p.19 抽出テキスト

............................................................................................................................................................................. Mendelian randomization studies also suggest that the association between plasma TGs and the risk of CHD may be causal; however, this evidence must be interpreted with caution because nearly all variants associated with TGs are also associated with HDL-C, LDL-C, or Lp(a).5659 A recent Mendelian randomization study demonstrated that TG-lowering lipoprotein lipase (LPL) variants and LDL-C-lowering LDL receptor variants had the same effect on the risk of ASCVD per unit change of ApoB, suggesting that all ApoB-containing lipoproteins have the same effect on the risk of CHD.53 Together, these studies strongly suggest that the causal effect of TG-rich lipoproteins and their remnants on the risk of ASCVD is determined by the circulating concentration of ApoB-containing particles, rather than by the TG content itself.

5.3.3 High-density lipoprotein cholesterol and risk of atherosclerosis The inverse association between plasma HDL-C and the risk of ASCVD is among the most consistent and reproducible associations in observational epidemiology.45,60 In contrast, Mendelian randomization studies do not provide compelling evidence that HDL-C is causally associated with the risk of ASCVD.49,61,62 However, this evidence must be interpreted with caution because most genetic variants associated with HDL-C are also associated with directionally opposite changes in TGs, LDL-C, or both, thus making estimates of the effect of HDL-C on the risk of ASCVD very difficult using the Mendelian randomization study design. Furthermore, there is no evidence from randomized trials that therapeutically increasing plasma HDL-C reduces the risk of CV events.6367 In the Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome (dal-OUTCOMES) trial, treatment with the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib increased HDL-C without any effect on LDL-C or ApoB, but did not reduce the risk of major CV events.65 Similarly, in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High-Risk for Vascular Outcomes (ACCELERATE) and Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification (REVEAL) trials, treatment with CETP inhibitors more than doubled HDL-C levels, but did not appear to reduce the risk of ASCVD events beyond that expected from the modest reductions in ApoB levels.2,63,64 Furthermore, several randomized trials have shown that directly infused HDL mimetics increase plasma HDL- C concentrations, but do not reduce the progression of atherosclerosis as measured by intravascular ultrasound.68,69 Therefore, there is currently no randomized trial or genetic evidence to suggest that raising plasma HDL-C is likely to reduce the risk of ASCVD events. Whether therapies that alter the function of HDL particles will reduce the risk of ASCVD is unknown.

5.3.4 Lipoprotein(a) and risk of atherosclerosis Lp(a) is an LDL particle with an Apo(a) moiety covalently bound to its ApoB component.70 It is <70 nm in diameter and can freely flux across the endothelial barrier, where it can become—similarly to LDL—retained within the arterial wall and thus may increase the risk of ASCVD. Pro-atherogenic effects of Lp(a) have also been attributed to pro-coagulant effects as Lp(a) has a similar structure to plasminogen, and it has pro-inflammatory effects most likely related to the oxidized phospholipid load carried by Lp(a).71

Higher plasma Lp(a) concentrations are associated with an increased risk of ASCVD, but it appears to be a much weaker risk factor for most people than LDL-C.72,73 In contrast, Mendelian randomization studies have consistently demonstrated that lifelong exposure to higher Lp(a) levels is strongly and causally associated with an increased risk of ASCVD.74,75 While randomized trials evaluating therapies that lower Lp(a) by 2030% (including niacin and CETP inhibitors) have not provided evidence that lowering Lp(a) reduces the risk of ASCVD beyond that which would be expected from the observed reduction in ApoB-containing lipoproteins, recent data with PCSK9 inhibitors have suggested a possible role for Lp(a) lowering in reducing CV risk.76 This conflicting evidence appears to have been reconciled by a recent Mendelian randomization study that showed that the causal effect of Lp(a) on the risk of ASCVD is proportional to the absolute change in plasma Lp(a) levels. Importantly, this study also suggested that people with extremely high Lp(a) levels >180 mg/ dL (>430 nmol/L) may have an increased lifetime risk of ASCVD similar to that of people with heterozygous FH (HeFH). Because about 90% of a person’s Lp(a) level is inherited, extremely elevated Lp(a) may represent a new inherited lipid disorder that is associated with extremely high lifetime risk of ASCVD and is twofold more prevalent than HeFH.77 However, this study77 and another based on the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial78 have shown that large absolute changes in Lp(a) may be needed to produce a clinically meaningful reduction in the risk of ASCVD events.

5.4 Laboratory measurement of lipids

and lipoproteins Measurement of lipids and lipoproteins is used to estimate the risk of ASCVD and guide therapeutic decision-making. Quantification of plasma lipids can be performed on whole plasma and quantification of lipoproteins can be achieved by measuring their protein component. Operationally, lipoproteins are classified based on their hydrated density (see Table 6).

5.4.1 Lipoprotein measurement Given the central causal role of ApoB-containing lipoproteins in the initiation and progression of atherosclerosis, direct measurement of the circulating concentration of atherogenic ApoB-containing lipoproteins to both estimate risk and guide treatment decisions would be ideal. Because all ApoB-containing lipoproteins—including VLDL, TG-rich remnant particles, and LDL—contain a single ApoB molecule, quantitation of ApoB directly estimates the number of atherogenic particles in plasma. Standardized, automated, accurate, and inexpensive methods to measure ApoB are available. Fasting is not required because even in the post-prandial state, ApoB48-containing chylomicrons typically represent <1% of the total concentration of circulating ApoB-containing lipoproteins. Furthermore, the analytical performances of ApoB measurement methods are superior to the measurement or calculation of LDL-C and non-HDL-C.79 Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026