Gal-3 - Col.BVH

ACNBH
42ème Colloque National des Biologistes des Hôpitaux
Strasbourg, 1‐4 octobre 2013
ODPC N°1495
UN MARQUEUR INNOVANT DE L’INSUFFISANCE
CARDIAQUE: LA GALECTINE
Michel Ovize
Hôpital Cardiologique et Inserm U1060-CarMeN
Université Claude Bernard Lyon 1, France
ACNBH
42ème Colloque National des Biologistes des Hôpitaux
Strasbourg, 1‐4 octobre 2013
ODPC N°1495
DECLARATION D’INTERET
DANS LE CADRE DE MISSIONS DE FORMATION REALISEES POUR L’ACNBH
Pr Michel OVIZE Exerçant au CHU de Lyon
déclare sur l’honneur ne pas avoir d'intérêt, direct ou indirect (financier) avec les entreprises pharmaceutiques, du diagnostic ou d’édition de logiciels susceptible de modifier son jugement ou mes propos, concernant le DMDIV et/ou le sujet présenté.
GALECTINE 3
LV REMODELING AND HEART FAILURE
HEART FAILURE
FOLLOWING ACUTE MYOCARDIAL INFARCTION
ACUTE ISCHEMIA-REPERFUSION INJURY
1
INFARCT SIZE
HEART FAILURE
LV REMODELING
2
INFLAMMATION AND TISSUE HEALING
INFARCT SIZE IS A DETERMINANT OF MORTALITY
Gibbons et al. JACC 2004;44:1533-1542
Kelle et al. JACC 2009
INFARCT SIZE - LV REMODELING – HEART FAILURE -SURVIVAL
Baks et al.
EHJ 2005
Bolognese et al.
Circ 2002
LV END-SYSTOLIC VOLUME AND SURVIVAL AFTER ACUTE MI
Volumes and EF were
assessed 4-8 weeks after
AMI by LV angiography
White HD et al. Circulation 1987
INFARCTION: A TWO-COMPONENT DAMAGE
Final
Infarct size
Ischemia
Reperfusion
No Reperfusion
Reperfusion salvage
PreC
reperfusion
injury
ischemic
injury
Postcond
Control
Postcond effect
coronary
occlusion
Garcia-Dorado et al. CVR 2006
time
Postconditioning
REPERFUSION INJURY: THE NEGLECTED TARGET
Onset of
chest pain
First medical
care
Reperfusion
therapy
Cath lab
admission
Treatment ?
30 minutes to 12 hours
CORONARY ARTERY OCCLUSION
_
Reperfusion
necrosis
_
Treatment ?
Reperfusion
inflammation
LV REMODELING
HEART FAILURE
INFLAMMATION FOLLOWING ACUTE INFARCTION
Acute RCA occlusion
Neutrophils Infiltration 48hrs post‐infarction
POST-INFARCTION LV REMODELING
AND STERILE INFLAMMATION
Fibroblastes
DAMPs
C3‐ C5
Mɸ
Mort cellulaire
MEC
TL
PNN
DC
Endothélium
Angiogénèse
IMMUNITY AND INFLAMMATION: THE « DANGER » MODEL
Danger
Signature
Sensors
Transmission
Response
EXOGENOUS
(INFECTION)
ENDOGENOUS
(TISSUE DAMAGE)
Pathogen Associated
Molecular Patterns
(PAMPs)
Danger Associated
Molecular Patterns
(DAMPs = alarmines)
Pattern recognition Receptors (PRRs)
Signaling
Expression of Inflammation mediators
INFARCT HEALING AND LV REMODELING (MOUSE MODEL)
Cytokines
PMN /macrophages
Clearing debris
Frangogiannis Pharmacol Res 2008
Macrophages
Cytokines/growth factors
Fibroblasts/ endo. cells
Myofibroblats
Granulation tissue
Collagen scar
Dilative remodeling
SEQUENTIAL INFILTRATION OF REPERFUSED MYOCARDIUM
BY VARIOUS CELL TYPES
FIBROSIS, SCARRING AND ADVERSE LV REMODELING
Role of Galectine 3
Galectin‐3 binds and activates the myofibroblast leading to collagen synthesis
Macrophages carrying galectin‐3 infiltrate necrotic tissue
Macrophages release galectin‐3, leading to differentiation of fibroblasts into myofibroblasts
Collagen deposition results in scar formation
HEART FAILURE: ROUTINE EVALUATION
Clinical evaluation
Treatment: beta-blockers, ACEI, anti-aldosterone, ivabradine…
Imaging: Xray, echocardiography, MRI
