Blood Lipids and Lipoproteins

and Cardiovascular Disease

Risk - III

Prof. Abayomi Akanji

Clinical Chemistry Unit
Department of Pathology
Faculty of Medicine
 Major Risk Factors (Exclusive of LDL
Cholesterol) That Modify LDL Goals
• Cigarette smoking
• Hypertension (BP ≥140/90 mmHg or on antiBP treatment
• Low HDL cholesterol (<40 mg/dL)†
• Family history of premature CHD
– CHD in male first degree relative <55 years
– CHD in female first degree relative <65 years
• Age (men ≥45 years; women ≥55 years)

Focus on Multiple Risk Factors

• Diabetes: CHD risk equivalent

• Multiple metabolic risk factors (metabolic syndrome)

†
HDL cholesterol ≥60 mg/dL counts as a “negative” risk factor; its
presence removes one risk factor from the total count.
 LDL Cholesterol
• Remains the cornerstone of dyslipidaemia therapy
• Strongly associated with atherosclerosis and CHD
• 10% increase results in a 20% increase in CHD
risk
• Most patients with elevated LDL untreated:
– only 4.5 million out of 28.4 million treated

1. Wood D et al. Atherosclerosis. 1998;140:199-270.

2. National Centre for Health Statistics. National Health and Nutrition
Examination Survey (III), 1994.
3. Jacobson TA, et al. Arch Intern Med. 2000;160:1361-1369.
 Increased Relative Risk of CHD
Associated With Increasing LDL Levels
ARIC Study
4.50 Men
Relative Risk of CHD

2.85

1.80 Adjusted for age and race

12-year follow-up
n = 5432
1.15

0.75
2.35 2.85 3.35 3.85 4.35 4.85 (mmol/L)
91 110 130 149 168 188 (mg/dL)
LDL Cholesterol

Adapted from Sharrett AR, et al. Circulation. 2001;104:1108-1113.

 Increased Relative Risk of CHD
Associated With Increasing LDL Levels
ARIC Study
Women
4.50
Relative Risk of CHD

2.85

1.80 Adjusted for age and race

12-year follow-up
n = 6907
1.15

0.75
2.15 2.65 3.15 3.65 4.15 4.55 (mmol/L)

84 103 123 142 162 177 (mg/dL)

LDL Cholesterol
Adapted from Sharrett AR, et al. Circulation. 2001;104:1108-1113.
LDL is the most Atherogenic Lipoprotein

R
ZA

BI
The quality and quantity of circulating

OH
D OH A

AZ
LDL particles are more important
BI

RDA
determinants of LDL atherogenicity
than its cholesterol content

BIOHAZARD
 Lowering cholesterol is
effective and safe in
hypercholesterolemic patients
with evidence of CHD and
leads to a reduction in
coronary events.

4S Group. Lancet. 1994;344:1383-1389.

Beyond
LDL
LDL Reduction and CHD Risk
The latest studies have confirmed the
positive correlation between CAD risk and
lowering cholesterol

• LDL reduction in primary and secondary prevention

can significantly reduce clinical cardiac events
• It can also significantly reduce the rate of
arteriographically defined disease progression

However, elevated LDL is only one of several

factors contributing to CAD risk
Benefit Beyond LDL Lowering: The Metabolic
Syndrome as a Secondary Target of Therapy
General Features of the Metabolic Syndrome
• Abdominal obesity
• Atherogenic dyslipidaemia
– Elevated triglycerides
– Small LDL particles
– Low HDL cholesterol
• Raised blood pressure
• Insulin resistance (± glucose intolerance)
• Pro-thrombotic state
• Pro-inflammatory state
Obese patients are
at ▲ CVD risk:
risk factors must be
treated early and
optimally. Effective
treatment to
prevent underlying
cause (body fat
accumulation)
would make better
clinical & economic
sense and is now
accepted as a
reasonable target
for drug
development
Stereotypical apple
(metabolically
harmful, more
common in men)
and pear
(metabolically
protective and more
common in women)
shapes. Making
obesity an object of
humour has
impeded the
understanding of its
medical
consequences.
Obesity can
contribute to
musculoskeletal and
psychological
problems and have
profound effects on
quality of life
CHD Risk Factors Beyond LDL
• Triglycerides
• HDL
• Small, dense LDL
• Apo CIII
• Lp(a)
• Homocysteine
• Fibrinogen
 HDL: A Major Risk Factor for CHD

• A low plasma HDL is an important risk factor

for CHD in the general population
• A high level of HDL may confer
cardioprotection
• Reverse cholesterol transport by HDL may be
the principle cardioprotective mechanism

