefore we present a systematic review using a more qualitative approach to combining results. Where the distribution of natriuretic peptide measurements is significantly skewed, they have been logarithmically transformed in the original studies before analysis. Natriuretic Peptides in AS Clinical decision making in AS. AS is the most common valve lesion requiring surgery in the developed world (23). The survival of patients with symptomatic AS is dismal, and the prognosis is greatly improved by aortic valve replacement (AVR), which is universally recommended (24). In contrast, management of patients with moderate to severe

Steadman et al. Natriuretic Peptides in Valvular Heart Disease

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asymptomatic AS is a controversial Abbreviations and Acronyms area and has been the subject of hot debate among cardiologists AF ⴝ atrial fibrillation and cardiac surgeons for ⬎40 years ANP ⴝ atrial natriuretic (25,26). Traditionally, the risk of peptide sudden cardiac death in asympAS ⴝ aortic stenosis tomatic patients has been regarded AUC ⴝ area under the as low, typically ⬍1% (27,28). curve However, rates of almost 5% per AVA ⴝ aortic valve area year have been reported where a AVR ⴝ aortic valve rigid policy of not operating on replacement asymptomatic patients was adBNP ⴝ B-type natriuretic hered to (29). Additionally, with a peptide watchful waiting approach to CAD ⴝ coronary artery guide surgery, concerns include disease patients not promptly seeking help CNP ⴝ C-type natriuretic when they become symptomatic peptide and the risk of mortality while LA ⴝ left atrial awaiting surgery when symptomLV ⴝ left ventricular atic (30). Over the past decade, LVEF ⴝ left ventricular several important prospective ejection fraction studies have been published on the LVESVI ⴝ left ventricular natural history of asymptomatic end-systolic volume index AS incorporating echocardioLVMI ⴝ left ventricular graphic measures of severity, funcmass index tional testing, the subsequent deMACE ⴝ major adverse velopment of symptoms, need for cardiac event(s) AVR, and death (27–29,31–34). MR ⴝ mitral regurgitation Even in research study populaNPR ⴝ natriuretic peptide tions, significant numbers underreceptor went AVR while asymptomatic at NT-proANP ⴝ N-terminal the discretion of the referring phypro-atrial natriuretic peptide sician. These patients tended to be NT-proBNP ⴝ N-terminal older and have more severe disease pro–B-type natriuretic (27,28). This variation in clinical peptide practice, along with differences NYHA ⴝ New York Heart between the American College Association of Cardiology/American Heart OR ⴝ odds ratio Association and the European Society of Cardiology guidelines (35,36), reflect the uncertainty regarding the best way to manage these patients (37). Potential role of natriuretic peptides in valve disease. It is clear from the currently available evidence that, in the absence of a randomized, controlled trial of surgery, better risk stratification of asymptomatic patients with moderate to severe AS and MR is still required, and biomarkers have a role to play. A useful biomarker would reflect disease severity, increase with progression of disease, reflect subclinical myocardial dysfunction, discriminate between patients in whom symptoms do and do not develop in the short to medium term, and be easily and reliably measured. The ideal biomarker would also allow the identification of a high-risk individual with severe disease before the development of symptoms who could undergo valve surgery without increased perioperative mortality.

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Parameter

First Author (Ref. #)/Year

n

Prospective

BNP

Aortic valve area

Pedrazzini et al. (52)/2008

144

Yes

Yes: lower with increasing tertile BNP, p ⫽ 0.016 (TTE)

Peak aortic valve velocity

Mean aortic valve gradient

Cemri et al. (40)/2008

37

Yes

Antonini-Canterin et al. (46)/2008

64

Yes

Weber et al. (45)/2006

NT-proBNP

ANP

NT-proANP

Statistical Methods Kruskal-Wallis

Yes: r ⫽ ⫺0.46, p ⫽ 0.008 (TTEi)

Spearman correlation

Yes: r ⫽ 0.4, p ⫽ 0.001 (TTE)

Univariate regression analysis Yes: r ⫽ 0.380, p ⬍ 0.001 (TTE)

159

Yes

Neverdal et al. (44)/2006

22

Yes

No: r ⫽ 0.18, p ⫽ 0.45 (TTE)

Spearman correlation Linear regression

Vanderheyden et al. (47)/ 2004

40

Yes

Yes: r ⫽ ⫺0.449, p ⫽ 0.006 (TTE)

Pearson correlation

Lim et al. (58)/2004

70

Yes

Yes: r ⫽ ⫺0.49, p ⬍ 0.0001 (TTE)

Gerber et al. (48)/2003

74

Yes

Yes: r ⫽ ⫺0.55, p ⬍ 0.05 (TTE)

Qi et al. (73)/2002

51

Yes

Qi et al. (17)/2001

67

Yes

Spearman correlation Yes: r ⫽ ⫺0.57, p ⬍ 0.05 (TTE)

Yes: r ⫽ ⫺0.55, p ⬍ 0.05 (TTE)

Yes: r ⫽ ⫺0.46, p ⫽ 0.037 (TTEi) Yes: r ⫽ ⫺0.56, p ⬍ 0.001 (TTEi)

Yes: r ⫽ ⫺0.52, p ⬍ 0.001 (TTEi)

Yes: r ⫽ ⫺0.33, p ⬍ 0.05 (TTEi)

Pearson correlation Yes: r ⫽ ⫺0.49, p ⫽ 0.023 (TTEi)

Pearson correlation

Yes: r ⫽ ⫺0.47, p ⬍ 0.001 (TTEi)

Pearson correlation and univariate linear regression

Neverdal et al. (44)/2006

22

Yes

No: r ⫽ 0.14, p ⫽ 0.54 (TTE)

Lim et al. (58)/2004

70

Yes

Yes: r ⫽ 0.33, p ⬍ 0.05 (TTE)

Weber et al. (61)/2004

146

Yes

Gerber et al. (48)/2003

74

Yes

Talwar et al. (39)/2001

15

Yes

Prasad et al. (38)/1997

30

Yes

Yes: r ⫽ 0.43, p ⬍ 0.02 (TTE)

Pedrazzini et al. (52)/2008

144

Yes

No: 3 tertiles BNP, p ⫽ 0.137 (TTE)

Kruskal-Wallis

Orlowska-Baranowska et al. (43)/2008

147

Yes

Yes: r ⫽ 0.25, p ⫽ 0.002 (TTE)

Linear regression

Linear regression Spearman correlation Weak: r ⫽ 0.04, p ⬍ 0.01 (TTE)

Yes: r ⫽ 0.33, p ⬍ 0.05 (TTE)

Steadman et al. Natriuretic Peptides in Valvular Heart Disease

Baseline in AS Table 1 Associations Baseline Associations in AS

Yes: r ⫽ 0.35, p ⬍ 0.05 (TTE)

Pearson correlation Yes: r ⫽ 0.38, p ⬍ 0.05 (TTE)

Pearson correlation

Yes: r ⫽ 0.53, p ⬍ 0.05

Pearson correlation NS: r ⫽ 0.31, p ⬍ 0.1 (TTE)

Univariate regression analysis

Yes: r ⫽ 0.38, p ⫽ 0.026 (TTE)

