Intérêt du dosage des peptides natriurétiques dans la prise en charge

d’une défaillance cardiaque

Alexandre Mebazaa, MD, PhDHôpital Lariboisière,

University Paris 7, U942 InsermParis, France

Maisel A., McCullough, P., N Engl J Med 2002; 347 (3): 161-7

1.0

0.8

0.6

0.4

0.2

0.0 0.2 0.4 0.6 0.8 1.01-Specificity

Sen

sitiv

ity

615Specificity

=73%

71Sensitivity

=90%

BNP <100 pg/ml “Test negative”

227673BNP 100 pg/ml “Test positive”

Final Diagnosis NOT Heart

Failure

Final Diagnosis

Heart Failure

Positive predictive value=75%

Negative predictive value=90%

Optimal cut-off point determined@ 100 pg/ml

BNP=50 pg/mlBNP=80 pg/ml

BNP=100 pg/ml

BNP=150 pg/mlBNP=125 pg/ml

Diagnostic Accuracy of BNP

Logeart D et al, JACC 2002;40:1794

BNP in acute dyspnea

:•Diagnostic value•Identification of a grey zone

log BNP(pg/ml)

LVEF< 0.45

1

1000

100

10

LVEF> 0.45

Pulmonary EmbolismLVEF< 0.45

LVEF> 0.45

**

**

ns

25% of patients

400

Acute Decompensated HF No Acute Decompensated HF

Grey zone for BNP and NT-proBNP

Maisel A EJHF 2008, 10:824

Patient presenting with dyspnea

Physical examination,chest x-ray, ECG,

BNP level

BNP <100 pg/mL BNP 100-400 pg/mL BNP > 400 pg/mL

CHF unlikelyBaseline LV dysfunction,

underlying cor pulmonale oracute pulmonary embolism?

Yes No

Possibleexacerbation of CHF CHF likely

CHF likely

AHF Diagnostic Algorithm

Maisel A Eur J Heart Failure 2008, 10:824

BACH trial: comparison MR-proANP and BNP in dyspneic patients

Comparison of MR-proANP and BNP as markers for heart failure in the emergency-department evaluation of dyspnea

Parameter Sensitivity (%) Specificity (%) Diagnostic accuracy (%) MR-proANP >120 pmol/L 95.6 59.9 72.6 BNP >100 pg/mL 97.0 61.9 73.5 p for noninferiority <0.0001 <0.0001 <0.0001 MR-proANP=mid-regional fragment of atrial natriuretic peptide prohormone; BNP=B-type natriuretic peptide

http://www.theheart.org/article/903059.do

BNP levels in LV diastolic dysfunction

BNP Levels in Patients Presenting With Either Systolic or Diastolic Dysfunction

J Am Coll Cardiol 2003;410(11):2010-17.

1000

500300200

100

503020

10

5

BN

P (p

g/m

L)

Non CHF LV Diastolic LV Systolicn=844 n=165 n=287

Median=34 pg/mL

Median=821 pg/mL

Median=413 pg/mL

BASEL I –

ED : impact of BNP measures on time to discharge

Ch Mueller NEJM 2004

Ensemble des patients (n = 186)

Réanimation médicale (n = 117)

Réanimation chirurgicale

(n = 69) Dosage des troponines 69 ( 37 ) 37 ( 33 ) 32 ( 46 )

Troponine anormale 14 ( 20 ) 11 ( 30 ) 3 ( 9 )

Taux de troponine 0 [ 0 - 0 ] 0 [ 0 - 1 ] 0 [ 0 – 0 ] Dosage du BNP 28 ( 15 ) 21 ( 18 ) 7 ( 10 ) BNP anormale 27 ( 96 ) 20 ( 95 ) 7 ( 100 ) BNP_taux 474 [ 260 - 1552 ] 498 [ 265 - 1470 ] 415 [ 175 - 1174 ] NTBNP_dosage 11 ( 6 ) 11 ( 9 ) 0 ( 0 ) NTBNP_anle 9 ( 90 ) 9 ( 90 ) 0 ( 0 ) NTBNP_taux 3488 [ 1600 - 9349 ] 3488 [ 1600 - 9349 ] --

FROG ICUFRench Outcome reGistry in Intensive Care

UnitEnquête du 1er Décembre 2009

BNP Group

Respiratory Failure

Start of specific therapy

Control Group

randomize

History, physical exam, ECG, chest X-ray, blood gases

BNP Test

Hospital Discharge

Tim

e to

dis

char

geStudy Algorithm: BASEL II - ICU

NIV

Inclusion criteria:• Pts >18 years• Respiratory failure (primary or secondary)• Requiring diagnostic evaluation

BASEL II - ICU

Exclusion criteria:• Serum Creatinin >250ymol/l• Sepsis• CPR <12h• Trauma• BNP measurement <6h

BASEL II-ICU 12-hours diagnosis no. (%) Post-discharge diagnosis, no.

