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Macrovascular Residual Risk Studies

25 March 2011
ApoB/ApoA-I ratio best predictor of first myocardial infarction: INTERHEART
Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study. Lancet. 2008;372:224-33.
McQueen MJ, Hawken S, Wang X, Ounpuu S, Sniderman A, Probstfield J, Steyn K, Sanderson JE, Hasani M, Volkova E, Kazmi K, Yusuf S
Objective: To compare the apolipoproteins and cholesterol as indices for risk of acute myocardial infarction.
Type of study: Case control study
Study population:
  • Patients from 52 countries in Asia, central, eastern, and western Europe, Middle East, Africa, North America, and South America, and Australia and New Zealand, comprising:

    • 9345 cases with a first acute myocardial infarction
    • 12 120 controls
      • Hospital-based controls (58%) admitted to the same hospital as the matched cases without known cardiovascular disease
    Controls (36%) from the community: attendants or relatives of a patient from a non-cardiac ward or unrelated attendants of a cardiac patient
Inclusion criteria
  • Patients: admitted to the coronary-care unit or equivalent cardiology ward within 24 h of initial characteristic symptoms together with electrocardiogram changes indicating a new acute myocardial infarction.
  • Controls: no history of chest pain on exertion or known heart disease.
Exclusion criteria
  • Unavailability of non-fasting lipids measured in blood samples obtained within 2 hours of admission
  • Il all patients, measurement of non-fasting levels of total cholesterol, HDL cholesterol, triglycerides, ApoA-I, and ApoB, plus calculation of LDL cholesterol and non-HDL cholesterol, ApoB/ApoA1 ratio, and total cholesterol/HDL cholesterol
  • Calculation of odds ratios (OR), 95% confidence intervals (95% CI) and population-attributable risks for each measure by comparison of the top four quintiles (Q2-Q5) with the lowest quintile (Q1)
  • Calculation of OR for one standard deviation (SD) change in each measure
Main results:
  • Patients had higher total cholesterol, non-HDL cholesterol, and ApoB concentrations, and lower HDL cholesterol and ApoA-I concentrations than did controls
  • ApoB/ApoA-I ratio had both the highest population-attributable risk and the highest OR per 1-SD increase (Table)
    • Result consistent across all ethnic groups (Figure), age groups and independent of gender

Population-attributable risk and odds ratio per one standard-deviation increase in lipids, apolipoproteins, and their respective ratios

Lipid parameter or ratio


OR per 1-SD increase (95% CI)

Total cholesterol


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)

ApoB/ApoA-I ratio


1·59 (1·53–1·64).

TC/HDL-C ratio


1·17 (1·13–1·20)


Author's conclusion: The non-fasting ApoB/ApoA-I ratio was superior to any of the other non-fasting cholesterol ratios for estimation of the risk of acute myocardial infarction in all ethnic groups, in both sexes, and at all ages. ApoB and ApoA-I should be introduced worldwide into clinical practice for the assessment of the risk of vascular disease.

Figure. Change in risk of acute myocardial infarction associated with a 1-SD change in cholesterol and apolipoprotein ratios in different ethnic groups.


One of the main strengths of the INTERHEART study is that it was conducted in a large number of patients and a large number of controls. The authors stress that a large population size was mandatory to ensure that “real differences in predictive power would not be obscured by the close correlation that exists between cholesterol and apolipoproteins,” especially when comparisons were made inside each ethnic group. Indeed, except for apolipoprotein B48-containing chylomicrons (and their remnants), all other atherogenic lipoprotein particles contains a single molecule of apolipoprotein B100 (ApoB), including LDL, the predominant atherogenic lipoprotein. ApoA-I is the hallmark lipoprotein of HDL.

The main result of INTERHEART is that the ApoB/ApoA-I ratio is a substantially better predictor of myocardial infarction than cholesterol ratios (TC/HDL-C and LDL-C/HDL-C). ApoB, the numerator, was a better predictor than LDL cholesterol. This is consistent with the fact that in people with atherosclerotic disease, LDL-C may be less representative of the number of LDL particles, when the latter are small and dense (whereas ApoB is unaffected by lipoprotein size, and mostly accounts for LDL-related apolipoprotein) and/or when LDL-C is computed using Friedewald’s formula in patients with raised triglycerides. The ratio denominator, ApoA-I was a better inverse predictor than HDL-C.

The INTERHEART findings are in line with those of the AMORIS cohort study1 conducted in 69,030 men and 57,168 women. In particular, the risk associated with a 1-SD change in the ApoB/ApoA-I ratio was virtually identical in both studies.

The measurement of ApoB and ApoA-I is simple and can be done with samples obtained from fasting or non-fasting individuals. The authors recommend to include these apolipoproteins in routine assessment of cardiovascular risk. A lesson can also be drawn in terms of reduction of residual cardiovascular risk. Through their action on cholesterol synthesis and LDL catabolism, statins markedly reduce the level of ApoB. The INTERHEART findings strongly suggest that therapeutic interventions able to raise ApoA-I may favorably impact on residual cardiovascular risk in patients treated with statins.

  1. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001;358:2026-33.
Key words ApoB/ApoA-I ratio – Total cholesterol/HDL cholesterol ratio – Acute myocardial infarction – Cardiovascular risk assessment.