Biomarkers (BNP / NT-ProBNP): diagnostic + follow-up
(ECHO/MRI) SURROGATE MARKERS IN AMI PATIENTS
GALECTINE 3: A NEW BIOMARKER
FOR HEART FAILURE
Galectin-3
the molecule and its role in disease
•
-galactoside-binding lectin
– Nucleus, cytoplasm, cell surface
– Binds to glycoconjugates on cell surfaces
and extracellular matrices
•
Demonstrated involvement in cancer,
inflammation, fibrosis and heart disease
•
Secreted by activated macrophages
– Link between inflammation and fibrosis
– Switch that turns queiescent fibroblasts into
activated collagen secreting myofibroblasts
Galectin-3 is a mediator of cardiac fibrogenesis contributing to
heat failure development and progression
Sharma CU et al. Circulation. 2004; 110: 3121-8
de Boer RA, et al. Eur J Heart Fail. 2009; 11: 811-7
19
GAL-3 AND ALDOSTERONE-INDUCED FIBROSIS
Data from pre-clinical models:
–
–
–
–
–
Aldosterone promotes Gal-3 expression and fibrosis
Gal-3 expression promotes fibrosis
Aldosterone blockers reduce fibrosis and Gal-3 expression
Direct inhibition of Gal-3 (e.g. with modified citrus pectin) reduces fibrosis
Gal-3 knock-out mice are resistant to aldosterone-induced fibrosis
Calvier L, et al. Arterioscler Thromb Vasc Biol. 2013; 33: 67-75
GALECTIN-3 MEDIATED HEART FAILURE
THE DISCOVERY
•
Hypertensive rats
–
•
Gal-3 production
Increased Gal-3 expression in rats that
developed HF
Gal-3 infusion in healthy rats
–
Increased collagen production
•
–
Predominantly ‘’stiff’’ collagen type I
(fibrotic phenotype)
Cardiac dysfunction (reduced LVEF)
Controls
Remained Developed HF
compensated
Collagen production
LVEF (%)
Placebo
(n=6)
Gal-3
(n=6)
Baseline
67
66
4-weeks
66
52 *
Placebo
(*) p<0.05
Sharma UC, et al. Circulation. 2004; 110: 3121-8
Placebo
Galectin-3
Galectin-3
COHORTS OF HEART FAILURE (HF) PATIENTS
PRIDE is a US cohort of acute HF patients, with mortality and HF
hospitalization events recorded over 60 days and long-term follow-up for
mortality over 4 years.
COACH is a Dutch cohort of moderate to severe chronic HF patients, with
mortality and HF hospitalization events recorded over a period of 18 months .
DEAL-HF is a Dutch cohort of severe chronic HF patients, with mortality
events recorded over 6.5 years.
HF-ACTION is a US cohort of predominantly moderately severe chronic HF
patients, with mortality and all-cause hospitalisation followed for a median of
2.5 years.
GAL-3 PREDICTS RISK FOR NEW-ONSET HF
Gal-3 measured in baseline samples from
Framingham Offspring Cohort

n=3353 (mean age 59 years)
Events recorded over 11.2 years


New-onset HF
HR 1.28 (1.14 – 1.43; p<0.0001)
166 HF
468 died
Higher Gal-3 is predictive of
new onset HF and all-cause mortality in
apparently healthy individuals
Men
Gal-3 (ng/mL)
Women
Gal-3
(ng/mL)
Q1
3.9 - 11.1
5.0 - 12.0
Q2
11.1 - 13.1
12.0 - 14.3
Q3
13.1 - 15.4
14.3 - 16.8
Q4
15.4 - 47.7
16.8 - 52.1
Ho, JE, et al. J Am Coll Cardiol. 2012; 60: 1249-56
Mortality
HR 1.15 (1.04 – 1.28; p=0.01)
ACUTE AND CHRONIC HF
ACUTE HF
PRIDE; 60-day all-cause mortality or
recurrent HF
CHRONIC HF
COACH; 1-year all-cause mortality
Gal-3 is elevated in HF, but not useful for diagnosis.
Gal-3 will not distinguish HF with reduced ejection fraction from HF with preserved
ejection fraction, or acute from decompensated HF.
