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