(%)

BNP group

Control group

p-value BNP group

Control group p-value

(n=159) (n=155) 0.018 (n=159) (n=155) 0.013 Heart failure (HF) alone 63 (39) 52 (34) 0.265 53 (33) 48 (31) .655 HF + any additional diagnosis 36 (22) 16 (10) 0.003 51 (32) 24 (16) .001

HF + pneumonia 21 (13) 7 (4.5) 0.007 29 (18) 13 (8) .010 HF + AECOPD 11 (7) 7 (4.5) 0.361 13 (8) 7 (5) .146 HF + other diagnosis 4 (2) 2 (1) 0.429 9 (6) 4 (3) .170

Pneumonia 17 (11) 28 (18) 0.063 23 (14) 27 (17) .475 Obstructive pulmonary disease 19 (12) 17 (11) 0.926 15 (9) 15 (10) .942 Pneumonia + AECOPD 1 (1) 7 (4.5) 0.029 2 (1) 9 (6) .029 Pulmonary embolism 3 (2) 7 (4.5) 0.185 5 (3) 10 (6) .170 Unknown cause 3 (2) 3 (2) 0.975 1 (1) 3 (2) .300 Other cause * 17 (11) 25 (16) 0.158 9 (6) 19 (12) .041

* Including aspiration, anaemia, atelectasis, pneumothorax, oversedation, interstitial lung disease, obesity hypoventilation syndrome and pleural effusion.

M Noveanu, A Mebazaa, Ch Mueller

F. Abroug et al. AJRCCM 2006; 990

ROC curves of NP and Tnused to assess LV dysfunction inAECOPD patients

Accuracy of NT-pro BNP in assessing RV failurein AECOPD

F. Abroug et al. AJRCCM 2006; 990

Multi-Marker Strategy:Addition of BNP to TnI

n=22 n=23TnI -, TnI <0.04 ng/mL

TnI+, TnI ≥

0.04 ng/mL

BNP-, BNP <485 pg/mL

BNP+, BNP ≥

485 pg/mL

4550

Mor

talit

y (%

)

n=17

05

10152025303540

P trend = 0.004

BNP- TnI+

RR=2.1

BNP+ TnI-

RR=4.7

BNP+TnI+

RR=12.3

BNP-TnI-

n=34

RR=1.0

Horwich TB, Fonarow GC. Circulation. 2003 & 2002

Multi-Marker Strategy:Addition of BNP to TnI

1.0

0.8

0.6

0.5

0

0 126 18 24

Surv

ival

Month

TnI - BNP -

TnI + BNP -0.9

0.7

TnI - BNP +

TnI + BNP +

RR

S/P Heart Transplant

1.0

2.1

4.7

12.3

•Improves Prognostic Value, Risk Stratification • Heart Transplant Selection

Metabolism of NPs?

Levin, NEJM 1998

Cardiac Resynchronisation (CRT) as a Rescue Therapy in Patients with

Catecholamine-Dependent Overt Heart Failure

Milliez et al. Eur J Heart Failure, 2008

Methods

20 patients were predominantly male with a mean age of 67 ± 10 yo, with ischemic cardiomyopathy in 12 and non-ischemic in 8 with mean QRS duration of 174 ± 25 ms and LVEF of 18 ± 3%.

All patients were on dobutamine infusion (7.5 ± 2.5 µg/kg/min).

Catecholamine-dependant overt HF (CDOHF) patient status was defined as the recurrence of clinical and biological signs of low cardiac output despite 3 attempts of very progressive weaning ofcatecholamine agents.

