Inflammatie en residueel cardiovasculair risico Dept. of Internal - - PowerPoint PPT Presentation

Inflammatie en residueel cardiovasculair risico

Niels Riksen, MD, PhD

Professor of Vascular Medicine

• Dept. of Internal Medicine

Nijmegen, The Netherlands

Disclosure potential conflicts of interest

Residual risk

Sabatine, NEJM 2017, FOURIER

Residual risk

Residual risk

Lawler et al, Eur Heart J 2020 [ahead of print]

Inflammation

Biological response of the body to harmful stimuli, involving:

• Immune cells
• Blood vessels
• Molecular mediators

Characterized by:

• Dolor

Pijn

• Calor

Warmte

• Tumor

Zwelling

• Rubor

Roodheid

• Functio laesa

Functieverlies

Targeting inflammation

Zhao, JACC 2019

Recent large RCTs

Ridker, NEJM 2017 CANTOS

CANTOS

• Canakinumab, 50-150-300 mg, sc every 3

months

• N=10.061 patients with previous AMI,

and hsCRP > 2 mg/l

• More fatal infections/sepsis

CIRT

• Methotrexate, 15-20 mg/week
• N=4786 patients with previous AMI,

and DM type 2 or MetS

• No selection on hs-CRP

COLCOT

• Colchicine, 0.5 mg/day
• N=4745 patients within 30 days after

AMI, and hsCRP > 2 mg/l

• Cave more pneumonia

Tardif, NEJM 2019 COLCOT Ridker, NEJM 2019 CIRT

Residual inflammatory risk in CANTOS

Ridker, Eur Heart J 2020

Colchicine: LoDoCo2

Nidorf et al, NEJM 2020

Nidorf et al, NEJM 2020

Colchicine: LoDoCo2

Colchicine: mechanism of action

Nidorf & Thompson, Clin Ther 2019

Mechanistic insight into the LoDoCo2

Opstal, Circulation 2020

• N=174 patients in run in phase
• Targeted proteomics, 184 proteins

Attenuation of NLRP3 inflammasome:

• ↓ IL 18
• ↓ IL 1 RA

1 2 Largest reduction in proteins involved in neutrophil degranulation

• 1. Monocytes/macrophages
• IL1 pathway
• Clonal hematopoiesis
• 2. Neutrophils

Atherosclerosis: role of monocytes and macrophages

Libby et al, Nature 2011

The interleukin 1 pathway

Abbate, Circ Res 2020

IL1 family members of cytokines

Interleukin-1: local effects

Libby, JACC 2017

Ridker, Circ Res 2016

Interleukin-1: systemic effects

CRP

Kaptoge, Lancet 2010

IL6

Ridker, Circ Res 2016

Vromman, Eur Heart J 2019

The interleukin 1 pathway and atherosclerosis

Activation of the innate immune system in CVD

Bekkering, Atherosclerosis 2016 Riksen & Stienstra, Curr Opin Lipidol 2018

Clonal hematopoiesis of indeterminate potential (CHIP)

Courtesy to Alexander Hoischen Libby et al, JACC 2019

Jaiswal, NEJM 2017

CHIP and CVD

Fuster, Science 2017

TET2-/- 10% TET2-/- 90% TET2+/+

More IL1b Due to ↑ NLRP3 act NLRP3 inhibitor

Nahrendorf, Science 2015 Doring, ATVB 2020

Atherosclerosis: role of neutrophils

Neutrophils associated with future CVD

Fani, Plos Med 2020

• Rotterdam study cohort
• 7,730 participants,

without CVD at baseline

• 2002-2008

Fani, Plos Med 2020

Neutrophils associated with present atherosclerosis

Evidence at the progenitor cell level?

Circulating PBMC’s Bone marrow progenitors LPS and P3C Participant

CAC>400

Agatston or Total plaque score

Control Patient Patient CAC:1-400 and TPS>4

Study participants

• Men with/without severe coronary atherosclerosis
• Optimal lipid lowering therapy
• Exclusion of CVD, DM2, AID

Outcomes

• Immunophenotype in circulation
• Immunophenotype of the bone marrow
• Innate immune response
• Progenitor cell response
• Metabolism of monocytes and progenitors

Laszlo Groh Marlies Noz

Many CVD risk factors affect bone marrow progenitors

Schloss, Circ Res 2020

Take home messages

• Despite optimal risk factor control: residual inflammatory risk
• Elucidation of mechanisms key to develop/select specific anti-inflammatory drugs
• Colchicin effective in lowering CVD risk
• This suggests important roles for
• Inflammasome/IL1 pathway
• Neutrophils
• Novel pathways to explore:
• Reprograming of circulating innate immune cells and bone marrow progenitors
• Clonal hematopoiesis