Cemri et al. (40)/2008

37

Yes

Antonini-Canterin et al. (46)/2008

64

Yes

Spearman correlation

Weber et al. (45)/2006

159

Yes

Yes: r ⫽ 0.351, p ⬍ 0.001 (TTE)

Spearman correlation

Weber et al. (72)/2005

109

Yes

Yes: severe ⬎ moderate ⬎ mild, p ⬍ 0.01 (TTE)

Kruskal-Wallis test

Weber et al. (61)/2004

Yes: r ⫽ 0.39, p ⬍ 0.01 (TTE)

Pearson correlation

No: r ⫽ 0.08, p ⫽ 0.52 (TTE)

Univariate regression analysis

146

Yes

Lim et al. (58)/2004

70

Yes

Yes: r ⫽ 0.34, p ⫽ 0.004 (TTE)

Gerber et al. (48)/2003

74

Yes

Yes: r ⫽ 0.36, p ⬍ 0.05 (TTE)

Yes: r ⫽ 0.37, p ⬍ 0.05 (TTE)

Yes: r ⫽ 0.38, p ⬍ 0.05 (TTE)

Qi et al. (17)/2001

67

Yes

Yes: r ⫽ 0.32, p ⬍ 0.01 (TTE)

Yes: r ⫽ 0.25, p ⬍ 0.05 (TTE)

No : r ⫽ 0.15 (TTE)

Prasad et al. (38)/1997

30

Yes

Yes: r ⫽ 0.57, p ⬍ 0.001 (TTE)

Spearman correlation

Pearson correlation and univariate linear regression Univariate regression analysis Continued on next page

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Yes: r ⫽ 0.38, p ⬍ 0.04 (TTE)

Pearson correlation No: r ⫽ 0.09 (TTE)

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No: r ⫽ 0.15, p ⫽ 0.05 (TTEi)

No: values not quoted (TTEi) No: values not quoted (TTEi)

Yes: r ⫽ 0.42, p ⬍ 0.03 (TTEi) 30

13

Prasad et al. (38)/1997

Ikeda et al. (41)/1997

Yes

67 Qi et al. (17)/2001

Yes

74 Gerber et al. (48)/2003

ANP ⫽ atrial natriuretic peptide; AS ⫽ aortic stenosis; BNP ⫽ B-type natriuretic peptide; LV ⫽ left ventricular; NQ ⫽ not quoted; NS ⫽ not significant; NT-proANP ⫽ N-terminal pro-atrial natriuretic peptide; NT-proBNP ⫽ N-terminal pro–B-type natriuretic peptide; TTE ⫽ transthoracic echocardiography; TTEi ⫽ transthoracic echocardiography measures indexed to body surface area.

Univariate regression analysis

Linear regression by least square method

Pearson correlation and univariate linear regression

Pearson correlation

Yes: r ⫽ 0.57, p ⬍ 0.001 (TTEi) Yes: r ⫽ 0.6, p ⬍ 0.001 (TTEi)

Yes: r ⫽ 0.46, p ⬍ 0.05 (TTEi) Yes: r ⫽ 0.59, p ⬍ 0.05 (TTEi) Yes: r ⫽ 0.62, p ⬍ 0.05 (TTEi)

Yes: r ⫽ NQ, p ⫽ 0.005 (TTEi) Yes 40 Vanderheyden et al. (47)/ 2004

Yes 109 Weber et al. (72)/2005

Yes

Yes: severe ⬎ moderate ⬎ mild, p ⬍ 0.01 (TTE) Yes: r ⫽ 0.45, p ⬍ 0.05 (TTEi) Yes 22 Neverdal et al. (44)/2006

Yes Weber et al. (45)/2006

Yes 45

159

Poulsen et al. (49)/2007

Yes

Yes: r ⫽ 0.53, p ⬍ 0.001 Yes: r ⫽ 0.49, p ⬍ 0.001 (TTEi) 64 Antonini-Canterin et al. (46)/2008

Yes

Yes: r ⫽ 0.55, p ⬍ 0.0001 (TTEi) 147 Orlowska-Baranowska et al. (43) 2008/

Yes

Yes: r ⫽ 0.434, p ⬍ 0.001 (TTEi)

Yes: r ⫽ 0.63, p ⬍ 0.001 (TTEi)

ANP NT-proBNP

Yes: r ⫽ 0.49, p ⫽ 0.003 (TTEi)

BNP Yes

Prospective n

37 Cemri et al. (40)/2008

First Author (Ref. #)/Year Parameter

LV mass

Continued Continued Table 1

Yes: r ⫽ 0.44, p ⬍ 0.001 (TTEi)

Yes: r ⫽ 0.52, p ⬍ 0.001 (TTEi)

Pearson correlation

Kruskal-Wallis

Linear regression

Spearman correlation

Spearman correlation

Univariate regression analysis

Linear regression

NT-proANP

Statistical Methods

Spearman correlation

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Baseline correlations. COMPARISON WITH CONTROLS. The presence of AS almost universally has been associated with increased levels of natriuretic peptides when compared with controls (17,38,39), even in asymptomatic mild AS (40,41). This is supported by increased BNP messenger RNA in myocardial samples (42). The N-terminal forms correlate closely with the parent molecules as expected (17). BNP and ANP levels could also distinguish between AS and CAD patients undergoing cardiac surgery, with BNP being the better discriminator (41). BNP (43,44) and NT-proBNP (45) at baseline weakly but significantly correlated with age. SEVERITY OF VALVE DISEASE. Natriuretic peptide levels correlate modestly with measures of AS severity on TTE. There is a modest inverse correlation with aortic valve area (AVA) and a slightly weaker positive correlation with peak and mean pressure gradient in the majority of studies (Table 1, Fig. 1). CARDIAC STRUCTURE AND FUNCTION. There is a significant association between LV mass index (LVMI) and BNP (17,38,43,44,46 – 48) and NT-proBNP (17,40,45,48,49). Results for ANP are variable, with some studies showing a correlation (17,48) and others not (39,41). NT-proBNP is significantly increased relative to controls already in the lowest LVMI quartile (78 to 139 g/m2); in comparison, NT-proANP was increased over controls only from the second quartile (141 to 180 g/m2) and above (17). The receiver-operator curve analyses in this study showed that BNP and NT-proBNP were most accurate in the detection of increased LVMI, whereas NT-proANP performed best in the detection of increased LA pressure, measured invasively (17). Thus, an elevation of BNP/NTproBNP levels in the circulation, with little or no increase in ANP/NT-proANP, may indicate a relatively early stage of AS, when LV hypertrophy compensates for the increase in afterload without preload increase, whereas the combined elevation of both natriuretic peptides may indicate a more advanced stage. Right ventricular systolic pressure also correlates with BNP, NT-proBNP, and ANP (48). Of note, eccentric LV hypertrophy was associated with a significantly higher serum BNP level than concentric-type hypertrophy (44). Elsewhere, eccentric hypertrophy has been associated with the most impaired systolic function and the worst clinical picture, and it is postulated that this represents the end stage of pressure overload (50). Natriuretic peptides correlate with markers of systolic function; BNP, ANP, and their N-terminal fragments correlate inversely with LVEF (43,45,46,48,51,52), and fractional shortening (17,41). NT-proBNP also correlates with tissue Doppler imaging systolic velocity (53). Natriuretic peptides also correlate with echocardiographic measures of diastolic function (46,48), although in the Gerber et al. (48) study, the majority additionally had systolic dysfunction. The early diastolic transmitral velocity (E) corrected for the influence of relaxation, the early diastolic velocity of

