Protective Role of HDL: Evidence from Epidemiological Studies

The protective role of HDL has been well established in several epidemiological studies. An increment of 2.5 % corresponding to 1 mg/dl or 0.04 mmol/l is associated with a 2 and 3 % reduction in CHD risk in men and women, respectively (Gordon et al. 1989; Jacobs et al. 1990). So far, it is mainly the total cholesterol concentration in HDL particles that has been determined using standardized methods applicable also to routine clinical work. However, cholesterol represents only a small fraction, approximately 15 %, of the HDL particle mass. Furthermore, the proportion of free cholesterol to esterified cholesterol varies between lipoprotein particles.

The relationship between HDL-C and CHD is complex and HDL-C may not be an appropriate indicator of the impact of this lipoprotein fraction on cardiovascular risk. This has been demonstrated, e.g., by the fact that carotid intima media thickness is not increased in apoA-I(Milano) mutation carriers with very low levels of HDL-C (Sirtori et al. 2001). Moreover, recently, drugs that increase HDL cholesterol (HDL-C) level have failed to reduce cardiovascular risk, and Mendelian randomization studies have failed to show a causal relationship between HDL-C and cardiovascular diseases (van Capelleveen et al. 2013).

Despite this controversy, the hard evidence for low HDL-C level as a risk factor of atherosclerosis will be described in the first part of this presentation. It is noteworthy that the cholesterol concentration in HDL fraction is not necessarily associated with the antiatherogenic properties of HDL. Therefore, later in this chapter, other potential HDL-related biomarkers for the prevention of atherosclerosis by HDL will be presented. These include not only the other major lipid and apolipoprotein components of HDL but also minor bioactive lipid molecules residing in the HDL particles. Furthermore, the physicochemical characteristics of various subfractions of HDL as well as the large number of molecules circulating more or less firmly bound to HDL particles may contribute to the antiatherogenic potential of HDL via antioxidative and anti-inflammatory effects or cholesterol transport capacity.

HDL Cholesterol as a Risk Factor for Atherosclerosis and Its Complications

Until recently, the clinical evaluation of HDL as a risk factor has focused almost exclusively on the total HDL-C without regard to the chemical composition or multiple subclasses of HDL particles. A large body of epidemiological research has shown a solid inverse and independent relationship between HDL-C and the risk of cardiovascular disease (Toth et al. 2013).

Gofman et al. first reported an inverse association between HDL-C levels and the risk of ischemic heart disease (Gofman et al. 1966). This was shown in case–control studies from Framingham and Livermore cohorts with 10–12 years of follow-up. Later, the inverse relationship has been observed also in several larger studies in the USA (the Honolulu Heart Program, Rhoads et al. 1976, and the Framingham Heart Study, Gordon et al. 1977), in Norway (the Tromsø Heart Study, Miller et al. 1977), in Germany (the Prospective Cardiovascular Mu¨nster Study, Assmann et al. 1996), and in Israel (the Israeli Ischemic Heart Disease Study, Goldbourt et al. 1997). Recent meta-analyses have corroborated the relationship between HDL-C and atherosclerosis and its complications (Chirovsky et al. 2009; Boekholdt et al. 2013; Touboul et al. 2014). The association is independent of triglyceride levels and other risk factors (Goldbourt et al. 1997). Many CHD risk algorithms have included HDL-C as a factor to improve the prediction of CHD events (Cooper et al. 2005; Halcox et al. 2013; Hippisley-Cox et al. 2013; Tehrani et al. 2013).

Recently, the picture has become less clear. Mendelian randomization studies have not supported a causal effect of HDL-C in the atherosclerotic disease process (Voight et al. 2012; Holmes et al. 2014). Moreover, statin trials have shown that HDL-C is predictive among patients treated with statin even at low LDL levels (Barter et al. 2007), whereas it is not predictive among patients taking placebo (Ridker et al. 2010; Mora et al. 2012). Further research is needed to clarify the role of HDL-C as a risk factor. It is possible that other characteristics of HDL particles may be more important in this respect than the total cholesterol concentration.

In patients with CHD, the protective role of HDL-C is controversial (Silbernagel et al. 2013). Some studies have shown that low HDL-C is associated with atherosclerotic progression in myocardial infarction survivors (Johansson et al. 1991; Duffy et al. 2012; Liosis et al. 2013), provides additional prognostic value also in patients with acute coronary syndrome (Correia et al. 2009), and reduces the risk after coronary interventions (Sattler et al. 2009), whereas some studies have shown that HDL-C has no protective role in the secondary prevention of CHD after bypass operation (Angeloni et al. 2013).

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