Dr. Julien Magne, PhD
Sart Tilman Liège, BELGIUM
B-type Natriuretic Peptide in VHD: a
Non-imaging Helper for the Cardiologist
Conflict of Interest Disclosure
None
BNP Molecular Forms and Processing
Lam et al. JACC, 2007
Brain Natriuretic Peptide: Sudoh et al, Nature, 1988
BNP and its inactive amino terminal portion are
neurohormones released by the ventricles in response to
increased LV wall stress
BNP
mRNA
Pre-proBNP
proBNP1-108
NT-BNP1-76
BNP77-108
N-terminal
proBNP1-76
BNP77-108
T1/2=22min
Elimination:
- Enzymatic: neutral endopeptidase
- Receptor mediated: CNP-receptors
Furin
Secretion
Cardiac Myocyte
Volume overload
Pressure overload
Wall stretch
BNP Release Activation
Specific
High myocardium/serum ratio
Not present in non-cardiac
tissue, even pathologically
Sensitive
Zero baseline
Marker of ‘early,’ reversible
cardiotoxicity
Immediate release with injury
Predictive
Long half-life in blood
Release proportionate to
extent of injury
Robust
Rapid, simple, and accurate
Non-invasive / accessible /
unexpensive
Characteristics of an ‘ideal’ biomarker
The Place of BNP in current VHD Guidelines
ESC Guidelines
In Aortic stenosis:
“Natriuretic peptides have been shown in preliminary
studies to predict symptom-free survival in AS.”
In Mitral regurgitation:
“Preliminary series have also suggested the value of
elevated BNP levels as predictors of long-term outcome but this
also remains to be validated””
BNP level in AS
BNP level is correlated with AS severity:
++ with AVA
+- with pressure gradient
BNP is correlated with the consequences
of AS on LV
Qi et al. AHC 2001
Gerber et al. Circulation, 2003
Lim et al. Eur Heart J, 2004
BNP level in AS
BNP level is well associated
with the symptomatic status
Bergler-Klein et al. Circulation 2004 Gerber et al. Circulation 2003
BNP level and Symptoms in AS
• BNP is more powerful than AS
severity parameters to identify
symptoms
• BNP level may predict the
occurrence of symptoms:
Bergler-Klein et al. Circulation 2004
BNP for Risk Stratification in
asymptomatic AS
• 107 pts followed in Créteil
• Risk score according to independent variables
• Validation in Liège (107 pts)
Score = (Peak velocity x 2)
+ (nat log BNP x 1.5) +
1.5 (if female)
< 10%
> 75%
16
Monin et al. Circulation, 2009
p<0.001
LF/LG
group
NF/LG
group
NF/HG
group
LF/HG
group
0
100
200
300
400
500
600
Bra
in n
atr
iure
tic p
epti
de,
pg
/ml
22 (13-44) 47.5 (32-74)
*
114 (68-133)
*†
78 (66-101)
*
BNP level in LF/LG AS
BNP is significantly elevated in LF AS, even in
paradoxical LF/LG AS.
BNP level >550pg/mL strong predictor of
outcome in LF/LG AS
TOPAS study
Bergler-Klein et al. Circulation, 2007 Lancellotti, Magne et al. JACC, 2012
Derivation (n=160) and validation (n=134) cohorts of asymptomatic
severe AR and no LV dilatation/dysfunction
Combined end-point defined as LV dysfunction, symptoms or death
0 0
20
40
100
60
80
1 2 3 4 Follow-up, years
Com
bin
ed e
nd
-poin
t, %
5
Baseline BNP<130pg/mL
Baseline BNP ≥130pg/mL p<0.0001
HR=6.7 (2.3-16.6)
Pizarro et al. JACC, 2011
BNP level in Aortic Regurgitation
0 1 2 3 4
0
20
40
100
60
80
Follow-up, years
Com
bin
ed e
nd
-poin
t, %
5
ERO<50mm² + BNP<130pg/mL
ERO≥50mm² + BNP<130pg/mL
ERO<50mm² + BNP ≥ 130pg/mL
ERO≥50mm² + BNP ≥ 130pg/mL
p<0.0001
Multivariate
predictors of
Cardiac events
BNP level in Aortic Regurgitation