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Unoperated With AS Table 2 Patients Unoperated Patients With AS

Symptoms in unoperated patients

First Author (Ref. #)/Year

n

Gerber et al. (66)/2005

29

Biomarkers

Subjects

Other Valve Disease

Design

End Points

Conclusions

NT-proBNP

Asymptomatic, at least mild AS (peak velocity ⱖ2.5 m/s)

Excluded ⬎mild MR or AR

Excluded MI ⬍6 months, RWMA, previous cardiac surgery

CAD

Not reported

Comorbidities

Prospective cohort mean follow-up 18 months

Symptoms developed in 8 patients

NT-proBNP predicts development of symptoms; OR ⫽ 9.6 for development of symptoms if NT-proBNP ⬎50 pmol/l by logistic regression

43 initially asymptomatic

BNP, NTproBNP, NT-proANP

Severe AS (peak velocity ⬎4 m/s or AVA ⬍1 cm2)

Excluded ⬎mild MVD or AR

9%; not all had angiography

67% HT

Prospective cohort follow-up 377 ⫾ 150 days

14 patients developed symptoms

NT-proBNP best predicts symptom-free survival, also BNP and NT-proANP; Kaplan-Meier analysis

Survival without AVR

Nessmith et al. (57)/ 2005

103 total; 24 asymptomatic, 79 symptomatic but unoperated

BNP

AVA ⬍1.2 cm2

Not reported

Excluded MI ⬍6 mo, RWMA, previous cardiac surgery

83% HT, 27% DM

Prospective cohort median followup 227 days

44 deaths

1-year mortality RR increased by 2.9 per tertile of BNP (2.4 after adjustment for symptoms) by Cox proportional hazards method

MACE: death/symptom or positive exercise test results–driven AVR

Monin et al. (69)/2009

107

BNP

Asymptomatic AS (mean peak velocity 4.1 m/s)

Excluded more than mild other valve lesions

22%, not all had angiography

56% HT, 12% DM, all SR

Prospective cohort follow-up 24 mo

3 deaths before AVR, 18 patients AVR for positive ETT, 37 patients AVR for symptoms, 4 patients AVR physician discretion

BNP independent predictor of outcome by multiple logistic regression model

MACE: CVS death/hospitalization for HF/AVR

Antonini-Canterin et al. (46)/2008

64

BNP

Mean AVA 0.9 cm2 (range 0.3–1.7 cm2); no more than mild AR

Did not exclude other valve disease; severe MR in 3

28%, not all had angiography

55% HT, 17% DM, 9% AF

Prospective cohort median followup 8 mo

Total MACE 18 (28%), 2 AVR, 7 CVS deaths, 9 admission with HF

BNP levels at baseline predicted eventfree survival by Kaplan-Meier analysis

MACE: cardiac death/ symptom-driven AVR

Poh et al. (55)/2008

53

NT-proBNP

Variable degrees of AS

Excluded ⬎mild additional valve disease

Known CAD 43%, not all had angiography

60% HT, 32% DM, all SR

Prospective cohort median followup 35 mo

Total MACE 18

NT-proBNP predicted end point on univariate analysis

MACE: CVS death/symptoms/ AVR

Dichtl et al. (68)/2008

47

NT-proBNP, CRP

Asymptomatic patients, at least mild calcific AS (mean gradient ⬎15 mm Hg, peak velocity ⬎2 m/s)

Excluded MS, severe MR, severe AR

No history of CAD

50% HT, 13% DM, 11% AF

Randomized trial of atorvastatin

Total MACE 24 (51%)

NT-proBNP predicted MACE by multiple regression analysis

MACE: CVS death/hospitalization for HF

Weber et al. (45)/2006

NT-proBNP

Mild (MPG ⬍30 mm Hg), moderate (30–50 mm Hg), or severe (⬎50 mm Hg) AS, excluded AR ⬎II

Excluded MR ⬎II

33% of conservatively managed, not all had angiography

11% AF

Prospective cohort mean follow-up 892 days

Total MACE 9 (16%), 5 deaths (9%), 4 admissions with HF (7%)

NT-proBNP independent predictor of end point on multivariate Cox regression

57 conservatively managed

Continued on next page

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Bergler-Klein et al. (51)/ 2004

Steadman et al. Natriuretic Peptides in Valvular Heart Disease

Outcome Measure

Steadman et al. Natriuretic Peptides in Valvular Heart Disease AF ⫽ atrial fibrillation; AR ⫽ aortic regurgitation; AVA ⫽ aortic valve area; AVR ⫽ aortic valve replacement; CAD ⫽ coronary artery disease; CRP ⫽ C-reactive protein; CVS ⫽ cardiovascular system; DM ⫽ diabetes mellitus; HF ⫽ heart failure; ETT ⫽ exercise treadmill test; HT ⫽ hypertension; MACE ⫽ major adverse cardiac event; MPG ⫽ mean pressure gradient; MVD ⫽ mitral valve disease; MI ⫽ myocardial infarction; MR ⫽ mitral regurgitation; MS ⫽ mitral stenosis; OR ⫽ odds ratio; ROC ⫽ receiver-operator curve; RR ⫽ relative risk; RWMA ⫽ regional wall motion abnormality; SR ⫽ sinus rhythm; other abbreviations as in Table 1.

NT-proBNP predicted referral for AVR area under ROC curve 0.73 105 patients, AVR recommended Weber et al. (61)/2004 MACE: referral for AVR

146

NT-proBNP

Mild, moderate, and severe AS (mean pressure gradient ⬍30 mm Hg, 30–50 mm Hg, and ⬎50 mm Hg, respectively)

Not reported

25%

74% HT, 21% DM, 13% AF

Prospective cohort

Conclusions End Points

11 patients (32%) composite end point, 10 patients symptoms (6 had AVR, 3 denied surgery, 1 declined surgery), 1 CVS death (sudden)

Design

Prospective cohort follow-up 18–24 months Not reported

Comorbidities CAD

Not reported Excluded ⬎2⫹ AR BNP Feuchtner et al. (67)/ 2006 MACE: CVS death/symptoms/ AVR

34

Asymptomatic AS

Other Valve Disease Subjects Biomarkers n First Author (Ref. #)/ Year Outcome Measure

