**6. Lp(a) and lipid lowering drugs**

748 Lipoproteins – Role in Health and Diseases

(p<0.001) [63]. Additionally one kringle V as well as protease domains of plasminogen are found in apo-a [58]. Later on cDNA sequencing revealed that human apolipoprotein(a) is homologous to plasminogen but despite the fact that apo-a contains a protease domain it does not act fibrinolytically like plasminogen because the arginine at the cleavage site for

Nevertheless Lp(a) might interfere with the fibrinolytic system in different ways due to its similarity to plasminogen as it may inhibit the binding of plasminogen to its receptor on endothelial cells thereby preventing generation of plasmin and increasing the thrombotic risk [65, 66]. Furthermore it could be demonstrated that Lp(a) accumulates in atherosclerotic lesions maybe via adherence to fibrinogen or fibrin incorporated in atherosclerotic plaques thereby inhibiting fibrinolysis [66]. Another mechanism by which Lp(a) is thought to attenuate fibrinolysis involves direct competition with plasminogen for fibrinogen or fibrin binding sites thus reducing the efficiency of plasminogen activation [67]. Fibrinolysis is initiated by binding of plasminogen to lysine residues on fibrin thereby initiating activation of plasmin and amplifying fibrinolytic processes [68]. Like plasminogen Lp(a) also binds to lysine residues [69] but without catalytical activity leading to interference with or inhibition of fibrinolysis resulting in hypofibrinolysis and accumulation of cholesterol included in the LDL-like component of Lp(a) [66]. The fact that low molecular weight isoforms of apo-a are associated with greater inhibition of fibrinolysis [70, 71] confirms the hypothesis that subjects with small apo-a phenotypes have a two-fold risk of CHD and stroke compared with those with larger isoforms of apo-a [34]. In contrast Knapp et al. [72] observed that the rate of plasmin formation was inversely related to Lp(a) but inhibition of plasmin generation increased with the size of apo-a using a standardized in vitro fibrinolysis model. From the fact that the inhibitory effect of free apo-a was much stronger than that of the complete Lp(a) particle they conclude that the apo-a component is responsible for the observed reduction of plasmin formation maybe due to the availability of additional lysine binding sites in the unbound apo-a which was formerly reported by Scanu et al. [73]. On the other hand there are also data showing that the plasma concentration of Lp(a) is inversely related to plasmin formation but that this relationship is not influenced by the size of apo-a isoforms [74]. Above all there are other reports explaining the inhibitory effect of Lp(a) on fibrinolysis not only by competition of Lp(a) with plasminogen for the binding sites on fibrin, endothelial cells and monocytes but also by reduction of tissue plasminogen activator

A novel contribution to the understanding of Lp(a)/apo-a-mediated inhibition of plasminogen activation comes from results showing the ability of the apo(a) component of Lp(a) to inhibit the key positive feedback step of plasmin-mediated conversion of Gluplasminogen to Lys-plasminogen an essential step for fibrin clot lysis [78]. Interestingly, with the exception of the smallest naturally-occurring isoform of apo(a), isoform size was

In summary, the proposed mechanisms modulating the antifibrinolytic effects of elevated Lp(a) levels in vitro are manifold and emphasize the prothrombotic effects of this lipoprotein particle. The in vivo situation however seems to be much more complex the

tissue plasminogen activator in plasminogen is changed to serine in apo-a [64].

or streptokinase-induced fibrinolytic activity [75, 76, 77].

found not to contribute to the inhibitory capacity of apo(a).

High levels of Lp(a) are strongly associated with atherosclerosis as revealed by numerous studies [4, 79, 80, 81, 82]. As plasma Lp(a) concentrations above 30 mg/dl, as measured in about 20 percent of white people, are associated with an approx. two-fold relative risk of coronary atherosclerosis [3] rising to the range of five-fold when LDL and Lp(a) are both elevated [4] reduction of plasma Lp(a) concentration is recommended. Dietary interventions do not seem to be effective in lowering Lp(a) plasma levels [9, 83] or even lead to an increase of Lp(a) in plasma, alone [84] or at least when combined with exercise 85]. The same phenomenon could be observed in case of exercise where cross-sectional data suggest that a lifestyle of moderate to intense exercise training does not exert a significant impact on the Lp(a) level [86, 87]. Therefore pharmacological reduction of plasma levels of Lp(a) would be desirable.

