Lefflux de cholestrol Pr Johanne SILVAIN johanne.silvain@aphp.fr 1 - PowerPoint PPT Presentation

L’efflux de cholestérol Pr Johanne SILVAIN johanne.silvain@aphp.fr 1 Sorbonne Université 2 ACTION Study Group 3 INSERM UMRS 1166 ICAN 4 Institut de Cardiologie (APHP) www.action- cœur.org PITIE-SALPETRIERE UNIVERSITY HOSPITAL

Disclosures DISCLOSURE STATEMENT OF FINANCIAL INTEREST Johanne SILVAIN MD, PhD Consulting fees, Speaker honorariums or Travel support from from Algorythm, Amed, Astra-Zeneca , Bayer, Boeringher Ingelheim, CLS Bering, Gilead Science, Sanofi-Aventis, Web MD Amgen, Astra-Zeneca and Saint-Jude Medical

Quel est l’impact du Choléstérol sur le risque de 1 er Evenement Cardiovasculaire ?

Combinaison polygénique 500 000 Anglais bien portants Score Génétique composé de 1.7 millions de variants Inouye M. J Am Coll Cardiol. 2018

Prédiction de 75% du risque 4 FACTEURS Pas de Tabac Pas de surpoids (IMC <30) Activité Physique une fois / semaine Alimentation équilibrée Inouye M. J Am Coll Cardiol. 2018 Khera AV et al. N Engl J Med 2016

Et le choléstérol alors ?

« Le bon » HDL « La brute » LDL « Le truand » Triglycérides « Les oubliés » Lp(a) Inflammation

Taux de LDL choléstérol et Coronaires LDLC (mg/dL) LDL Levels in 136,905 Patients Hospitalized With CAD Sachdeva et al, Am Heart J 2009

Non-HDL Choléstérol LDL, TG , Lp(a) Brunner F et al, Lancet 2019

Non-HDL Choléstérol LDL, TG , Lp(a) Brunner F et al, Lancet 2019

Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis n= 996 patients (case control study) OR for Coronary Artery Disease According to Efflux Capacity and Selected Risk Factors. Khera AV et al. N Engl J Med 2011;364:127-35.

What is Efflux Capacity ? 1) Global cholesterol efflux capacity , a biomarker that integrates contributors and modulators of the initial step of the reverse cholesterol transport, has been associated with atherosclerosis independently of HDL-Cholesterol level.

Silvain J et al. JACC 218

L’Efflux de choléstérol A- Serum Cholesterol Efflux Capacity = Nettoyage de nos vaisseaux

HDL Cholesterol Efflux Capacity and Incident Cardiovascular Events n= 2924 adults free from cardiovascular disease Dallas Heart Study, Rohatgi A et al. N Engl J Med 2014;371:2383-93.

The failure of HDL 2) HDL raising drugs (niacin but mostly CETP inhibitors) failed to prevent cardiovascular events and decreased mortality despite an increase in HDL levels, demonstrating that steady state HDL-Cholesterol levels do not represent the most appropriate risk factor index

HDL therapies Rader DJ et al. Lancet 2014.

NIACIN => Landray MJ et al. N Engl J Med. 2014 => Boden WE et al. N Engl J Med. 2011 TORCETRAPID => Barter PJ et al. ILLUMINATE Trial. N Engl J Med. 2007 DALCETRAPID => Schwartz GG et al. dal-OUTCOMES. N Engl J Med. 2012 HDL INFUSIONS => Tardif JC et al. Eur Heart J. 2014 Lincoff MA et al. ACCELERATE. N Engl J Med. 2017

Limitations 1/ Failure to raise functional HDL => Cholesterol Efflux +++ 2/ Bad Timing ? = long-term pharmacotherapy was intitiated in the chronic phase and not in the post MI period. = target in primary prevention ? 3/ Patients with high modifiable risk 4/ Off-target toxicity ?

Un bon efflux de cholestérol = 56% de moins de 1 er Evènement Cardiovasculaire Rohatgi A et al. N Engl J Med 2014

*Drs. Guerin and Silvain are first authors Silvain J et al. JACC 218

Un bon efflux de cholestérol = 46% de mortalité en moins après un infarctus n= 1609 STEMI patients Silvain J et al. JACC 218

Serum cholesterol efflux capacity and mortality in STEMI patients Silvain J et al. JACC 218

Silvain J et al. JACC 218

Nambi V et al. JACC 2018

Essai Clinique AEGIS-2 = Infusion de HDL recombinant (CSL- 112) ou “Bon Choléstérol “ chez des patients souffrants d’un infarctus et à risque de récidive pour booster leur Efflux de Cholestérol

Conclusion • Non-HDL cholesterol and inflammation are probably more important than LDL alone as risk factor for 1 st CV events. • CETP activity and HDL cholesterol do not reflect the cardiovascular risk of patients • “Reverse cholesterol transport” measured by global cholesterol efflux capacity, is independently associated with atherosclerosis, 1 st CV events and long term survival in post MI patients. • HDL function is a new biomarker to identify patients at higher risk of CV events and mortality and should be a target for atheroprotection

Merci Pr Johanne SILVAIN johanne.silvain@aphp.fr 1 Sorbonne Université 2 ACTION Study Group 3 INSERM UMRS 1166 ICAN 4 Institut de Cardiologie (APHP) www.action- cœur.org PITIE-SALPETRIERE UNIVERSITY HOSPITAL