Continued Continued Table 2

BNP risk factor for adverse clinical outcome

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the mitral annulus (Em), the E/Em ratio, is a marker of diastolic dysfunction (54). This correlates significantly with NT-proBNP in severe symptomatic AS (53) and better with NT-proBNP than AVA in mild to moderate AS (55) and also is the strongest correlate in asymptomatic patients (r ⫽ 0.53, p ⫽ 0.001) (40). Wall stress is an important stimulus to natriuretic peptide production. LV end-systolic midwall wall stress, calculated by the method of Grossman et al. (56), highly correlated with BNP (r ⫽ 0.96, p ⬍ 0.0001) (41), ANP (41,48), and NT-proBNP (48), as did LV end-diastolic wall stress (47). NT-proBNP is significantly related to mean LV strain (r ⫽ 0.61, p ⬍ 0.001) (49). BNP (46,48,51,57– 60), NTproBNP (45,48,51,60,61), and ANP (38,48) are higher in symptomatic than asymptomatic patients with AS. A multivariate logistic regression model including BNP levels and AVA revealed that only BNP values were predictive of symptomatic AS (odds ratio [OR]: 3.4; 95% confidence interval [CI]: 1.6 to 7.3; p ⬍ 0.01) (58). NT-proBNP remained higher in symptomatic patients after adjustment for age, sex, creatinine level, AVA, and LVEF, a mean 1.74 times higher (95% CI: 1.12 to 2.69, p ⫽ 0.014). This held true even when the AVA was ⬍1 cm2 (48), although another study suggests that only BNP, and not NTproBNP, was useful for those with severe AS (60). In symptomatic patients, natriuretic peptides increase with New York Heart Association (NYHA) functional class, irrespective of the severity of the AS (38,45,46,48,61). Differentiating asymptomatic from minimally symptomatic (i.e., NYHA functional classes I and II) is more difficult, with one study showing a significant difference (58) and another not (51). BNP can identify with good diagnostic accuracy patients in NYHA functional class III to IV; the area under the receiver-operator curve was 0.78 (95% CI: 0.66 to 0.87; best cutoff was 254.64 pg/ml) (46). In contrast to NYHA functional class, angina and syncope do not seem to be related to natriuretic peptides (46,48,58), highlighting the possible different pathophysiologies of these symptoms compared with dyspnea. SYMPTOMATIC STATUS.

In asymptomatic or minimally symptomatic AS, higher plasma levels of BNP are a better predictor of an abnormal blood pressure response to exercise than echocardiographic measures of severity (62). In moderate to severe asymptomatic AS, BNP was associated with lower peak velocity of the mitral valve annulus on exercise and reduced exercise capacity compared with controls (63). Both of these studies only included patients with LVEF ⬎50%. Taken together, these reports suggest that elevated BNP reflects a reduced myocardial functional reserve and is therefore indicative of LV dysfunction with exercise despite normal measures of systolic function at rest in asymptomatic AS.

RESPONSE TO EXERCISE.

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Outcome Measure

First Author (Ref. #)/Year

No. of Patients With AS 79 underwent AVR (incidence of comorbidities refers to whole group of 130 patients)

Other Valve Disease

Biomarkers

Subjects

Comorbidities

Design

Results

Conclusions

BNP, NTproBNP, ANP, NTproANP

Severe AS (peak velocity ⬎4 m/s or AVA ⬍1 cm2)

Excluded ⬎mild MVD or AR

25%

CAD

62% HT

Prospective cohort

8 deaths (6 perioperative, 2 late), 71 survivors (63 normal LVEF, 65 NYHA I–II)

NT-proBNP only independent predictor of survival and post-operative symptoms; pre-operative LVEF and NT-proBNP independently predicts post-operative LVEF by multivariate analysis

BNP

Severe AS (peak velocity ⬎4 m/s, AVA ⬍1 cm2)

Not reported

60 (42%) patients had concomitant CABG

92% SR

Prospective cohort: patients with symptomatic AS referred for AVR, comparison of logistic Euroscore to BNP; baseline, 1, and 3 months postAVR assessment with clinical follow-up after 2 yrs

9 (6%) perioperative deaths, overall mortality: 16 (11%)

BNP predicts post-operative survival by logistic and Cox regression

Post-operative: survival/ symptoms/LVEF

Bergler-Klein et al. (51)/2004

Post-operative: mortality

Pedrazzini et al. (52)/ 2008

Post-operative: AF

Yilmaz et al. (75)/2006

22

NT-proANP

Symptomatic AS

Excluded ⬎mild other valve disease

6 (27%) had concomitant CABG

All SR

Prospective cohort

9 patients had AF after ⬎2 months

NT-proANP at 2 mo postoperatively independently predicts AF

Post-operative: symptoms of left- or right-sided HF/ hypotension

Vanderheyden et al. (47)/2004

40

BNP

Symptomatic, at least mild AS (peak velocity ⱖ2.5 m/s)

Not reported

Not reported

All SR

Prospective cohort: patients referred for LRHC for symptomatic AS, followed up until hospital discharge postAVR

17 patients had clinical deterioration

BNP at baseline significantly higher in patients with clinical deterioration by t test

Post-operative: CVS death/hospitalization for HF

Weber et al. (45)/2006

NT-proBNP

Mild (MPG ⬍30 mm Hg), moderate (30–50 mm Hg), or severe (⬎50 mm Hg) AS

Excluded MR ⬎II

29% of AVR

15% AF

Prospective cohort: mean follow-up 901 days

Total MACE: 12 patients (12%), 8 deaths (8%), 4 admissions with HF (4%)

NT-proBNP had no predictive value for those undergoing AVR

144

102 AVR

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CABG ⫽ coronary artery bypass graft; LRHC ⫽ left-right heart catheterization; LVEF ⫽ left ventricular ejection fraction; NYHA ⫽ New York Heart Association; other abbreviations as in Tables 1 and 2.

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Post-Operative Outcome in AS Table 3 Post-Operative Outcome in AS

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Baseline in MR Table 4 Associations Baseline Associations in MR Parameter