PRIDE: van Kimmenade RR, et al. J Am Coll Cardiol. 2006; 48: 1217-24
COACH: de Boer RA, et al. Ann Med. 2011; 43: 60-8
PROGNOSTIC VALUE IN CHRONIC HF – CORONA COHORT
N
HR (95% CI)
Model-1
HR (95% CI)
Model-2
Low
(Gal-3 ≤ 17.8 ng/mL)
894
(64.5%)
1.00
1.00
Intermediate
(Gal-3 >17.8 – 25.9 ng/mL)
375
(27.0%)
1.26 (1.08-1.47)
(p=0.003)
1.18 (1.00-1.40)
(p=0.056)
High
(Gal-3 > 25.9 ng/mL)
118
(8.5%)
1.96 (1.57-2.44)
(p<0.001)
1.74 (1.33-2.28)
(p<0.001)
MODEL-1:
Multivariable model adjusted for age, sex,
NYHA class, LVEF, diabetes and smoking status
MODEL-2:
Model-1 + adjustment for NT-proBNP
CORONA cohort (N=1387):
-Mean age 72 years
-77% Male
-68% NYHA III/IV
-32% NYHA II
-Mean LVEF 32%
1
< 17.8 ng/mL
0.9
> 17.8 and < 25.9 ng/mL
> 25.9 ng/mL
0.8
Event-Free Survival Probability
Risk Category
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
200
400
600
800
1000
Days from Baseline to Death or Hospitalization
1200
1400
IMPACT OF CHANGES OVER TIME – COACH COHORT
592 HF patients who had been hospitalized for moderate to severe HF and were
followed for 18 months. The primary end-point was a composite of all-cause mortality
and HF hospitalization.
Cut-off (High vs. Low) = 17.8 ng/mL
115 (35.5%)
18 (5.6%)
58 (17.9%)
133 (41.0%)
Gal-3 cut-off (High vs.
Low) = 17.8 ng/mL
van der Velde AR, et al. Circ Heart Fail. 2013; 6: 219-26
58 (17.9%)
119 (37.7%)
147 (45.4%)
EVIDENCE FROM OBSERVATIONAL STUDIES
Study
Mean
age;
Gender
NYHA
III/IV (%)
Mean
LVEF (%)
Endpoint
Follow-up
Risk
ACUTE HF
PRIDE (1)
(n=209)
73 years
51% male
46
Mortality and HF
hospitalization (n=60)
60 days
OR=14.3
(p<0.001)
PRIDE (2)
(n=76)
65 years
56% male
46
Mortality (n=38)
4 years
HR=14.5
(p=0.001)
CHRONIC HF
COACH (3)
(n=592)
72 years
65% male
50
33
Mortality (n=164) and
HF hospitalization
(n=84)
18 months
HR=1.97
(p<0.001)
DEAL-HF (4)
(n=232)
71 years
72% male
100
31
Mortality (n=98)
6.5 years
HR=1.24
(p=0.003)
HF-ACTION (5)
(n=895)
59 years
71% male
37
24
Mortality (n=168) and
all-cause hospitalization
(n=469)
Median
2.5 years
HR=1.14
(p<0.0001)
1.
2.
3.
4.
5.
JACC. 2006; 48: 1217-24
Eur J Heart Fail. 2012; 12: 826-32
Ann Med. 2011; 43: 60-8
Clin Res Cardiol. 2010; 99: 323-8
Circ Heart Fail. 2012; 5: 72-8
CUT-OFF VALUES FOR PROGNOSIS
•
3 Categories of risk
– Low
≤ 17.8 ng/mL
– Intermediate
> 17.8 and ≤ 25.9 ng/mL
– High
>25.9 ng/mL
•
Approx. 50% have Gal-3 > 17.8 ng/mL
Compared with low-risk,
patients in high-risk category
have 2-fold higher risk for
death or rehospitalization
COACH study; CV mortality or HF hospitalization
HOSPITAL READMISSION
Elevated Gal-3 (>17.8 ng/mL) upon discharge is
associated with 2-fold higher risk for near-term
readmission for HF
Data from COACH
(n=582), PRIDE (n=181)
and UMD (n=129) cohorts
(total n=892)
de Boer R, et al. HFSA 2011
•
•
•
Repeated mesures of Gal-3
(baseline, 3-6 months) in 1653
HF patients (CORONA, COACH)
Prognosis value on
hospitalisation for HF and death
Evaluation of variation of Gal-3
(baseline):
•
•
•
•
Incidence hospitalisation for HF and death
Augmentation ≥15%
Pas de changement ± 15%
Réduction ≤ 15%
Adjusted for age, Gal-3 at
admission, NT-pro BNP, renal
function, LVEF and diabetes
+50% risque d’événement CV dans le groupe avec augmentation Gal‐3
TAKE HOME MESSAGE
Galectin-3 is a mediator of cardiac fibrogenesis contributing to heaRt failure
development and progression
Gal-3 is elevated in HF, but not useful for diagnosis.
GAL-3 helps predict heart failure and cardiovascular death in acute and
chronic HF patients (on top of ANP)
Gal-3 will not distinguish HF with reduced ejection fraction from HF with
preserved ejection fraction, or acute from decompensated HF
Reassessing Gal-3 levels at 3-6 month time interval seems reasonable.
Cut-off value for over-risk is 17.8 ng/ml
INFLAMMATION AND POST-INFARCTION HEALING
Mortensen. Circulation 2012
POST-INFARCTION REMODELING OF THE LEFT VENTRICLE