Milliez et al. Eur J Heart Failure, 2008

Parameters Before CRT implantation 24 hours after pCRT implantation

SBP (mmHg) 84 ±

7 99 ±

10 <0.0001

DBP (mmHg) 55 ±

5 60 ±

6 <0.001

Urine output (ml/day) 817 ±

264 2256 ±

1550 <0.01

Dobutamine (µ/kg/mn) 7.5 ± 2.5 0 <0.0001

QRS duration 174 ±

25 163 ±

18 <0.01

BNP (pg/ml) 2176 ±

863 960 ±

520 <0.001

Uremia (mmol/l) 12 ±

5 9 ±

4 <0.001

Creatinine (µmol/l) 185 ±

42 153 ±

34 <0.001

LVEF (%) 18 ±

3 21 ±

4 <0.05

BNP level post cardiac resynchronisation implantation

Milliez et al. Eur J Heart Failure, 2008

Paradox of BNP in septic shock

• No relationship, in septic shock patients, between plasma BNP and– mortality– LVEF (50% have a

preserved LVEF)– LV filling pressure

Mc Lean AS et al. Crit Care Med 2007

plasma BNP

Log(pg/mL)NEP activity

(nmol/mL/min)

1

10

100

1000

10000

Normal Septicshock

BNP

NEP 24.11

*

Sepsis

without shock

Cardiogenic shock

0.60

0.45

0.15

0.30

* *

* P < 0.05

NEP 24.11 activity may play a role in BNP increase during septic shock

Pirracchio et al Crit Care Med 2008

0.0

0.2

0.4

0.6

0.8

1.0

NEP

24-

11 (n

mol

/ml/m

in)

Normal range

Severe sepsis Septic shock Cardiogenic shock

Pirracchio et al Crit Care Med 2008

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

1.25 1.5 1.75 2 2.25 2.5 2.75 3 3.25 3.5 3.75

Y = ,944 - ,256 * X; R^2 = ,765

Log baseline BNP (pg/ml)

NEP

24-

11 a

ctiv

ity(n

mol

/ml/m

in)

Pirracchio et al Crit Care Med 2008

Could NP predict outcome of unselected ICU patients?

Valeur pronostique du BNP avant la sortie (de

l’hôpital)

Logeart et al JACC 2004;43:635

Prognostic value of BNP at admission to predict long term outcome

BNP = 350

0.00

0.25

0.50

0.75

1.00

Sens

itivi

ty

0.00 0.25 0.50 0.75 1.001 - Specificity

Area under ROC curve = 0.80 BNP < 350 ng/l

Predischarge BNP > 700 ng/l

0 30 60 90 120 150 180

Follow-up (days)

1

5.1

15.2

p < 0.0001

p < 0.0001

0

25

50

75

100

Dea

th o

r re

adm

issi

on (%

)

Hazard ratios of 2nd and 3rd

versus 1st BNP range

BNP 350 - 700 ng/l

NT-proBNP is an independant predictor of outcome in unselected patients in ICU

Meyer et al. CCM 2007;35:2268

289 ICU patients

202 ICU patientsadmitted for cardiac

reasons

87 ICU patientsadmitted for non-cardiac

reasons

NT-proBNP is an independant predictor of outcome in unselected patients in ICU

Meyer et al. CCM 2007;35:2268

Outcome: hospitalsurvival

NT-proBNP is an independant predictor of outcome in unselected patients in ICU

Meyer et al. CCM 2007;35:2268

JAMA 2007;297,1883-1891

SURVIVE Mean Change from Baseline in BNP

-800

-700

-600

-500

-400

-300

-200

-100

0

0 1 2 3 4 5 6

Days Since Start of Study Drug Infusion

Mea

n C

hang

e Fr

om B

asel

ine

Dobutamine

Levosimendan

For comparison between treatment groups at all time points (P<0.0001) Due to the skewness in the data, median percent change is presented versus mean percent change from baseline

Mebazaa et al. JAMA 2007;297,1883-1891

HR for BNP changes to predict outcome improves over the first 5 days: results of SURVIVE trial

Mortality is lower when change in BNP was > 30% at Day 5:results of SURVIVE trial

A. Cohen Solal et al JACC 2009

> 30 % decrease in BNP at Day 5

< 30 % decrease in BNP at Day 5

A. Cohen Solal et al JACC 2009

Mortality is lower when change in BNP was > 30% at Day 5:results of SURVIVE trial

NP-guided therapy in outpatients

Jourdain et al. JACC 2007; 49:1733

Jourdain et al. JACC 2007; 49:1733

STARS-BNP trial

Jourdain et al. JACC 2007; 49:1733

50

60

70

80

90

100

30 90 150

210

270

330

390

450

T (days)

Even

t fre

e su

rviv

al %

Clinical groupBNP group

50

60

70

80

90

100

30 90 150

210

270

330

390

450

T (days)

Even

t fre

e su

rviv

al %

Clinical groupBNP group

P <.01

BNP for treatment strategy: BNP for treatment strategy: BNPBNP--guided HF therapy: STARSguided HF therapy: STARS