Innumerable investigations however indicate that the plasma concentration of Lp(a) is resistant to drug therapy in most cases. As Lp(a) resembles LDL especially with regard to the lipid content (Tab.1) medications reducing LDL-cholesterol should be suitable for lowering Lp(a) as well. Bile acid resins such as cholestyramine which actually cause a significant reduction of LDL-cholesterol as well as of apo-B have no effect on Lp(a) levels [88, 89]. Therapies with bezafibrate or clofibrate [90, 91] showed that there is no role for fibrates in the treatment of elevated Lp(a) concentrations and estrogens also do not seem to significantly affect Lp(a) [92, 93].

Stanozolol, an anabolic steroid used in the treatment of postmenopausal osteoporosis, showed a significant reduction of Lp(a) by about 65% after six weeks therapy but five weeks after the drug was discontinued Lp(a) was near pretreatment levels [94]. Although drastic reductions of Lp(a) up to 40-50% are reported in another study [95] these compounds seem to be unsuitable for the routine treatment due to their harmful side effects [96].

Statins, also known as HMG-CoA-reductase inhibitors are another group of lipid lowering drugs which could be interesting with regard to Lp(a). These drugs have proven to be extremely effective in lowering plasma LDL and apo-B levels presumably through inhibition of intracellular cholesterol synthesis concomitant with an increase of the LDL receptors in the liver [97]. Although Lp(a) and LDL are very similar especially concerning the content of cholesterol, inhibitors of HMG-CoA-reductase, the regulating enzyme of cholesterol biosynthesis, show no influence [98, 99], only modest reduction of about 10% [100, 101] or even an increase of serum Lp(a) levels [102]. Altogether the limited magnitude of decrease of Lp(a) by HMG-CoA-reductase inhibitors confirms the assumption that the LDL-receptor does not seem to play a major role in Lp(a) clearance from plasma [103].

Nicotinic acid, also known as niacin has been shown to lower not only plasma total cholesterol, LDL-cholesterol and triglycerides thereby increasing HDL-cholesterol [104] but

also Lp(a) in a dose-dependent manner up to 40% [105]. A more pronounced effect could be observed in a combination therapy with niacin and neomycin showing a reduction of LDLcholesterol by 48% and of Lp(a) by 45% respectively [106]. In a recently published study niacin was applied in combination with omega-3-fatty acids and the Mediterranean diet. The average reduction of Lp(a) after 12 weeks combination therapy was reported to be about 23%. Additionally a significant association with increasing baseline levels of Lp(a) was observed [107].

Diets rich in fish oils containing considerable amounts of omega-3 polyunsaturated fatty acids are recommended to have beneficial effects on plasma lipids thereby lowering the risk of vascular complications [108, 109]. In a study investigating the influence of dietary fish oils on plasma Lp(a) levels a decrease of triglycerides could be observed after six weeks dietary supplementation while total cholesterol, LDL- and HDL-cholesterol as well as Lp(a) remained unchanged [110]. Furthermore collagen- and thrombin-stimulated platelet aggregation and TXB2-formation in platelets decreased by approx. 45% irrespective of the plasma concentration of Lp(a) [111]. This is in agreement with many other studies showing that fish oils only seem to be able to reduce Lp(a) in combination with other therapies [107] or moderate exercise [112] but not when used alone [113, 114, 115].

Summarizing it can be shown that increased Lp(a) levels are minimally if at all influenced by drug treatment or drugs reducing Lp(a) to a greater extent like nicotinic acid are not widely used due to undesirable side effects. From previous turnover studies it could be demonstrated that plasma Lp(a) levels correlate with its rate of biosynthesis rather than with the fractional catabolic rate [116, 117] and therefore attempts to reduce Lp(a) should focus on an interference with apo-a biosynthesis. This is supported by the fact that adenovirusmediated apo-a-antisense RNA expression efficiently inhibits apo-a synthesis in vitro in stably transfected liver cells but also in vivo in transduced mice expressing recombinant human apo-a [118]. In a recently published study it was found that patients suffering from biliary obstructions have very low plasma Lp(a) levels that rise substantially after surgical intervention. Consistent with this, common bile duct ligation in mice transgenic for human apo-a lowered plasma concentrations and hepatic expression of apo-a. Treatment of transgenic mice with cholic acid led to farnesoid X receptor (FXR) activation followed by markedly reduced plasma concentrations and hepatic expression of human apo-a [119]. From that it is concluded that transcription of the apo-a gene is under strong control of the farnesoid X receptor which may have important implications in the development of Lp(a) lowering medications.