First Author (Ref. #)/Year

n

Etiology

BNP

NT-proBNP

ANP

Statistical Method

MR severity Severity

Potocki et al. (93)/2009

144

Organic

r ⫽ 0.18, p ⫽ 0.03

RVolume

Kerr et al. (92)/2008

33

Organic

r ⫽ ⫺0.2, p ⫽ 0.27

Spearman

Severity

Dini et al. (87)/2007

207

Functional

p ⬍ 0.0001

Kruskal-Wallis

RFraction

Yusoff et al. (90)/2006

38

Organic

RFraction

Detaint et al. (86)/2006

78

Both

No association

EROA

Detaint et al. (91)/2005

124

Organic

r ⫽ 0.17, p ⫽ 0.06

VC width

Sutton et al. (85)/2003

49

Organic

r ⫽ 0.60, p ⬍ 0.0001

NYHA ⱖII

Potocki et al. (93)/2009

144

Organic

p ⬍ 0.001

NHYA II

Kerr et al. (92)/2008

33

Organic

p ⫽ 0.02

NYHA ⱖII

Shimamoto et al. (94)/2007

62

Organic

NYHA ⱖII

Yusoff et al. (90)/2006

38

Organic

NYHA ⱖII

Detaint et al. (86)/2006

78

Both

p ⫽ 0.003

NYHA ⱖII

Detaint et al. (91)/2005

124

Organic

r ⫽ 0.37, p ⬍ 0.0001

NYHA ⱖII

Sutton et al. (85)/2003

49

Organic

p ⬍ 0.001

Potocki et al. (93)/2009

144

Organic

r ⫽ ⫺0.25, p ⫽ 0.01

Kerr et al. (92)/2008

33

Organic

r ⫽ 0.23, p ⫽ 0.93

Detaint et al. (86)/2006

78

Both

r2 ⱖ 0.4, p ⬍ 0.001

Detaint et al. (91)/2005

124

Organic

r ⫽ ⫺0.22, p ⫽ 0.01

Sutton et al. (85)/2003

49

Organic

r ⫽ 0.003, p ⫽ 0.98

LVEDD

Potocki et al. (93)/2009

144

Organic

r ⫽ ⫺0.12, p ⫽ 0.15

Pearson

LVEDVI

Kerr et al. (92)/2008

33

Organic

r ⫽ ⫺0.02, p ⫽ 0.28

Spearman

LVEDVI

Yusoff et al. (90)/2006

38

Organic

r ⫽ 0.46, p ⫽ 0.003

LVEDVI

Detaint et al. (86)/2006

78

Both

p ⬍ 0.01

LVEDVI

Detaint et al. (91)/2005

124

Organic

r ⫽ 0.16, p ⫽ 0.08

LVEDD

Sutton et al. (85)/2003

49

Organic

r ⫽ 0.19, p ⫽ 0.20

LVESD

Potocki et al. (93)/2009

144

Organic

r ⫽ 0.33, p ⫽ 0.001

Pearson

LVESVI

Kerr et al. (92)/2008

33

Organic

r ⫽ ⫺0.19, p ⫽ 0.31

Spearman

LVESVI

Yusoff et al. (90)/2006

38

Organic

r ⫽ 0.52, p ⫽ 0.001

LVESVI

Detaint et al. (86)/2006

78

Both

r2 ⱖ 0.4, p ⬍ 0.001

LVESVI

Detaint et al. (91)/2005

124

Organic

r ⫽ 0.26, p ⫽ 0.002

LVESD

Sutton et al. (85)/2003

49

Organic

r ⫽ 0.20, p ⫽ 0.16

LAD

Potocki et al. (93)/2009

144

Organic

r ⫽ 0.21, p ⫽ 0.01

LAAI

Kerr et al. (92)/2008

33

Organic

r ⫽ 0.42, p ⫽ 0.02

LAV

Detaint et al. (86)/2006

78

Both

p ⬍ 0.01

LAV

Detaint et al. (91)/2005

124

Organic

r ⫽ 0.50, p ⬍ 0.0001

LAD

Sutton et al. (85)/2003

49

Organic

r ⫽ 0.65, p ⬍ 0.0001

Potocki et al. (93)/2009

144

Organic

r ⫽ 0.35, p ⫽ 0.001

Pearson

Kerr et al. (92)/2008

33

Organic

r ⫽ 0.53, p ⫽ 0.002

Spearman

Detaint et al. (86)/2006

78

Both

p ⬍ 0.01

Detaint et al. (91)/2005

124

Organic

r ⫽ 0.49, p ⬍ 0.0001

Right ventricular systolic pressure

Sutton et al. (85)/2003

49

Organic

r ⫽ 0.42, p ⬍ 0.03

Systolic wall stress

Yusoff et al. (90)/2006

38

Organic

Detaint et al. (86)/2006

78

Both

r2 ⱖ 0.4, p ⬍ 0.0001

Sutton et al. (85)/2003

49

Organic

r ⫽ 0.02, p ⫽ 0.88

Pearson

r ⫽ 0.46, p ⫽ 0.003

Pearson Univariate regression Linear regression

r ⫽ 0.54, p ⬍ 0.0001

r ⫽ 0.37, p ⫽ 0.009

Pearson

Symptoms

LVEF

p ⫽ 0.036

ANOVA Linear regression p ⫽ 0.031

Not specified

Linear regression Linear regression Linear regression Linear regression

p ⬍ 0.001

p ⬍ 0.001

Linear regression Pearson Spearman Univariate regression Linear regression

r ⫽ 0.01, p ⫽ 0.92

r ⫽ 0.20, p ⫽ 0.17

Pearson

LV diastolic size

Pearson Univariate regression Linear regression

r ⫽ 0.17, p ⫽ 0.26

r ⫽ 0.13, p ⫽ 0.37

Pearson

LV systolic size

Pearson Univariate regression Linear regression

r ⫽ 0.16, p ⫽ 0.27

r ⫽ 0.16, p ⫽ 0.26

Pearson

LA size

Pulmonary artery systolic pressure

Pearson Spearman Univariate regression Linear regression

r ⫽ 0.66, p ⬍ 0.0001

r ⫽ 0.49, p ⫽ 0.0004

Pearson

Univariate regression Linear regression r ⫽ 0.33, p ⬍ 0.09

r ⫽ 0.47, p ⫽ 0.01

r ⫽ 0.34, p ⫽ 0.048

Pearson Pearson Univariate regression

r ⫽ 0.11, p ⫽ 0.45

r ⫽ ⫺0.01, p ⫽ 0.95

Pearson

ANOVA ⫽ analysis of variance; EROA ⫽ effective regurgitant orifice area; LA ⫽ left atrial; LAAI ⫽ left atrial area index; LAD ⫽ left atrial diameter; LAV ⫽ left atrial volume; LV ⫽ left ventricular; LVEDD ⫽ left ventricular end-diastolic diameter; LVEDVI ⫽ left ventricular end-diastolic volume index; LVESD ⫽ left ventricular end-systolic diameter; LVESVI ⫽ left ventricular end-systolic volume index; RFraction ⫽ regurgitant fraction; RVolume ⫽ regurgitant volume; VC ⫽ vena contracta; other abbreviations as in Tables 1 through 3.

CAD. The prevalence of CAD in AS is significant and has been reported as ⬎50% (64). Unless coronary angiography has been performed in all patients included in a study, the exact prevalence is unclear; estimations are usually made on the basis of clinical history. This is reflective of the clinical

setting during the surveillance of asymptomatic patients with AS when the presence or absence of coexisting CAD is unknown. In AS patients with associated CAD, there are reports of increased BNP (52) and NT-proBNP (65) or no effect on NT-proBNP (61). Where reported, we have

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Outcome Table 5 in MR Outcome in MR

Outcome Measure

First Author (Ref. #)/Year

n

Etiology

Baseline Status

End Points

Conclusions

Death/CCF/LV dysfunction

Pizarro et al. (89)/ 2009

269

Organic

Asymptomatic

Prospective cohorts, derivation, and validation; mean followup: 36 months derivation, 31 months validation

Design

BNP

Biomarker

21% in derivation, 20.6% in validation

BNP ⬎105 pg/ml predicts death/ CCF/LV dysfunction; HR: 4.7 in validation cohort

Death/CCF

Dini et al. (87)/ 2008

207

Functional

NYHA II–IV

Prospective cohort, median follow-up 29 months

NT-proBNP

67 died, 76 CCF

NT-proBNP ⬎1,941 pg/ml predicts CCF or death; HR: 3.19

Death/CCF

Detaint et al. (91)/2005

124

Organic

NYHA I–IV

Prospective cohort, mean follow-up 4.4 yrs

BNP

7 deaths, 11 CCF

BNP ⬎31 pg/ml predicts death or CCF; HR: 1.09 per 10 pg/ml

CCF ⫽ congestive cardiac failure; HR ⫽ hazard ratio; other abbreviations as in Tables 1 through 4.

