Apolipoproteins vs Lipoproteins and their ratios: what s best?

Vascular disease is the most common cause of death in the developed world and will become the leading cause of death in the developing world as well (Levenson et al., 2002). Therefore, the identification of individuals at increased CV risk represents a priority. Cholesterol has been the conventional index to measure the concentrations of low density lipoprotein (LDL) and high density lipoprotein (HDL) particles in plasma, whereas triglycerides have been used to estimate the concentration of very low density lipoprotein (VLDL). Targeting of LDL-C with statins has been shown to reduce the incidence of CV disease by about one third. However, a considerable proportion of patients with active atherosclerotic disease have levels of LDL-C within the recommended range, and some patients who achieve significant LDL reduction with lipid-C lowering therapy still develop CV events (Genest et al., 1992; Sacks et al., 2000; Pyrl et al., 2004). Therefore, there is need for improving the cardiovascular risk assessment. Indeed, when small, dense, cholesterol-depleted LDL particles (more likely to penetrate in the arterial wall) predominate, as they often do in patients at high risk of vascular disease, LDL-C necessarily underestimates LDL particle number (Barter et al., 2006). In fact, although LDL-C is widely recognized as the major atherogenic lipoprotein, other lipoproteins are involved in atherogenesis, including very low-density (VLDL), intermediate-density (IDL) and high-density lipoproteins (HDL). This is an important reason why all apolipoprotein B containing lipoproteins, collectively measured as non -high-density lipoprotein cholesterol (non-HDL-C) are now considered of equivalent importance to LDL-C (Contois et al., 2009; Brunzell et al., 2008; Sniderman, 2009). Total cholesterol, more common in clinical practice, can be considered equivalent to non-HDL-C measurement (Kappelle et al., 2011). Alternatively, since each VLDL and LDL particle contains one molecule of apoB, total atherogenic particle number can be accurately estimated using standardized methods by measuring plasma apoB (Marcovina et al., 1994). ApoA-I instead, is the major apolipoprotein associated with HDL and it is crucial in transferring excess cholesterol from tissues to the liver (Walldius et al., 2001; Walldius et al., 2004). The INTERHEART study demonstrated that apoB and apoA-I, either individually or taken together as the apoB/apoA-I ratio were substantially superior as risk markers of AMI than the conventional cholesterol indices (Yusuf et al., 2004; McQueen et al., 2008). Though INTERHEART was case-control in design, its results are virtually identical to prospective longitudinal studies such as apolipoproteinrelated mortality risk (AMORIS) (Walldius et al., 2001). Thus, this ratio was suggested to have a stronger relationship with CV risk than any other lipid ratio (Sniderman et al., 2003; Walldius et al., 2006) and cut-off values 0.9 and 0.8 have been proposed to define a high CV risk for males and females, respectively (Walldius et al., 2004; Walldius et al., 2006). In support of apolipoprotein evaluation in clinics, other considerations have been done: measurement of apolipoproteins is not more expensive than traditional lipoprotein measurement, does not require fasting (Walldius et al., 2001) and the measurement error is < 5% (Steinmetz et al., 1997; Denke et al., 2005). Moreover, apolipoproteins are stable in acute stroke (Kargman et al., 1998) and the apolipoprotein ratio showed to be better than the lipoprotein ratio (total cholesterol/HDL-C) in predicting recurrent events during statin treatment (Kastelein et al., 2008).

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