#### **7. Conclusion**

High levels of Lp(a) are strongly associated with atherosclerosis. About 10-15% of the white population exhibit plasma Lp(a) concentrations above the atherogenic cut-off value of approx. 30 mg/dl. Therefore the European Atherosclerosis Society recommended screening for Lp(a) in a consensus report, in which the desirable cut-off was set at less than 50 mg/dl [82]. On the other hand it is very well known that Lp(a) is an inherited atherogenic plasma component determined to more than 90% by genetic factors a fact that aggravates the influence on plasma levels of this lipoprotein. So far there are only speculations about the mechanism by which Lp(a) accelerates atherosclerosis and the exact mechanism could not yet be clarified. Its prothrombotic effects may be ascribed to impaired fibrinolysis by inhibition of plasminogen activation rather than to amplification of platelet aggregation which is shown to be reduced by Lp(a) in most cases. At present dietary interventions or drug therapies seem to be only minimal if at all successful concerning reduction of plasma Lp(a). Up to now it was assumed that the atherogenicity of high Lp(a) levels in blacks must be decreased by other factors [5]. However data published recently show that associations between Lp(a) levels and cardiovascular disease are at least as strong in blacks compared with whites [120] and emphasize the recommendation that factors such as total cholesterol, LDL-cholesterol, smoking, diabetes mellitus or overweight that can still increase the atherosclerotic risk of Lp(a) should be kept under observation.

#### **Author details**

750 Lipoproteins – Role in Health and Diseases

was observed [107].

lowering medications.

**7. Conclusion** 

also Lp(a) in a dose-dependent manner up to 40% [105]. A more pronounced effect could be observed in a combination therapy with niacin and neomycin showing a reduction of LDLcholesterol by 48% and of Lp(a) by 45% respectively [106]. In a recently published study niacin was applied in combination with omega-3-fatty acids and the Mediterranean diet. The average reduction of Lp(a) after 12 weeks combination therapy was reported to be about 23%. Additionally a significant association with increasing baseline levels of Lp(a)

Diets rich in fish oils containing considerable amounts of omega-3 polyunsaturated fatty acids are recommended to have beneficial effects on plasma lipids thereby lowering the risk of vascular complications [108, 109]. In a study investigating the influence of dietary fish oils on plasma Lp(a) levels a decrease of triglycerides could be observed after six weeks dietary supplementation while total cholesterol, LDL- and HDL-cholesterol as well as Lp(a) remained unchanged [110]. Furthermore collagen- and thrombin-stimulated platelet aggregation and TXB2-formation in platelets decreased by approx. 45% irrespective of the plasma concentration of Lp(a) [111]. This is in agreement with many other studies showing that fish oils only seem to be able to reduce Lp(a) in combination with other therapies [107]

Summarizing it can be shown that increased Lp(a) levels are minimally if at all influenced by drug treatment or drugs reducing Lp(a) to a greater extent like nicotinic acid are not widely used due to undesirable side effects. From previous turnover studies it could be demonstrated that plasma Lp(a) levels correlate with its rate of biosynthesis rather than with the fractional catabolic rate [116, 117] and therefore attempts to reduce Lp(a) should focus on an interference with apo-a biosynthesis. This is supported by the fact that adenovirusmediated apo-a-antisense RNA expression efficiently inhibits apo-a synthesis in vitro in stably transfected liver cells but also in vivo in transduced mice expressing recombinant human apo-a [118]. In a recently published study it was found that patients suffering from biliary obstructions have very low plasma Lp(a) levels that rise substantially after surgical intervention. Consistent with this, common bile duct ligation in mice transgenic for human apo-a lowered plasma concentrations and hepatic expression of apo-a. Treatment of transgenic mice with cholic acid led to farnesoid X receptor (FXR) activation followed by markedly reduced plasma concentrations and hepatic expression of human apo-a [119]. From that it is concluded that transcription of the apo-a gene is under strong control of the farnesoid X receptor which may have important implications in the development of Lp(a)-

High levels of Lp(a) are strongly associated with atherosclerosis. About 10-15% of the white population exhibit plasma Lp(a) concentrations above the atherogenic cut-off value of approx. 30 mg/dl. Therefore the European Atherosclerosis Society recommended screening for Lp(a) in a consensus report, in which the desirable cut-off was set at less than 50 mg/dl [82]. On the other hand it is very well known that Lp(a) is an inherited atherogenic plasma

or moderate exercise [112] but not when used alone [113, 114, 115].

Anna Gries *Institute of Physiology, Medical University of Graz, Austria* 

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