commented on the impact of CAD on outcome. As this is not always well described, it is a potential confounding factor and a recognized limitation when using biomarkers to assess AS. Prediction of outcome in unoperated patients. SYMPTOM ONSET. Asymptomatic patients in whom symptoms develop during follow-up have higher levels of BNP (51), NT-proBNP (51,66), and NT-proANP (51) at baseline. Patients with at least mild AS and a plasma level of NT-proBNP that exceeded normal limits (⬎50 pmol/l) at

Figure 1

baseline were more likely to have symptoms develop (55%) than patients with levels of NT-proBNP within normal limits (11%) (OR: 9.6, 95% CI: 2 to 64, p ⫽ 0.02) (66). AVA, peak aortic velocity, and LVEF were less reliable predictors of symptomatic onset (66). In severe AS, symptom-free survival at 3, 6, 9, and 12 months was best separated by NT-proBNP levels of ⬍80 pmol/l versus ⬎80 pmol/l: 100% versus 92%, 88% versus 58%, 88% versus 35%, and 69% versus 18%, respectively (51). Those in whom symptoms developed did not differ significantly with regard

NT-proBNP Levels According to Severity of AS

Values are mean ⫾ SEM. Aortic stenosis (AS) I ⫽ mild-moderate AS; AS II ⫽ moderate-severe AS; AS III ⫽ very severe AS (AVA ⬍0.7 cm2); AVR ⫽ AS patients who have had aortic valve replacement. Reprinted with permission from Weber et al. (60).

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to age, peak and mean gradients, and the presence of CAD. They had a slightly smaller AVA and slightly lower LVEF; however, by multivariate analysis, only NT-proBNP (p ⬍ 0.05) and LVEF (p ⬍ 0.05) were independent predictors of remaining free of symptoms during follow-up (51). Survival/major adverse cardiovascular events (MACE). In an elderly cohort of 124 unoperated patients with moderate to severe AS, survival was significantly influenced by the presence of symptoms (relative risk: 7.5, p ⬍ 0.01) and BNP tertile (relative risk: 2.9, p ⬍ 0.001) (57). The 1-year mortality rate without surgery was 6%, 34%, and 60% with each increasing tertile. No patients with BNP ⬍100 pg/ml died (57). The combination of BNP and symptoms provided a better prediction of survival than symptoms alone (chi-square 13.6, p ⬍ 0.001) (57). BNP significantly (relative risk: 2.8, p ⬍ 0.01) influenced survival after correction for other univariate predictors: CAD, symptoms, NYHA functional class, LVEF, and AVA (57). Two other studies in patients with variable severity of AS, many of whom had symptoms or in whom symptoms developed but were still predominantly managed medically, have also shown increased mortality or hospitalization with heart failure in those with elevated BNP (46) or NT-proBNP (45). In the Weber et al. (45) study of the conservatively managed patients with an adverse outcome, only one-third (n ⫽ 3) had severe AS, and, compared with event-free survivors, the prevalence of CAD was almost double and LVEF was significantly lower. In the Antoni-Canterin et al. (46) study, despite 24 patients being of NYHA functional classes III to IV, only 2 had AVR (46). These studies are unlikely to be representative of those patients being followed serially and being considered for surgery with the development of symptoms. PREDICTING MACE INCLUDING AVR. Three relatively small studies in patients with asymptomatic mild-severe AS have shown that those with elevated levels of NT-proBNP are more likely to die, be hospitalized, or need AVR due to the development of symptoms (55,67,68). Weber et al. (61) also demonstrated that NT-proBNP using an optimized cutoff of 550 pg/ml is a good indicator (85% accuracy) of the clinician’s decision to refer for AVR in 105 patients with severe AS, 84 of whom had American College of Cardiology/American Heart Association indications for surgery. The group from Vienna also showed that low BNP/ NT-proBNP/NT-proANP are predictive of short-term symptom-free survival in 43 asymptomatic patients with severe AS (51), with NT-proBNP having the best discrimination. Monin et al. (69), from France, recently suggested incorporating BNP levels into a continuous risk score to predict MACE (69). The model was developed in 107 patients with moderate to severe AS and incorporated the score [peak velocity (m/s)x2] ⫹ (natural logarithm of BNP ⫻ 1.5) ⫹ 1.5 (if female sex), which was subsequently validated in another 107 patients from Belgium. MACE were largely driven by positive exercise tests leading to referral for AVR while still

2043

asymptomatic. Although these studies clearly demonstrate the potential of BNP/NT-proBNP as useful prognostic markers in asymptomatic AS, they do not give us evidence that operating on asymptomatic patients with high levels leads to a reduction in mortality or better functional outcome. Predictors of post-operative outcome. CARDIAC FUNCTION. In the hours after surgical AVR for AS, there is an increase in BNP (70) and ANP (71). BNP then decreases significantly at 6 and 12 months post-AVR but does not return to normal (44,61). Decreases occur in parallel with decreases in mean transvalvular pressure gradient and left ventricular mass (72), with patients with the largest post-operative valve area index having the largest decrease in NT-proBNP (73). The fact that BNP levels were still elevated postoperatively might indicate that BNP is a marker of insufficient reverse remodeling with ongoing stimulus for BNP synthesis. Alternatively, because BNP inhibits myocyte growth and fibrosis (74), it may have a more direct role in the reverse-remodeling process. Mean myocardial systolic strain increases after AVR, which occurs in parallel with decreases in LVMI, both of which are independently related to changes in NT-proBNP (r ⫽ ⫺0.67, p ⬍ 0.001; r ⫽ ⫺0.71, p ⬍ 0.001) during 12 months of follow-up after AVR (49). NT-proBNP is a significant predictor of normal post-operative LVEF, along with pre-operative LVEF, by multivariate analysis (51). Post-operative changes in LA volume and LA pressure were reflected in ANP (49) and NT-proANP (73) levels, respectively. Persistently high NT-proANP seems to be predictive of late post-operative atrial fibrillation (AF), consistent with high LA pressure being an important determinant of AF (75). Three studies demonstrated that high preoperative BNP/NT-proBNP levels are associated with decreased symptomatic improvement in AS patients (47,51,72). Patients in whom there is no symptomatic improvement tend to have nonsignificant decreases in NT-proBNP and LVMI even though the transvalvular pressure gradient decreases (72). Seventeen of 40 patients with symptomatic AS who underwent AVR and in whom symptoms of left-sided heart failure, right-sided heart failure, or hypotension developed in-hospital were characterized by significantly higher baseline pre-operative BNP levels (399 ⫾ 82 pg/ml vs. 124 ⫾ 41 pg/ml, p ⫽ 0.011), end-diastolic wall stress, and pulmonary capilliary wedge pressure but with similar severity of AS and systolic function (47). SYMPTOMS.

Three moderately large studies examined the prognostic value of BNP/NT-proBNP for survival in operated patients with severe AS (51,52,72) and a fourth reported on 70 patients, of whom 43 had AVR (58). Two studies showed that NT-proBNP (51) and BNP (52) were independent predictors of perioperative mortality. The latter study also demonstrated the superiority of BNP in the prediction of perioperative and long-term mortality compared with the commonly used logistic EuroSCORE (52). These results tend to be supported by Lim et al. (58),

SURVIVAL.

