Structure of LipoproteinsStructure of LipoproteinsFree cholesterolFree cholesterol

PhospholipidPhospholipid TriglycerideTriglyceride

Cholesteryl esterCholesteryl esterApolipoproteinApolipoprotein

LDL-Cholesterol

• Strongly associated with atherosclerosisand CHD events

• 10% increase results in a 20% increasein CHD risk

• Risk associated with LDL-C is increased by other risk factors:– low HDL-cholesterol– smoking– hypertension– diabetes

LDL-Cholesterol

• Strongly associated with atherosclerosisand CHD events

• 10% increase results in a 20% increasein CHD risk

• Risk associated with LDL-C is increased by other risk factors:– low HDL-cholesterol– smoking– hypertension– diabetes

HDL-Cholesterol

• HDL-cholesterol has a protective effect for risk of atherosclerosis and CHD

• The lower the HDL-cholesterol level, the higher the risk for atherosclerosis and CHD– low level (<40 mg/dL) increases risk

• HDL-cholesterol tends to be low when triglycerides are high

• HDL-cholesterol is lowered by smoking, obesity and physical inactivity

Triglycerides• Associated with increased risk of CHD events• Link with increased CHD risk is complex

– may be related to:• low HDL levels

• highly atherogenic forms of LDL-cholesterol

• hyperinsulinaemia/insulin resistance

• procoagulation state

• hypertension

• abdominal obesity

• May have accompanying dyslipidaemias• Normal triglyceride levels <150 mg/dL• Very high triglycerides (>1000 mg/dL,

11.3 mmol/L) increase pancreatitis risk

Cardiovascular disease is the leading cause

of death among adults worldwide (1996)Coronary disease 7.2 million

Cancer 6.3

Cerebrovascular disease 4.6

Acute lower respiratory tract infections 3.9

Tuberculosis 3.0

COPD (chronic obstructive pulmonary disease) 2.9

Diarrhea (including dysentery) 2.5

Malaria 2.1

AIDS 1.5

Hepatitis B 1.2

Adapted from Adapted from Ross RRoss R. N Engl J Med. N Engl J Med 1999; 1999;362362:115–126:115–126Adapted from Adapted from Ross RRoss R. N Engl J Med. N Engl J Med 1999; 1999;362362:115–126:115–126

Endothelial Dysfunction in Atherosclerosis

Upregulation of endothelial

adhesion molecules

Upregulation of endothelial

adhesion molecules

Increased endothelial

permeability

Increased endothelial

permeability

Migration of leukocytesinto the

artery wall

Migration of leukocytesinto the

artery wall

Leukocyteadhesion

Leukocyteadhesion

Adapted from Ross R. N Engl J Med 1999;362:115–126Adapted from Ross R. N Engl J Med 1999;362:115–126

Fatty Streak Formation in Atherosclerosis

Formationof foam cellsFormation

of foam cells

Activation of T cellsActivation of T cells

Adherence and aggregation ofplatelets

Adherence and aggregation ofplatelets

Adherence andentry of

leukocytes

Adherence andentry of

leukocytes

Migration ofsmooth

muscle cells

Migration ofsmooth

muscle cells

Adapted from Ross R. N Engl J Med 1999;362:115–126Adapted from Ross R. N Engl J Med 1999;362:115–126

Formation of the Complicated Atherosclerotic Plaque

Formation of the fibrous capFormation of

the fibrous cap

Accumulation ofmacrophages

Accumulation ofmacrophages

Formation ofnecrotic coreFormation ofnecrotic core

Adapted from Ross R. N Engl J Med 1999;362:115–126Adapted from Ross R. N Engl J Med 1999;362:115–126

The Unstable Atherosclerotic Plaque

Rupture of the

fibrous cap

Rupture of the

fibrous cap

Thinning of thefibrous cap

Thinning of thefibrous cap Haemorrhage from

plaquemicrovessels

Haemorrhage from plaque

microvessels

Adapted from Weissberg PL. Eur Heart J Supplements 1999:1:T13–18Adapted from Weissberg PL. Eur Heart J Supplements 1999:1:T13–18

Atherosclerotic Plaque Rupture and Thrombus

FormationIntraluminal thrombusIntraluminal thrombus

Growth of thrombusGrowth of thrombus

Intraplaque thrombusIntraplaque thrombus Lipid poolLipid pool

Blood FlowBlood Flow

Adapted from Libby P. Circulation 1995;91:2844–2850Adapted from Libby P. Circulation 1995;91:2844–2850

The Vulnerable Atherosclerotic Plaque

IntestineIntestine

Skeletal muscleSkeletal muscle

Adipose tissue

Adipose tissue

ChylomicronChylomicron

Chylomicron remnant

Chylomicron remnant

Remnant receptorRemnant receptor

LiverLiver

Dietary triglycerides and cholesterol

Dietary triglycerides and cholesterol

LP lipaseLP lipase

Exogenous Pathway of Lipid Metabolism

Exogenous Pathway of Lipid Exogenous Pathway of Lipid MetabolismMetabolism

to atheromato atheroma

FFAFFA

Endogenous Pathway of Lipid Metabolism

Endogenous Pathway of Lipid Endogenous Pathway of Lipid MetabolismMetabolism

IDLIDLIDL

Large VLDL

Large VLDL

SmallVLDLSmallVLDL

LDLreceptorLDLreceptor

LiverLiver

LPL Lipoprotein lipaseLPL Lipoprotein lipase

HL Hepatic lipaseHL Hepatic lipase

LDLLDL

LPLLPL

LPLLPL

LPLLPL

HLHL

HLHL

HLHL

Reverse cholesterol transportReverse Cholesterol Transport

Peripheraltissuestissues

CellCell

membranemembrane

VLDL, IDL, LDLVLDL, IDL, LDL

LDLLDL receptorreceptor

LCATLCAT CETPCETPFCFC

CECECECE

TGTGHDLHDL HDL3HDL3

TGTGCECE

Free cholesterolFree cholesterolTriglyceridesTriglyceridesCholesterol estersCholesterol esters

CETPCETP Cholesteryl ester transfer proteinCholesteryl ester transfer proteinLCATLCAT Lecithin cholesterol acyl transferaseLecithin cholesterol acyl transferase

SRB1SRB1

FCFC

ABCA1ABCA1

LiverLiver

Adapted from Libby P. Circulation 1995;91:2844–2850Adapted from Libby P. Circulation 1995;91:2844–2850

The Synthesis and Breakdown of Atheromatous

Plaques

Statins and Lipid-modifying Statins and Lipid-modifying TherapiesTherapies

Statins and Lipid-modifying Statins and Lipid-modifying TherapiesTherapies

Mechanism of Action of Statins: Cholesterol Synthesis Pathway

acetyl CoAacetyl CoA

HMG-CoAHMG-CoA

squalenesqualene

cholesterolcholesterol

HMG-CoA synthaseHMG-CoA synthase

HMG-CoA reductaseHMG-CoA reductase

XX StatinsStatins

Metabolismelemak

• The global epidemic of modern living

ATHEROSCLEROSIS

Coronary mortality:alarming worldwide forecasts

Atherosclerosis:a multifactorial disease

Main risk factors for coronary heart disease

Atherosclerosis

Arterial wall:structure and function

~10% Weight loss = ~30% Visceral

adipose tissue loss

Classification of lipids and lipoproteins

Characteristics of lipoproteins

Triglyceride-rich lipoproteins:size, structure and composition

Digestion and metabolism of dietary fat

How to reduce plaque formationIntervention on risk factors