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
