Introduction
Estimation of cardiovascular risk has become the cornerstone of cardiovascular prevention. Although atherogenesis is a multifactorial process, abnormalities in lipoprotein metabolism are one of the key factors, representing around 50% of the population-attributable risk of developing cardiovascular disease.1 Despite of the considerable progress made in cardiovascular disease management in recent decades, there is almost unanimous agreement among epidemiologists and clinicians that coronary risk assessment based exclusively on low-density lipoprotein (LDL) cholesterol is not optimal,2 particularly in individuals at intermediate risk.3 Efforts have been made in seeking emergent or new cardiovascular risk factors to improve cardiovascular disease prediction.1 However, it must be emphasized that in an attempt to optimize the predictive capacity of the lipid profile, several lipoprotein ratios or “atherogenic indices” have been defined. These ratios can provide information on risk factors difficult to quantify by routine analyses and could be a better mirror of the metabolic and clinical interactions between lipid fractions. Since lipoprotein ratios are under-used in cardiovascular prevention, but can add to risk assessment, in this review, we briefly summarize their physiological and pathophysiological aspects. Furthermore, we highlight the rationale for using these lipoprotein ratios as cardiovascular risk factors in clinical practice, specifying their cut-off risk levels and a target for lipid-lowering therapy (Table 1).
Total cholesterol/HDL cholesterol and LDL/HDL cholesterol ratios
The total/high-density lipoprotein (HDL) cholesterol ratio, known as the atherogenic or Castelli index and the LDL/HDL cholesterol ratio are two important components and indicators of vascular risk, the predictive value of which is greater than the isolated parameters. In this respect, an increase in total cholesterol concentration, and specifically LDL cholesterol, is an atherogenic lipid marker, whereas reduced HDL cholesterol concentration is correlated with numerous risk factors, including the components of the metabolic syndrome, and probably involves independent risk.4 When total cholesterol, HDL cholesterol, and total/HDL cholesterol ratio are compared between an apparently healthy population and myocardial infarction survivors, the total/HDL cholesterol ratio is found to present less superposition of populations.5 This illustrates the high discriminatory power for coronary heart disease presented by the total/HDL cholesterol ratio, as well as its great predictive capacity. The value of this parameter when the lipid profile is within desirable range should be emphasized. For example, total cholesterol of 231 mg/dL (5.89 mmol/L) and HDL cholesterol of 42 mg/dL (1.09 mmol/L) gives a total/HDL cholesterol ratio of 5.5, which indicates moderate atherogenic risk.6 On the other hand, with the same level of total cholesterol, if HDL cholesterol were 60 mg/dL (1.55 mmol/L), the ratio would be 3.8. As total cholesterol/HDL ratio is considered a more sensitive and specific index of cardiovascular risk than total cholesterol, the Canadian working group has chosen this lipid ratio as a secondary goal of theraphy.7
The LDL/HDL cholesterol ratio appears to be as useful as the total/HDL cholesterol ratio. Their similarity can be explained by the fact that approximately two thirds of plasma cholesterol are found in LDL and, consequently, total and LDL cholesterol are closely related. Like the total/HDL cholesterol ratio, LDL/HDL cholesterol may have more predictive power if triglyceridemia is taken into account.8 Although, the increase in these ratios predicted a greater cardiovascular risk in a wide range of cholesterol or triglyceride concentrations, the risk is significantly higher when hypertriglyceridemia is present, as shown by the Helsinki Heart Study.9
However, it is clear than when there is no reliable calculation of LDL cholesterol, as when triglyceridemia exceeds 300mg/dL (3.36 mmol/L), it is preferable to use the total/HDL cholesterol ratio; furthermore, the very-low-density lipoprotein (VLDL) fraction shows cholesterol enrichment in individuals with high triglyceride concentrations, and thus the LDL/HDL cholesterol ratio may underestimate the magnitude of the lipoprotein abnormality in these patients.
Individuals with a high total/HDL cholesterol or LDL/HDL cholesterol ratio have greater cardiovascular risk owing to the imbalance between the cholesterol carried by atherogenic and protective lipoproteins. This may be due to an increase in the atherogenic component contained in the numerator, a decrease in the anti-atherosclerotic trait of the denominator, or both.10
ApoB/ApoA-I ratio
Apolipoprotein (apo) B represents most of the protein content in LDL and is also present in intermediate-density lipoproteins (IDL) and VLDL. ApoA-I is the principal apolipoprotein in HDL. Both apolipoproteins, therefore, separately provide information for detecting high-risk individuals. ApoA-I is also believed to be a more reliable parameter for measuring HDL than cholesterol content since it is not subject to variation. Therefore, the apoB/apoA-I ratio is also highly valuable for detecting atherogenic risk, and there is currently sufficient evidence to demonstrate that it is better for estimating vascular risk than the total/HDL cholesterol ratio.11–14 The apoB/apoA-I ratio was stronger than the total cholesterol/HDL holesterol and LDL/HDL cholesterol ratios in predicting risk.11 Furthermore, Walldius and colleagues have reported that addition of lipids, lipoproteins or any cholesterol ratio to apoB/apoA-I in risk models did not further improve the strong predictive value of apoB/apoA-I.13
LDL cholesterol/apoB ratio
Although apoB is not an apolipoprotein exclusive to LDL, since it is present in other atherogenic lipoprotein fractions such as IDL and VLDL, the LDL cholesterol/apoB concentration ratio provides approximate information on LDL particle size. In this respect, it has been suggested that a ratio of less than 1.3 would indicate the predominance of LDL particles with lower cholesterol content, consistent with small, dense LDL particles.18 However, a study comparing LDL particle size determination by gradient-gel electrophoresis with the LDL cholesterol/apoB ratio in healthy and hyperlipidemic subjects failed to find a good correlation and did not recommend the use of this ratio as a surrogate LDL size marker.19
