**7. References**

270 Dyslipidemia - From Prevention to Treatment

In arterial intima, oxLDLs are taken up by macrophages via scavenger receptors. This induces foam cell formation and subsequent atheroma development (Henriksen et al., 1981, 1983; Steinbrecher et al., 1984). Oxldls are commonly present in atherosclerotic lesions of experimental animals and humans (Palinski et al., 1989; Yla-Herttuala et al., 1989). OxLDL has also been identified in plasma of healthy individuals (Avogaro et al., 1988; Ehara et al., 2001; Itabe and Takano, 2000). In patients with cardiovascular disease, plasma levels of oxLDL have been reported to be approximately fourfold higher than in healthy subjects (Ehara et al., 2001; Holvoet et al., 1998b). In addition to cardiovascular disease, increased levels of oxLDL are associated with ageing (Brinkley et al., 2009) and certain age-related pathologies, such as Alzheimer's disease (Kankaanpaa et al., 2009), glomerulosclerosis (Lee,

Therefore, timely clearance and maintenance of low circulatory levels of oxLDLs appear to be important for the prevention of atherosclerosis (Holvoet et al., 1998b; Itabe, 2003). Previously, it has been shown that intravenously injected radiolabeled oxLDLs are rapidly removed from blood by uptake in Kupffer cells and LSECs (Ling et al., 1997; Van Berkel et al., 1991). However, a recent study demonstrated that Kupffer cells are only active in uptake of heavily oxidized LDL (Li et al., 2011). which is mainly present in atherosclerotic plaques (Yla-Herttuala et al., 1989) or formed as an artifact during *in vitro* oxLDL preparation. At the same time, LSECs hold an exclusive role in the uptake of mildly oxidized LDL from the circulation (Li et al., 2011). Mildly oxidized LDL is the major form of oxLDL found in the blood (Chang et al., 1997; Holvoet et al., 1998a; Holvoet et al., 1998b), and has proatherogenic properties (Berliner et al., 1990; Watson et al., 1997; Witztum and Steinberg, 1991). Both stabilin-1 and stabilin-2 are involved in the endocytic uptake of oxLDL by LSECs. Stabilin-1, however, appears to be more important for the uptake of mildly oxidized LDL, which represents physiological blood-borne oxLDL, while stabilin-2 is important for

The morphological changes in the LSEC in old age might also affect its role in endocytosis. Recently, *in vivo* microscopy was used to examine the real time uptake of scavenger receptor ligands by LSECs (Ito et al., 2007). Endocytosis was clearly diminished in old mice, particularly in the pericentral zone which may indicate hypoxic liver damage. The effect of old age on clearance of oxLDL by LSEC has not been examined yet. However, involvement of stabilin 1 and 2, the two major LSEC scavenger receptors, in the process of oxLDL uptake (Li et al., 2011) makes it likely that oxLDL clearance would be diminished in old age. This change would increase the level of oxLDL in the circulation, thereby promoting its extrahepatic concentration and increasing the risk of the development of atherosclerosis.

Age-related changes in morphology and function of LSECs apparently contribute to dyslipidemia and, as a consequence, to the development of cardiovascular disease. Old age is associated with reduced fenestrae in the LSEC which impedes the hepatic uptake of chylomicron remnants and possibly other lipoproteins. In addition, aging is associated with reduced LSEC endocytic capacity which will impact on circulating levels of oxLDL. Thus the LSEC is a novel therapeutic target for the treatment of age-related dyslipidemia and has

great potential for the prevention of atherosclerosis and cardiovascular events.

1999), and diabetes mellitus (Lopes-Virella et al., 1999).

uptake when there is greater LDL modification (Li et al., 2011).

**6. Conclusions** 


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**14** 

Telmo Pereira

*Portugal* 

**Dyslipidemia and Cardiovascular Risk:** 

There are extensive epidemiological data demonstrating that high blood cholesterol levels increase cardiovascular risk, and that this risk is dependent on the levels of the different blood cholesterol fractions. Moreover, the reduction of total blood cholesterol has been clearly related to a reduction in the risk of stroke, coronary disease and overall cardiovascular death. However, the traditional cholesterol measurements tend to be most accurate at predicting risk for those at the lower and higher ends of the risk spectrum. Recent data has shown LDL-Cholesterol/HDL-Cholesterol ratio and even Total-Cholesterol/HDL-Cholesterol ratio, to be accurate predictors of cardiovascular risk. In fact, changes in ratios have been shown to be better indicators of successful CHD risk reduction than changes in absolute levels of lipids or lipoproteins. In the Helsinki Study, the LDL-C/HDL-C ratio had more prognostic value than LDL-C or HDL-C alone (Manninen, Tenkanen, Koskinen *et al*, 1992). The ratio was especially accurate at predicting risk among those who also had elevated triglyceride levels. The PROSPER trial, a retrospective analysis of 6,000 patients, found that the ratio of LDL-C/HDL-C was the most powerful measure of cardiovascular disease risk in elderly people (Packard, Ford, Robertson *et al*, 2005). The PROCAM Study, which included almost 11,000 men aged 36 to 65 who were studied for 4 to 14 years, found a continuous and graded relationship between the LDL-C/HDL-C ratio and CVD mortality (Cullen, Schulte, Assmann *et al*, 1997). In addition, comparison of individual LDL-C/HDL-C ratios from subjects in the Framingham Study clearly indicates that these ratios are significantly more robust predictors of CVD than the individual levels of LDL-C

Cardiovascular diseases are an unavoidable topic when discussing health related issues, particularly in developed societies. Cardiovascular disease is the leading cause of mortality in these countries (World Health Organization, 2002), assuming a progressively more important role in developing countries and even in less developed countries. In the latter, we may consider the presence of a *double-frontier* of health risk. These countries show

**1. Introduction** 

or HDL-C (Kannel, 2005).

**2. Theoretical framework** 

**2.1 Cardiovascular risk – Generalities** 

**Lipid Ratios as Risk Factors for** 

 *College of Health Technologies, Polytechnic Institute of Coimbra* 

**Cardiovascular Disease** 