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although the mortality results included death in 7 patients who did not have surgery. The 4 patients who did have AVR and died all had increased BNP (58). In contrast, however, NT-proBNP was not predictive of survival or hospitalization for heart failure in 102 patients with severe AS undergoing AVR (45). There is not a clear explanation why these results differed but may be related to the lower frequency of concomitant coronary artery bypass graft and slightly younger age of patients in the Weber et al. (45) study compared with the Pedrazzini et al. (52) study (29% vs. 42% coronary artery bypass graft, 69 ⫾ 10 years vs. 73 ⫾ 9 years, respectively). Low-flow, low-gradient aortic stenosis. BNP is higher in patients with truly severe compared with pseudosevere AS and correlates with AS severity and LVEF (76). BNP was a strong predictor of outcome. With BNP levels ⱖ550 pg/ml, the cumulative 1-year survival rate of the total cohort when compared with those with BNP levels ⬍550 pg/ml was 47 ⫾ 9% versus 97 ⫾ 3% (p ⬍ 0.0001), and the postoperative survival rate was 53 ⫾ 13% versus 92 ⫾ 7% (76). When subdivided into truly severe and pseudosevere AS, the groups were too small for statistical analysis; however, a consistent pattern of higher mortality was observed in patients with BNP ⱖ550 pg/ml. The poorer survival in patients with high BNP/NT-proBNP undergoing AVR does suggest that those patients may have more irreversible myocardial dysfunction, which may be directly related to overt replacement myocardial fibrosis (77). Natriuretic Peptides in MR Clinical decision making in MR. MR is the second most common form of valve disease. MR may be divided into organic and functional, depending on whether the valve leaflets or chords themselves are abnormal or whether the leak reflects an abnormality of the supporting structures. In the developed world, degenerative valve disease is the most common cause of moderate or severe MR, with endocarditis and rheumatic disease making up most of the remainder. Ischemic heart disease is the most common cause of functional MR. Chronic MR, if sufficiently severe, leads to volume overload of the left ventricle, which in turn results in compensatory chamber dilation and eccentric hypertrophy. The transition to a decompensated state is poorly understood but might be due to a progressive increase in regurgitant volume, a decrease in contractility, an increase in afterload, or a combination of these factors (78). It is usually associated with the onset of symptoms but may be insidious. The decompensated state is characterized by marked ventricular dilation, increased diastolic pressure, increased systolic wall stress, and a decrease in ejection fraction to less than 60%. In most instances, the management of functional MR is treating the underlying condition, whereas in organic MR, therapy is targeted at the specific valvular abnormality. Current guidelines for the management of severe organic MR reflect strong evidence that surgical intervention is best

JACC Vol. 55, No. 19, 2010 May 11, 2010:2034–48

performed before the onset of limiting symptoms or even a minor reduction in LVEF (35,79,80). Wherever possible, mitral valve repair is a better option than valve replacement because the outcome is superior (35,81). In asymptomatic patients with normal LVEF, management is less clear. One approach is to recommend surgery in patients with proven severe organic MR on the basis that it is highly likely that symptoms or LV dysfunction will develop sooner or later (82); a second approach is to refer for surgery at the first sign of symptoms, a decline in LV function, onset of AF, or increasing pulmonary arterial pressures (83). As with AS, the watchful waiting approach may result in patients with early symptoms slipping through the net, particularly without functional testing. Equally, misplaced enthusiasm for early surgery might condemn a previously asymptomatic patient to the hazards of surgery and the far-from-trivial risks of a failed repair and a mechanical prosthesis. Current American College of Cardiology/American Heart Association guidelines are explicit in stating that mitral valve repair in asymptomatic patients should only be attempted if there is a 90% expectation that a successful repair can be achieved, and a surgical mortality rate of ⬍1% and 5-year recurrence rate of ⬍5% have been suggested as standards in this group of patients (35,84). Although this might be possible in expert centers, it is far from clear that is achievable more widely. There is no clear evidence that surgical treatment of functional MR carries a prognostic benefit. Baseline correlations. COMPARISONS WITH CONTROLS. There are limited data on levels of natriuretic peptides in MR in comparison with normal controls. In one study of 49 patients with varying degrees of isolated organic MR and an LVEF of ⬎55%, plasma levels of ANP, BNP, and NTproBNP were greater in both asymptomatic and symptomatic patients with MR compared with controls after adjustment for age, sex, and body surface area (85). A second study of 78 patients with varying degrees of both organic and functional MR also found increased ANP and BNP levels compared with controls (86). SEVERITY OF VALVE DISEASE. There is a variable relationship between plasma levels of natriuretic peptides and the severity of MR in published studies. A number of studies demonstrated a positive relationship between natriuretic peptides and the severity of both organic and functional MR (87–90), whereas others have shown either no correlation or a relationship only on univariate analysis (86,91–93). Findings are summarized in Table 4. This variability in findings likely reflects heterogeneous patient populations, but the implication is that natriuretic peptides are not a clinically useful marker of the severity of the regurgitation per se. In practice, this is not a particular issue because the severity of regurgitation can usually be determined by echocardiography.

The majority of studies fail to show a significant association between any of the natriuretic peptides and LVEF (85,86,89 –92) (Table 4).

CARDIAC STRUCTURE AND FUNCTION.

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Exceptions are a study including patients with organic MR in which there was a weak negative correlation between NT-proBNP and LVEF (r ⫽ ⫺0.25) (93) and a study in which the BNP/ANP ratio showed a similar finding (94). Similarly, there is no consistent association with right ventricular function, LV diastolic filling parameters, or measures of end-diastolic size (86,90,92,93). Increased LV end-systolic dimensions or volumes are important markers of ventricular decompensation in chronic MR and are associated with BNP and NT-proBNP in most but not all series (86,89,90,93) as are increased pulmonary arterial systolic pressures (86,89,92). The most consistent, but not universal, association is with LA dimensions or volumes (85,89,90,92,93). AF was an independent predictor of BNP levels in one study (91), but another showed that both ANP and BNP decreased with very large atria in the presence of AF (94). BNP levels are higher in patients with functional compared with organic MR, but this reflects a greater degree of LV dysfunction with larger end-systolic volumes and greater wall stress (86). Stratification for LV endsystolic volume index (LVESVI) removed the effect of the etiology of MR. The concept that BNP provides an integrated index of cardiac remodeling including systolic LV dilation, LA dilation, and pulmonary hypertension is an attractive one but is not supported by all studies. Again, this is related to the highly heterogeneous patient populations studied. Table 6 summarizes findings from 4 studies that included data on LVESVI. The majority found that BNP was a marker for increased LVESVI (86,87,90), with the one study with negative findings having a small range of LVESVI (92). Thus, BNP is a marker for systolic ventricular remodeling in chronic MR but only in the context of a wide range of ventricular volumes and hence probably not useful in identifying the earliest stages of ventricular decompensation. The consistent relationship between BNP and LA size suggests that BNP may be produced by LA myocardium in response to chronic increases in atrial wall stress rather than solely by ventricular myocardium (92). The relationship to pulmonary arterial systolic pressure is less easy to explain given the lack of relationship between BNP and measures of right ventricular function. SYMPTOMATIC STATUS. BNP, NT-proBNP, and ANP are all higher in symptomatic than asymptomatic patients after adjustment for the severity of MR and the extent of atrial and ventricular remodeling (85). A cutpoint of BNP of 12