Non-HDL cholesterol/HDL cholesterol ratio
Non-HDL cholesterol, which is total cholesterol minus HDL cholesterol, is a measure of the cholesterol in LDL, IDL and VLDL particles. Non-HDL cholesterol has therefore been recommended as a secondary therapeutic target in individuals with high triglyceride concentration, and it has been suggested that it could be a surrogate marker of serum apoB concentration in clinical practice. However, non-HDL cholesterol is not always strongly associated with apoB, particularly in the presence of hypertriglyceridemia.20 The non-HDL cholesterol/HDL ratio is a lineal combination of total/HDL cholesterol. Although few studies have evaluated this lipoprotein ratio for predicting cardiovascular disease, and as it is a lineal combination of the results can be assumed to be similar to those of the total/HDL cholesterol or LDL/HDL cholesterol ratios.21
Predictive power of lipoprotein ratios for cardiovascular risk
The evidence derived from large observational studies, including the Framingham Study,22 the LRCP23 and the PROCAM,24,25 suggests that the total/HDL cholesterol ratio is a more powerful coronary risk predictor than independently-used total cholesterol, LDL cholesterol and HDL cholesterol. The predictive value for the development of coronary events of the baseline total/HDL cholesterol and LDL/HDL cholesterol ratios in the placebo groups of WOSCOPS,26 AFCAPS/TexCAPS,27 and 4S28 studies was higher than that of other lipid parameters in multivariate analyses. Indeed, the total/HDL cholesterol ratio was included in the Framingham equation to improve risk prediction.
The total/HDL cholesterol ratio has also been shown to be a good predictor of carotid intima-media thickness; it has greater power than the isolated variables and similar power to that of the apoB/apoA-I ratio and non-HDL cholesterol.35 More controversial is the role of the ratio between the principal protein fractions of LDL and HDL, apoB and A-I, which is the apoB/apoA-I ratio, as contradictory results regarding its use for predicting cardiovascular risk and its relative value compared with the LDL/HDL cholesterol and total/HDL cholesterol ratios have been obtained in the different observational studies.36,37 In the Interheart study, which included around 30,000 subjects from 52 countries, the apoB/apoA-I ratio was the variable which predicted a larger proportion of risk of myocardial infarction. Indeed, nearly 50% of the population-attributable risk corresponded to that ratio.1 However, the Interheart study did not include any other lipid measurement, such as HDL or LDL cholesterol, and thus did not compare the relative usefulness of this ratio.
Although the total/HDL cholesterol and LDL/HDL cholesterol ratios predict greater cardiovascular risk with a wide range of cholesterol or triglyceride concentrations, the risk is considerably higher in the presence of hypertriglyceridemia. In the Helsinki study,41 the LDL/HDL cholesterol ratio was a powerful predictor of cardiovascular risk, mainly in subjects with elevated triglycerides. The greatest risk was observed in subjects with an LDL/HDL ratio >5 and triglycerides >200 mg/dL (2.24 mmol/L), who represented around 10% of the population studied; it was precisely this group which most benefited from treatment with gemfibrozil, with a remarkable 71% reduction in the incidence of coronary events, more than double that of the overall active-treatment group. In the cohort of 4,559 adult men in the PROCAM observational study,24,25 it was found that subjects with an LDL/HDL cholesterol ratio >5 presented more than six times the rate of coronary events of those with an LDL/HDL ratio <5; however, when the LDL/HDL cholesterol ratio was >5 and associated with triglycerides ≥200 mg/dL (2.24mmol/L), the risk was double that of subjects with triglycerides <200 mg/dL (2.24 mmol/L). In the Physicians Health Study,31 this synergic effect was also found between the increase in the atherogenic/protective cholesterol ratio and hypertriglyceridemia.
What do lipoprotein ratios provide that other conventional risk variables do not?
Classic cardiovascular risk factors such as age, sex, smoking, diabetes, hypertension, high LDL and low HDL cholesterol levels have been widely analyzed and established as independent cardiovascular risk factors. Many other predictors, such as triglycerides, apoB, lipoprotein(a), homocysteine, C-reactive protein and others have also been studied. Furthermore, the total/HDL cholesterol and LDL/HDL cholesterol ratios are of great interest as major predictors of cardiovascular disease.
Guidelines for lipid management are based on LDL cholesterol concentrations, although other parameters including the total/HDL cholesterol index are better cardiovascular risk predictors than LDL cholesterol and have not been included.47 The beneficial use of these indices as important cardiovascular risk predictors is based on multiple epidemiological studies which have shown that these ratios (total/HDL cholesterol and LDL/HDL cholesterol) have a greater correlation with cardiovascular disease and are therefore better predictors of cardiovascular disease than simple lipid parameters.5,31,48
There is reason to believe that these lipoprotein ratios, mainly total/HDL cholesterol, based on two values directly measured in a clinical laboratory and which indicate the relationship or proportion between the atherogenic and antiatherogenic lipid fraction, have predictive power for cardiovascular disease and cardiovascular risk reduction after intervention superior to that of classic lipid parameters and should be used in regular clinical practice.
With regard to identifying the “best” lipoprotein ratio, there is an interesting contrast between the use of cut-off points46 and quantiles.50 Thus it must be taken into account that while cut-off points can provide clinical relevant information, with regard to comparing ratios it would seem more logical to use quantiles within the cohort/population.
Referência :
(1) Vasc Health Risk Manag. 2009;5:757-65.
