Break the Fast:
“Lipids, lipoproteins, and apolipoproteins as
risk markers of myocardial infarction in 52
countries (the INTERHEART study):
a case-control study.”
Journal Club 9/10/08
Background
• Coronary Heart Disease is now the major
cause of death worldwide
Brunzell JD, et al. JACC 2008; 51: 1513
Clinically Important Lipoprotein Parameters
• Parameters should be easily measured, have
available treatment strategies and strategies should
reduce cardiovascular events
• LDL cholesterol:
major predictor of CVD and lowering
LDL lowers CVD events but limitations: LDL cholesterol is
estimated (Friedewald equation) which progressively
underestimates LDL cholesterol as TG levels , not as
predictive in the elderly, individual variability, influenced by
disease states, AND even with adequate lowering, significant
residual risk remains; requires fasting
• HDL:
strong inverse predictors of CVD events; non-
fasting
• Non-HDL cholesterol:
ATP III guidelines suggest
using this as secondary goal after LDL in patients with
hypertriglyceridemia; non-fasting
Some New Parameters
• LDL particle number:
shown to be better
predictor of risk and can be calculated using nuclear
magnetic resonance (NMR) but not widely available and
currently $$$
• ApoB-100:
found in atherogenic VLDL, IDL, and
LDL with each particle containing single apoB molecule;
non-fasting sample; found to be a better predictor of CVD
risk than LDL cholesterol, especially on-treatment one as
statins lower non-HDL cholesterol more than they lower
apoB
An LDL particle
A low-density lipoprotein (LDL) particle
contains a core of about 1500 cholesterol
molecules bonded to long-chain fatty acids
that is surrounded by a lipid monolayer. A
single molecule of a 500,000-dalton
protein (an apolipoprotein) organizes the
particle and mediates the specific binding
of LDL to its receptor on other cells. Of
note, there is a 1:1 relationship between
protein and the LDL particle.
Alberts, et. al. Molecular Biology of the Cell, 4th edition, 2002
Properties of Plasma Lipoproteins
Lipoprotein
Apoproteins
Chylomicron
B-100, B-48, C, E
VLDL (very low density)
B-100, C, E
IDL (intermediate density) B-100, E
LDL (low density)
B-100
Lipoprotein (a)
B-100
HDL (high density)
A
Adapted from Berg, et. al. Biochemistry, 5th ed. 2002: 727.
Consensus Statement of the ADA and ACC
• “Because apoB appears to be a more sensitive index of
residual CVD risk when LDL cholesterol or non-HDL
cholesterol are < 130 mg/dl or < 160 mg/dl, respectively,
measurement of apoB, using a standardized assay, is
warranted in patients with CMR on pharmacologic
treatment. In particular, apoB levels should be used to
guide adjustments of therapy.”
Brunzell JD, et al. JACC 2008; 51: 1513
Study Outline
• Hypothesis:
lipoproteins are better markers than lipids
for risk of coronary heart disease
• Study Design: case-control
• Setting: hospital admissions from 262 centers in 52 countries
• Participants:
– CASES: 12, 461 individuals admitted with a first acute
MI screened within 24 hours of initial symptoms
– CONTROLS: 14, 637 age-matched and sex-matched
• Hospital-based (58%): admitted to same hospital as matched
cases without known CAD
• Community based (36%): attendants or relatives of patients from
a non-cardiac ward or unrelated attendant of a cardiac patient
• 3% from WHO MONICA study, 3% undocumented source
Study Outline Continued
• Data Collection:
non-fasting blood samples obtained
and concentrations of TC, HDL cholesterol, ApoA1 and
ApoB-100 measured
• Analytic Method:
odds ratio and populationattributable risk, using ANOVA logistic regression
Study participants with myocardial
infarction and controls by ethnic origin
Concentrations of Lipids and their
Ratios in Cases and Controls
Figure 1: Risk of
myocardial infarction for
increasing decile medians
(adjusted for age, sex, and
region) of (A) lipids,
lipoproteins, and
apolipoproteins and (B)
ratios of apolipoprotein
B/apolipoprotein A1 and
total cholesterol/HDL
cholesterol
Note the doubling scale on the
y axis for both fi gures.
ApoA1=apolipoprotein A1.
ApoB=apolipoprotein B100.
Change in risk of MI (Odds ratios, 95% CI) with 1
SD change in parameter
1 SD
change
TC
HDL
NonHDL
ApoA1
ApoB
TC /
HDL
ApoB /
ApoA1
1.16
(1.13 –
1.19)
0.85
(0.83 –
0.88)
1.21
(1.17 –
1.24)
0.67
(0.65 –
0.70)
1.32
(1.28 –
1.36)
1.17
(1.13 –
1.20)
1.59
(1.52 –
1.64)
Stratification by Age
A Look at Population Attributable Risk
(PAR)
Conclusions
• ApoB/ApoA1 ratio was better risk marker of
myocardial infarction than ratio of total
cholesterol/HDL cholesterol
• This was seen in nearly all ethnic groups, both
sexes and all age groups
• Depending on costs and added risk to expanding
treatment, ApoB and ApoA1 may replace lipid
measures especially in older age groups or in nonfasting patients
• These measures can be used in clinical practice
for assessment of risk of vascular disease and to
determine adequacy of cholesterol-lowering
treatment
What It’ll Cost You – at JHH
• Lipid profile - $31.42
• Apo B - $24.81
• Apo A1 - $24.81
Strengths
• Large number of study patients
• Inclusion of many ethnic groups
• Large generalizability
Weaknesses
• Controls – concern for selection bias; no
baseline characteristics table to determine
effectiveness of matching
• Retrospective
• Cholesterol measurement in different labs
• Small percentage of Africans in this study
References
• Brunzell JD, et al. Lipoprotein management in patients with
cardiometabolic risk: consensus conference report from the American
diabetes Association and the American College of Cardiology
Foundation. J Am Coll Cardiol 2008; 51: 1512 – 24.
• Berg, JM, et al. Biochemistry, 5th edition, 2002: 727.
• Alberts, B et. al. Molecular Biology of the Cell, 4th edition, 2002.
• McQueen, MJ, et. al. Lipids, lipoproteins and apolipoproteins as risk
markers of myocardial infarction in 52 countries (the INTERHEART
study): a case-control study. Lancent 2008; 372: 224 – 232.