UN MARQUEUR INNOVANT DE L INSUFFISANCE CARDIAQUE: LA GALECTINE

Transcription

1 ACNBH ODPC N ème Colloque National des Biologistes des Hôpitaux Strasbourg, 1 4 octobre 2013 UN MARQUEUR INNOVANT DE L INSUFFISANCE CARDIAQUE: LA GALECTINE Michel Ovize Hôpital Cardiologique et Inserm U1060-CarMeN Université Claude Bernard Lyon 1, France

2 ACNBH ODPC N ème Colloque National des Biologistes des Hôpitaux Strasbourg, 1 4 octobre 2013 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.

3 GALECTINE 3 LV REMODELING AND HEART FAILURE

4 HEART FAILURE FOLLOWING ACUTE MYOCARDIAL INFARCTION 1 ACUTE ISCHEMIA-REPERFUSION INJURY INFARCT SIZE HEART FAILURE LV REMODELING 2 INFLAMMATION AND TISSUE HEALING

5 INFARCT SIZE IS A DETERMINANT OF MORTALITY Gibbons et al. JACC 2004;44: Kelle et al. JACC 2009

6 INFARCT SIZE - LV REMODELING HEART FAILURE -SURVIVAL Baks et al. EHJ 2005 Bolognese et al. Circ 2002

7 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

8 INFARCTION: A TWO-COMPONENT DAMAGE Final Infarct size Ischemia Reperfusion Reperfusion salvage No Reperfusion Postcond effect reperfusion injury Control Postcond ischemic injury PreC coronary occlusion Postconditioning time Garcia-Dorado et al. CVR 2006

9 REPERFUSION INJURY: THE NEGLECTED TARGET Onset of chest pain First medical care Cath lab admission Reperfusion therapy 30 minutes to 12 hours CORONARY ARTERY OCCLUSION Treatment? _ Reperfusion necrosis Treatment? _ Reperfusion inflammation LV REMODELING HEART FAILURE

10 INFLAMMATION FOLLOWING ACUTE INFARCTION Acute RCA occlusion Neutrophils Infiltration 48hrs post infarction

11 POST-INFARCTION LV REMODELING AND STERILE INFLAMMATION Fibroblastes DAMPs Mɸ Mort cellulaire C3 C5 TL MEC PNN DC Endothélium Angiogénèse

12 IMMUNITY AND INFLAMMATION: THE «DANGER» MODEL Danger EXOGENOUS (INFECTION) ENDOGENOUS (TISSUE DAMAGE) Signature Pathogen Associated Molecular Patterns (PAMPs) Danger Associated Molecular Patterns (DAMPs = alarmines) Sensors Pattern recognition Receptors (PRRs) Transmission Signaling Response Expression of Inflammation mediators

13 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

14 SEQUENTIAL INFILTRATION OF REPERFUSED MYOCARDIUM BY VARIOUS CELL TYPES

15 FIBROSIS, SCARRING AND ADVERSE LV REMODELING Role of Galectine 3 Galectin 3 binds and activates the myofibroblast leading to collagen synthesis Collagen deposition results in scar formation Macrophages carrying galectin 3 infiltrate necrotic tissue Macrophages release galectin 3, leading to differentiation of fibroblasts into myofibroblasts

16 HEART FAILURE: ROUTINE EVALUATION Clinical evaluation Treatment: beta-blockers, ACEI, anti-aldosterone, ivabradine Imaging: Xray, echocardiography, MRI Biomarkers (BNP / NT-ProBNP): diagnostic + follow-up

17 (ECHO/MRI) SURROGATE MARKERS IN AMI PATIENTS

18 GALECTINE 3: A NEW BIOMARKER FOR HEART FAILURE

19 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: de Boer RA, et al. Eur J Heart Fail. 2009; 11:

20 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

21 GALECTIN-3 MEDIATED HEART FAILURE THE DISCOVERY Hypertensive rats 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) Gal-3 production Controls Remained compensated Developed HF Collagen production LVEF (%) Placebo (n=6) Gal-3 (n=6) Baseline weeks * (*) p<0.05 Placebo Galectin-3 Sharma UC, et al. Circulation. 2004; 110: Placebo Galectin-3

22 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.

23 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 166 HF 468 died Higher Gal-3 is predictive of new onset HF and all-cause mortality in apparently healthy individuals New-onset HF HR 1.28 ( ; p<0.0001) Men Gal-3 (ng/ml) Women Gal-3 (ng/ml) Mortality Q HR 1.15 ( ; p=0.01) Q Q Q Ho, JE, et al. J Am Coll Cardiol. 2012; 60:

24 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: COACH: de Boer RA, et al. Ann Med. 2011; 43: 60-8

25 PROGNOSTIC VALUE IN CHRONIC HF CORONA COHORT Risk Category N HR (95% CI) Model-1 Low (Gal ng/ml) Intermediate (Gal-3 > ng/ml) High (Gal-3 > 25.9 ng/ml) 894 (64.5%) 375 (27.0%) 118 (8.5%) HR (95% CI) Model ( ) (p=0.003) 1.96 ( ) (p<0.001) 1.18 ( ) (p=0.056) 1.74 ( ) (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% Event-Free Survival Probability < 17.8 ng/ml > 17.8 and < 25.9 ng/ml > 25.9 ng/ml Days from Baseline to Death or Hospitalization

26 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 58 (17.9%) 119 (37.7%) 147 (45.4%) van der Velde AR, et al. Circ Heart Fail. 2013; 6:

27 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 Mortality (n=164) and HF hospitalization (n=84) 18 months HR=1.97 (p<0.001) DEAL-HF (4) (n=232) HF-ACTION (5) (n=895) 71 years 72% male 59 years 71% male Mortality (n=98) 6.5 years HR=1.24 (p=0.003) Mortality (n=168) and all-cause hospitalization (n=469) Median 2.5 years HR=1.14 (p<0.0001) 1. JACC. 2006; 48: Eur J Heart Fail. 2012; 12: Ann Med. 2011; 43: Clin Res Cardiol. 2010; 99: Circ Heart Fail. 2012; 5: 72-8

28 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

29 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

30 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): Augmentation 15% Pas de changement ± 15% Réduction 15% Adjusted for age, Gal-3 at admission, NT-pro BNP, renal function, LVEF and diabetes Incidence hospitalisation for HF and death +50% risque d événement CV dans le groupe avec augmentation Gal 3

31 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

32 INFLAMMATION AND POST-INFARCTION HEALING Mortensen. Circulation 2012

33 POST-INFARCTION REMODELING OF THE LEFT VENTRICLE