On average, a 10% decrease in CHD risk occurs for each

increase of 4 mg/dL in the HDL level.
The ILIB Lipid Handbook for Clinical Practice. 1995:26.
HDL: Major Factor in Predicting
Reduced CAD
N=4407
120

100
Incidence of CHD (per
1000 in 6 years)

80

60

40

20

0
<35 35 - 55 >55
HDL-cholesterol (mg/dL)
Assmann G, et al. Atherosclerosis. 1996;124(suppl):S11-S20.
 HDL in Clinical Practice
• Routinely measured in all adult patients
• HDL-C <0.9mmol/L is a major risk factor
• Nonpharmacologic therapy (exercise, weight
loss, smoking cessation)
• Pharmacologic therapy

Consider drug therapy that lowers LDL-C

and also increases HDL-C levels.
Expert Panel. JAMA. 1993;269:3015-3023.
Possible Atherogenic Changes
Accompanying Hypertriglyceridemia
Increased VLDL Small,
cholesterol-rich Low HDL dense LDL
remnants

Hypertriglyceridemia

Coagulation Increased
changes chylomicron
remnants
Miller M. Eur Heart J. 1998;19(Suppl H):H18-H22.
 Risk of CHD by Triglyceride Level
(The Framingham Heart Study)
N=5127

3
Men Women
2.5
Relative Risk

1.5

0.5

0
50 100 150 200 250 300 350 400
TG Level (mg/dL) Castelli WP. Am J Cardiol. 1992;70: 3H-9H.
 The Copenhagen Male Study
Adjusted IHD Incidence Rates
N=2906
2.5
Adjusted for
Compared With Lowest Tertile

2 • Age
• BMI
• Alcohol use
1.5 • Smoking
• Physical
activity
1
• Hypertension
• NIDDM
0.5 • Social class
• LDL
0 • HDL
Lowest Middle Highest
Tertile of TG Level
Jeppesen J, et al. Circulation. 1998;97:1029-1036.
 Small, Dense LDL
• Dangerous: Small, dense LDL trait
increases heart disease risk up to three fold
• Common: 40% to 50% of men with heart
disease have small, dense LDL
• Measurable: Tests are now available to
physicians
• Treatable: Approaches can involve lifestyle
changes and/or drugs
The ILIB Lipid Handbook for Clinical Practice. 1995:26.
Austin MA, et al. JAMA. 1988;260(13):1917-1921.
Atherogenicity of Small, Dense LDL
Endothelial
LDL Chemoattractants
Endothelium Monocyte

LDL Macrophag
e
Mildly oxidized
Macrophage

Foam Cell
Smooth
Muscle Cell Highly oxidized

Evidence from in vitro studies suggests that large, buoyant LDL particles are
more resistant to oxidative stress and small, dense LDL particles more
susceptible to oxidation.
 Elevated Plasma Fibrinogen
A Major, Independent Cardiovascular
Risk Factor

• Epidemiological studies
• Cross-sectional analyses
• Clinical cohort studies

There is a sizeable body of evidence

identifying fibrinogen as a major,
independent cardiovascular risk factor
Ernst E, et al. Eur Heart J. 1995;16(supplA):47-53.
 Lipoprotein (a)
• A low density lipoprotein (LDL)-like particle that may be
involved in both atherogenesis and thrombogenesis
• contains apoB100 and Apo(a)
• Apo(a) has strong structural homology with plasminogen,
and is recognized by the plasminogen receptor. It is
heterogeneous because of differences in numbers of
repeats
• Levels of plasma Lp(a) differ between individuals but
remain constant in the same individual – levels are
unrelated to those of other lipoproteins
• Factors influencing plasma levels include: age, diet,
genetics, race, hormones such as insulin and estrogen,
liver and kidney function
• An important risk factor for atherogenesis by its
competition with plasminogen
 Lipid and Lipoprotein Classification
LDL Cholesterol HDL Cholesterol (mmol/L)
(mmol/L) <1.03 Low
<2.60 Optimal ≥1.55 High
2.60–3.39 Near optimal Total Cholesterol
/above optimal (mmol/L)
3.40–4.09 Borderline high
< 5.2 Desirable
4.10–4.89 High
5.2 – 6.2 Borderline high
≥4.90 Very high
≥ 6.2 High
 Primary Prevention With
LDL-Lowering Therapy
Public Health Approach

• Reduced intakes of saturated fat and

cholesterol
• Increased physical activity
• Weight control