BNP level in Mitral Regurgitation
BNP level is not related to MR itself but to the atrial and
ventricular consequences of MR
124 patients with primary MR; BNP vs. MR
severity (ERO): r=0.17, p=0.06
Detaint et al. Circulation, 2005
BNP level in Mitral Regurgitation
Determinants
of BNP level Impact of BNP level on survival
Detaint et al. Circ, 2005
BNP level in Asymptomatic MR
BNP is a good marker of advanced stage of the disease
Pizarro et al. JACC, 2009
20
40
100
60
80
BNP level in Asymptomatic MR
Pizarro et al. JACC, 2009
Multivariate
predictor of
combined end-point
0 0
1 2 3 4 Follow-up, years
Com
bin
ed e
nd
-poin
t, %
Baseline BNP<105pg/mL
Baseline BNP ≥105pg/mL 20
40
100
60
80
0 0
1 2 3 4 Follow-up, years
Com
bin
ed e
nd
-poin
t, %
p=0.0001 p<0.0001
Validation cohort
LV Longitudinal Function and BNP Level
Magne et al. Heart 2012
Bi-centric study, n=135 asymptomatic
MR (moderate & severe) with no LV
dysfunction/dilatation
-35
-30
-25
-20
-15
-10
-5
0
LV
GL
S, %
Whole cohort
(n=135) Q1
-20±4% -23.3±3
-16.5±4
†‡§
p<0.0001
Q2 Q3 Q4
-21.2±3
*
-19.6±3
†‡
BNP Quartiles
-35 -30 -25 -20 -15 -10 -5
1
2
3
4
5
6
7
r=0.64
p<0.0001
Log B
NP
LV GLS, %
BNP and Impact on Outcome
0 6 12 18 24 30 36 42 48
0
20
40
60
80
100
Ca
rdia
c E
ven
t-fr
ee S
urv
iva
l, %
Follow-up, months
BNP <41pg/ml
BNP >41pg/ml
p<0.0001
75±6%
21±8%
KM curves: median of BNP
HR=3.5, 95%CI: 1.7-7.2, p=0.001
1 5 10 15 20 30 35 40
HR=1, 95%CI: 1-1
HR=3.5, 95%CI: 0.9-14.1; p=0.075
HR=8.5, 95%CI: 2.2-32.5, p=0.002
HR=8.8, 95%CI: 2.1-36.7, p=0.002
Multivariable Analysis
Q1
Q2
Q3
Q4
Exercise BNP and Impact on Outcome
0
100
200
300
400
500
600
700
Bra
in n
atr
iure
tic
pep
tid
e, p
g/m
L
Rest Exercise
37 (19-67)
57±67
41 (21.5-75)
67±72
p<0.0001
-35 -30 -25 -20 -15 -10 -5
0
1
2
3
4
5
6
7
8
Exer
cise
Log B
NP
Exercise LV global longitudinal strain, %
r=0.65
p<0.0001
Magne et al. Submitted 2012
BNP level significantly
increase during exercise
Exercise BNP is determined by
ex. LV longitudinal function
Exercise BNP and Impact on Outcome
Follow-up, months
Ad
just
ed i
nci
den
ce o
f ca
rdia
c e
ven
ts,
%
Tertile 1
(Ex. BNP: 5-29pg/mL)
Tertile 2
(Ex. BNP: 30-62pg/mL)
Tertile 3
(Ex. BNP: 63-412pg/mL)
0
20
40
60
80
100
0 6 12 18 24 30
p=0.02
38 34 30 23 18 15 Pt.
at
risk
38 32 27 18 8 6
37 29 17 11 6 6
0
10
20
30
40
50
60
70
Pre
dic
tio
n o
f ca
rdia
c ev
ents
, χ²
24.3
35.8
45.6
Demographic
and echo.
data
+ Resting
BNP
+ Exercise
BNP
+47%
+27%
Exercise BNP level and outcome Incremental prognostic value of
exercise BNP
Magne et al. Submitted 2012
BNP in VHD: Take Home Messages
• In severe AS, BNP is a powerful predictor of the occurrence of
symptoms and of poor outcome in asymptomatic pts (when combined
with AS severity and gender)
• In LF/LG AS, BNP>550pg/mL is associated with significant reduced
survival.
• In severe AR, BNP>130pg/mL multiplies by 7 the risk of cardiac
events.
• In severe primary MR, BNP>105pg/mL multiplies by 4.5 the risk of
cardiac events.
• In asymptomatic primary MR, exercise BNP level may have
important incremental prognostic value.
DON’T MISS
5-8 December 2012
MAICC – Athens, Greece
Abstract submission deadline
31 May
Early bird registration
30 September
Thank you for your
attention.
“In these matters the only certainty is
that nothing is certain.”
Pliny The Elder, 23 AD-79 AD