Jourdain, Cohen-Solal et al, JACC, 2007

BNP-Guided vs Symptom-Guided Heart Failure TherapyThe Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) Randomized Trial

Matthias Pfisterer, MDPeter Buser, MDHans Rickli, MDMarc Gutmann, MDPaul Erne, MDPeter Rickenbacher, MDAndre´

Vuillomenet, MDUrs Jeker, MDPaul Dubach, MDHansjürg Beer, MDSe-Il Yoon, MDThomas Suter, MDHans H. Osterhues, MDMichael M. Schieber, MDPatrick Hilti, MDRuth Schindler, RNHans-Peter Brunner-La Rocca, MDfor the TIME-CHF Investigators

JAMA. 2009;301(4):383-392

Time-HF

Pfisterer et al JAMA 2009, 301:383

ProBNP Outpatient Tailored CHF Therapy (PROTECT)

•

PROTECT enrolled 151 patients out of a projected 300, of whom 126 had been treated for at least the prespecified one year

•

Principal Investigator Dr James L Januzzi (Massachusetts General Hospital, Boston).

•

Composite primary end point that included worsening heart failure, HF hospitalization, and CV death

•

The primary end-point reduction associated with natriuretic-peptide-guided therapy was significant at p=0.008

NP-guided therapy in ICU ?

•

Does it make sense in acute conditions? In the ER? Diuretics ?

•

Can we improve patient’s outcome?

Plasma biomarker(s) of HF:

new biomarkers by proteomics

Pronota-Paris 7- APHP-Inserm U942

Principle of N-terminal sorting based on a COFRADIC®

approach

H2 N R R RCOOH 1. Modification of all

protein N-termini

2. Protein cleavage → peptides

3. Peptide separation

4. Modification of ‘internal’ peptides

5. Peptide separation

COOHH2 N

RH2 N

RH2 N

R

COOHH2 N

R

RH2 N

R

Separation based on hydrophobicity

Identical separation conditions as the first runAltered peptides: modified chromatographic behavior

6. Collection window

www.pronota.com

Tissue: Differential features => identified proteins

SAMmax #features # validated protein groups

>0.99 121 (0.98%) 21

>0.95 587 (4.8%) 90

>0.9 1437 (11.7%) 185

12275 featuresanalyzed

SHAM1 SHAM2 SHAM3 SHAM4 TAC1 TAC2 TAC3 TAC4

Log2

ratio

sam

ple/

refe

renc

e

Ratio Profile Chart

132 proteins UP

53 proteins DOWN

01234

-1-2-3-4

Cardiac biomarker NT-pro-BNP is top of list

SAM

max

Nppb: Natriuretic peptides B (BNP)

SAM scores

pro-BNP

NT-pro-BNP BNP

27 121

121777627

<Pyro-glu (N-term Q)>QLSKDQGPTKELLKR

Myosin Switch in rat thoracic aortic constriction model

Myosin Switch

SAM

max

SAM scores

MYH7

MYH6

Normal heart Hypertrophic heart (pathological)

MHC - alpha MHC - beta

Myosin-7Myosin-6

SHAM1 SHAM2 SHAM3 SHAM4 TAC1 TAC2 TAC3 TAC4

Log2

ratio

refe

renc

e/sa

mpl

e

Ratio Profile Chart

Myosin-7 ↑

Myosin-6 ↓01234

-1-2-3-4

Acute decompensated heart failure ?

ID of known biomarkers with high confidence in patient plasma using unbiased proteomics

•

NT-proBNP “re-discovered”

by MASStermind®

in patient plasma•

To our knowledge, first time detected with unbiased proteomics platform

↑WALLSTRESS↑WALLSTRESS

Pre-proBNP

proBNP + signal peptide

NT-ProBNP + BNP

Heart Tissue

Blood

Pre-proBNP

proBNP + signal peptide

NT-ProBNP + BNP

Heart Tissue

Blood

Other reported biomarkers Identified:

Creatine Kinase MB AdrenomedullinC-reactive proteinTNFα receptor (2 isoforms)OsteopontinAdiponectinInsulin-like growth factor-1 (2 isoforms)

Novel candidates from >760 unique proteins ID’d:

Circulating fragments of membrane receptorsSignaling moleculesCytokinesGrowth factorsCytoskeletal proteinsProteins overexpressed at mRNA level in hypertrophic heart tissue

Summary• NPs are the first biomarkers specific to

the heart

• Their role in ICU is still uncertain

• A multimarker strategy appears to show favorable results

• New markers are still needed