HANDBOOK OF DYSLIPIDEMIA AND ATHEROSCLEROSIS Part One Professor Jean-Charles Fruchart Department of Atherosclerosis (Inserm UR545) Pasteur Institute of Lille University of Lille II France

 The global epidemic of modern living ATHEROSCLEROSIS

Cardiovascular disease is the leading cause of death among adults worldwide (1996) Coronary disease7.2 million Cancer6.3 Cerebrovascular disease4.6 Acute lower respiratory tract infections3.9 Tuberculosis3.0 COPD (chronic obstructive pulmonary disease)2.9 Diarrhea (including dysentery)2.5 Malaria2.1 AIDS1.5 Hepatitis B1.2

Coronary mortality: alarming worldwide forecasts

Atherosclerosis: a multifactorial disease

Main risk factors for coronary heart disease

Global projections for the diabetes epidemic:

Atherosclerosis

 The stages of development of atherosclerosis PATHOPHYSIOLOGY

Arterial wall: structure and function

Different stages of atherosclerotic plaque development

Vascular endothelium modification in atherosclerosis

Plaque formation 1 — Fatty streak

Plaque formation 2 — Fibrous cap

Plaque formation 3 — Lipid core

From plaque to thrombosis, key event: plaque rupture

 The role of the macrophage PATHOPHYSIOLOGY

Plaque vulnerability Key role of macrophages

Vulnerable plaque Key role of the macrophage in vascular wall inflammation

Fibrinogen is an independent risk factor for atherosclerosis

Vulnerable plaque Key role of the macrophage in the degradation of the fibrous cap

Thrombus formation The macrophages release coagulation factors

Tissue factor: the initiator of coagulation and thrombogenesis in vivo

Oxidized LDL and thrombogenesis

Plaque disruption (plaque cracking, fissuring, rupture – thrombosis start point)

 The role of atherogenic lipoproteins PATHOPHYSIOLOGY

Lipid core constitution Activated macrophages accumulate lipids

Lipid core constitution LDL oxidation

Parietal vascular inflammation The activated macrophage produces inflammatory cytokines

Parietal vascular inflammation NF  B action in the inflammation process

 The influence of risk factors PATHOPHYSIOLOGY

Diabetes and atherosclerosis

Tobacco and atherosclerosis

Dyslipidemia and atherosclerosis

HTN, hemodynamic factor and atheroclerosis

How to reduce plaque formation Intervention on risk factors

 The goals of treatment PATHOPHYSIOLOGY

How to reduce the risk of plaque rupture

How to reduce the risk of thrombosis

~10% Weight loss = ~30% Visceral adipose tissue loss

Characteristics of an unstable plaque

Plaque vulnerability factors Intrinsic factors

Modification of extrinsic vulnerability factors

Plaque rupture The main releasing factors

 Synthesis and transport PHYSIOLOGY OF LIPIDS AND LIPOPROTEINS

Classification of lipids and lipoproteins

Characteristics of lipoproteins

Triglyceride-rich lipoproteins: size, structure and composition

Digestion and metabolism of dietary fat

HDL metabolism and reverse cholesterol transport

Cholesterol efflux and reverse cholesterol transport is modulated by two receptors

Atherogenicity of small dense LDL

 Atherogenicity PHYSIOLOGY OF LIPIDS AND LIPOPROTEINS

Size and apolipoprotein composition are the main factors determining atherogenicity of triglyceride-rich particles

Apo C-III modulates VLDL

Apo C-III in apo B particles is atherogenic

Relationship between apo C-III in apo B containing lipoproteins and atherogenicity

PROCAM Study MI-Incidence according to LDL-cholesterol and triglycerides

PROCAM Study CHD risk according to LDL-C and TG increased TG confers raised CHD risk at all levels of LDL-C

HDL: an anti-atherogenic lipoprotein

HDL metabolism: 5 key genes

HDL: apo AI-rich particles

Apo A-I protects against atherosclerosis

Apo A-II protects against atherosclerosis The human apo A-II transgenic mouse model