pmol/l predicted the presence of symptoms with 75% sensitivity, 85% specificity, and an area under the curve (AUC) of 0.90. AUCs for NT-proBNP and ANP were both 0.89, and all were superior to LA size, LV size, and severity of MR. Similarly, Potocki et al. (93) demonstrated an AUC of 0.80 for NT-proBNP. Levels of BNP and NT-proBNP increase progressively with worsening symptomatic class, albeit with a considerable degree of overlap (86,87,90 –93). Shimamoto et al. (94) found that plasma ANP was increased in patients with NYHA functional class II symptoms but then decreased in those with NYHA functional class III and IV symptoms, whereas BNP and hence the BNP/ANP ratio increased progressively. For NYHA functional class II, III, or IV, a cutpoint for a BNP/ANP ratio of 1.2 gave 88% sensitivity, 83% specificity, and an AUC of 0.82. For NYHA functional class III or IV, a cutpoint of 2.97 gave 78% sensitivity, 87% specificity, and an AUC of 0.86. Yusoff et al. (90), in a study of 38 patients with severe degenerative MR, identified NTproBNP levels as a strong independent predictor of maximal oxygen uptake, whereas there were only weak correlations between exercise parameters and resting echocardiographic variables. Kerr et al. (92) performed exercise echocardiography in 33 patients with moderate to severe or severe MR and preserved LVEF at rest. Increased BNP levels were associated with increased pulmonary arterial pressures at rest and on exercise and increased LA volumes and lower functional capacity on exercise testing, but not with either resting or exercise measures of LV size and function. The implication of these findings is that although resting BNP levels are clearly related to impaired functional capacity, they may not be a marker of the failure of LV contractile reserve per se. Predictors of outcome. Detaint et al. (91) followed 124 patients with chronic isolated organic MR for a mean of 4.4 ⫾ 1.4 years after diagnosis and sampling for BNP. At diagnosis, 35% had severe MR, 69% were NHYA functional class I, 21% functional class II, and 7% functional class III or IV. After adjustment for age, sex, symptoms, LVEF, and severity of MR, BNP was an independent predictor of survival with a hazard ratio of 1.23 per 10 pg/ml. For death or heart failure, the hazard ratio was 1.09 per 10 pg/ml. In an elegant study, Pizarro et al. (89) enrolled 269 patients with severe organic MR and normal results of

RESPONSE TO EXERCISE.

2 Data for and End-Systolic Volume Index (ml/mIndex Organic Functional MR From 4Volume Studies )Demonstrating for Controls and Marked Controls Patients Heterogeneity and With Patients With Data for End-Systolic (ml/m2) for Table 6 Organic and Functional MR From 4 Studies Demonstrating Marked Heterogeneity

Organic MR First Author (Ref. #)

Controls

Detaint et al. (86)

26 ⫾ 5

Kerr et al. (92)

16 ⫾ 6

Yusoff et al. (90) Dini et al. (87) Abbreviation as in Table 2.

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Asymptomatic

Symptomatic

Functional MR

42 ⫾ 14

96 ⫾ 33

27 ⫾ 7

26 ⫾ 6

37 ⫾ 9

40 ⫾ 10 87 ⫾ 34

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Steadman et al. Natriuretic Peptides in Valvular Heart Disease

treadmill exercise testing. The first 167 patients were used as a derivation cohort and the second 102 as a validation cohort. BNP was assayed on samples taken as baseline and 1 year, and patients were followed to a combined end point of death, development of LV systolic dysfunction (LVEF ⬍60%), or the onset of heart failure (NYHA functional class III or IV). The AUC for the receiver-operator characteristic curve of BNP as a predictor of the combined end point was 0.80 for the derivation cohort and 0.81 for the validation cohort. Stratification of baseline BNP into quartiles gave event-free survival rates at 48 months of 99%, 97%, 93%, and 29%. Using a cutpoint of 105 pg/ml from the derivation cohort, the combined end point occurred in 66% of the validation cohort with a BNP ⬎105 pg/ml as opposed to 4% with a BNP ⬍105 pg/ml (p ⬍ 0.00001) with a hazard ratio of 4.7 on Kaplan-Meier analysis (p ⬍ 0.0001). In the validation cohort, BNP ⬎105 pg/ml was the strongest independent predictor of the combined end point (OR: 4.1), followed by an effective regurgitant orifice area ⬎55 mm2 (OR: 3.7) and an end-systolic diameter/body surface area of ⬎22 mm2 (OR: 3.1). In a study of patients with functional MR, NT-proBNP ⬎1,941 pg/ml was second only to a marked increase in the LVESVI (⬎82 ml/m2) as an independent predictor of death, with a hazard ratio of 2.17 (p ⫽ 0.026), and was the most powerful predictor of death or hospitalization, with a hazard ratio of 3.19 (p ⬍ 0.001) (87). Conclusions The role of natriuretic peptides as cardiac hormones is clear given their close relationship to cardiac structure and function, reflecting LV wall stress and subclinical myocardial dysfunction. In valvular heart disease, they are correlated with disease severity, although this is more reliable in AS than MR, as well as symptomatic status. Determining symptomatic status itself can be difficult even with a rigorous clinical history. Breathlessness in particular is very subjective; in a large group of elderly people, one-third of patients were classified as breathless, using the Medical Research Council Scale, but only one-half of them had any identifiable pathology (95). Natriuretic peptides could play a role here. Perhaps the most exciting prospect for future use comes from their ability to predict outcome. BNP and NT-proBNP show the most promise. In AS, low levels are good predictors of symptom-free survival and high levels are indicative of subsequent mortality, at least in medically managed patients. High levels may also be strong predictors of perioperative and long-term mortality. In MR, plasma levels are associated with adverse outcomes in both organic and functional MR, and there are preliminary data to suggest that BNP might be a useful predictor of incipient decompensation in asymptomatic patients with organic MR. In both AS and MR, the difficulty remains in deciding on the optimum timing of surgery in asymptomatic patients. A

JACC Vol. 55, No. 19, 2010 May 11, 2010:2034–48

reliable biomarker that appropriately risk-stratifies such patients would be invaluable. Natriuretic peptides have been extensively studied in valvular heart disease, as we have detailed; however, there are no studies that have tested the hypothesis that early surgical intervention in asymptomatic patients with severe valvular heart disease and elevated levels of natriuretic peptides reduces mortality or improves functional outcome. Additionally, there are many comorbidities that are not uncommon in valvular heart disease, such as CAD, diabetes, and hypertension, and their impact on natriuretic peptide levels has not been clearly established. Whether natriuretic peptides will have a clinically useful role is yet to be proven; prospective, randomized, controlled trials in well-described patient populations are needed before they can be incorporated into the routine management of these challenging and increasingly prevalent patient groups. Reprint requests and correspondence: Dr. Christopher D. Steadman, Department of Cardiovascular Sciences, Clinical Sciences, University Hospitals of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, United Kingdom. E-mail: [email protected].

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