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Lipoprotein(a) (Lp(a)) is a low-density lipoprotein-like particle containing apolipoprotein(a) (apo(a)) that increases the risk of atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolemia (FH). Postprandial redistribution of apo(a) protein from Lp(a) to triglyceride-rich lipoproteins (TRLs) may also increase the atherogenicity of TRL particles. Omega-3 fatty acid (ω3FA) supplementation improves postprandial TRL metabolism in FH subjects. However, its effect on postprandial apo(a) metabolism has yet to be investigated.We carried out an 8-week open-label, randomized, crossover trial to test the effect of ω3FA supplementation (4 g/day) on postprandial apo(a) responses in FH patients following ingestion of an oral fat load. Postprandial plasma total and TRL-apo(a) concentrations were measured by liquid chromatography with tandem mass spectrometry, and the corresponding areas under the curve (AUCs) (0-10h) were determined using the trapezium rule.Compared with no ω3FA treatment, ω3FA supplementation significantly lowered the concentrations of postprandial TRL-apo(a) at 0.5 (-17.9%), 1 (-18.7%), 2 (-32.6%), and 3 h (-19.2%) (P＜0.05 for all). Postprandial TRL-apo(a) AUC was significantly reduced with ω3FA by 14.8% (P＜0.05). By contrast, ω3FA had no significant effect on the total AUCs of apo(a), apoC-III, and apoE (P＞0.05 for all). The decrease in postprandial TRL-apo(a) AUC was significantly associated with changes in the AUC of triglycerides (r=0.600; P ＜0.01) and apoB-48 (r=0.616; P＜0.01).Supplementation with ω3FA reduces postprandial TRL-apo(a) response to a fat meal in FH patients; this novel metabolic effect of ω3FA may have implications on decreasing the risk of ASCVD in patients with FH, especially in those with elevated plasma triglyceride and Lp(a) concentrations. However, the clinical implications of these metabolic findings require further evaluation in outcome or surrogate endpoint trials.

Cellular cholesterol efflux is a key step in reverse cholesterol transport that may impact on atherosclerotic cardiovascular risk. The process may be reliant on the availability of apolipoprotein (apo) B-100-containing lipoproteins to accept cholesterol from high-density lipoprotein. Evolocumab and atorvastatin are known to lower plasma apoB-100-containing lipoproteins that could impact on cholesterol efflux capacity (CEC).We conducted a 2-by-2 factorial trial of the effects of subcutaneous evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) for 8 weeks on CEC in 81 healthy, normolipidaemic men. The capacity of whole plasma and apoB-depleted plasma, including ATP-binding cassette transporter A1 (ABCA1)-mediated and passive diffusion, to efflux cholesterol, was measured.Evolocumab and atorvastatin independently decreased whole plasma CEC (main effect p .01 for both). However, there were no significant effects of evolocumab and atorvastatin on apoB-depleted plasma, ABCA1-mediated and passive diffusion-mediated CEC (p .05 in all). In the three intervention groups combined, the reduction in whole plasma CEC was significantly correlated with the corresponding reduction in plasma apoB-100 concentration (r = .339, p .01). In the evolocumab monotherapy group, the reduction in whole plasma CEC was also significantly correlated with the corresponding reduction in plasma lipoprotein(a) concentration (r = .487, p .05).In normolipidaemic men, evolocumab and atorvastatin decrease the capacity of whole plasma to efflux cellular cholesterol. These effects may be chiefly owing to a fall in the availability of apoB-100-containing lipoproteins. Reduction in circulating lipoprotein(a) may also contribute to the decrease in whole plasma cholesterol efflux with evolocumab monotherapy.

Inhibition of proprotein convertase subtilisin/kexin type 9 with alirocumab decreases plasma lipoprotein(a) [Lp(a)] levels. The kinetic mechanism for lowering Lp(a) by alirocumab may differ according to pre-treatment apolipoprotein(a) [apo(a)] levels.The effect of 12-week alirocumab (150 mg subcutaneously fortnightly) on the kinetics of apo(a) was compared in statin-treated patients with high (n = 10) and very high Lp(a) concentrations (n = 11).In patients with high apo(a) concentrations, alirocumab lowered plasma apo(a) pool size (-17%, p0.01) chiefly by increasing the fractional catabolic rate (FCR) of apo(a) (+27%, p0.001). By contrast in patients with very high apo(a) concentrations, alirocumab significantly lowered plasma apo(a) pool size (-32%, p0.001) by both increasing apo(a) FCR (+30%, p0.001) and lowering production rate (-11%, p0.05).In statin-treated patients with very high apo(a) concentrations, alirocumab lowers plasma Lp(a) concentration by a dual mode of action that increases the clearance and decreases the production of Lp(a) particles.

Dysregulated lipoprotein metabolism is a major cause of atherosclerotic cardiovascular disease (ASCVD). Use of stable isotope tracers and compartmental modelling have provided deeper understanding of the mechanisms underlying lipid disorders in patients at high risk of ASCVD, including familial hypercholesterolemia (FH), elevated lipoprotein(a) [Lp(a)] and metabolic syndrome (MetS). In patients with FH, deficiency in low-density lipoprotein (LDL) receptor activity not only impairs the catabolism of LDL, but also induces hepatic overproduction and decreases catabolism of triglyceride-rich lipoproteins (TRLs). Patients with elevated Lp(a) are characterized by increased hepatic secretion of Lp(a) particles. Atherogenic dyslipidemia in MetS patients relates to a combination of overproduction of very-low density lipoprotein-apolipoprotein (apo) B-100, decreased catabolism of apoB-100-containing particles, and increased catabolism of high-density lipoprotein-apoA-I particles, as well as to impaired clearance of TRLs in the postprandial state. Kinetic studies show that weight loss, fish oils, statins and fibrates have complementary modes of action that correct atherogenic dyslipidemia. Defining the kinetic mechanisms of action of proprotein convertase subtilisin/kexin type 9 and angiopoietin-like 3 inhibitors on lipid and lipoprotein mechanism in dyslipidemic subjects will further our understanding of these therapies in decreasing the development of ASCVD. “Everything changes but change itself. Everything flows and nothing remains the same... You cannot step twice into the same river, for other waters and yet others go flowing ever on.” Heraclitus (c.535- c. 475 BCE)