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.............................................................................................................................. lipoproteins retained in the arterial wall provoke a complex process that leads to lipid deposition and the initiation of an atheroma.43

Continued exposure to ApoB-containing lipoproteins leads to additional particles being retained over time in the artery wall, and to the growth and progression of atherosclerotic plaques. On average, people with higher concentrations of plasma ApoB-containing lipoproteins will retain more particles and accumulate lipids faster, resulting in more rapid growth and the progression of atherosclerotic plaques. Because atherosclerotic plaques grow over time as additional ApoB-containing lipoprotein particles are retained, the size of the total atherosclerotic plaque burden is likely to be determined by both the concentration of circulating LDL-C and other ApoB-containing lipoproteins, and by the total duration of exposure to these lipoproteins. Therefore, a person’s total atherosclerotic plaque burden is likely to be proportional to the cumulative exposure to these lipoproteins.44 Eventually, the increase of the atherosclerotic plaque burden along with changes in the composition of the plaque reaches a critical point at which disruption of a plaque can result, with the formation of an overlying thrombus that acutely obstructs blood flow resulting in unstable angina, myocardial infarction (MI), or death. Therefore, the risk of experiencing an acute ASCVD event rises rapidly as more ApoB-containing lipoproteins become retained and the atherosclerotic plaque burden increases. This provides the rationale for encouraging a healthy lifestyle to maintain low levels of ApoB-containing lipoproteins throughout life to slow the progression of atherosclerosis; it also explains the motivation to recommend treatment to lower LDL-C and other ApoB-containing lipoproteins, for both the primary prevention of ASCVD and the secondary prevention of recurrent CV events.44

5.3 Evidence for the causal effects of

lipids and lipoproteins on the risk of atherosclerotic cardiovascular disease 5.3.1 Low-density lipoprotein cholesterol and risk of atherosclerosis Plasma LDL-C is a measure of the cholesterol mass carried by LDL particles, by far the most numerous of the ApoB-containing lipoproteins, and is an estimate of the concentration of circulating LDL. Numerous epidemiological studies, Mendelian randomization studies, and RCTs have consistently demonstrated a log-linear relationship between the absolute changes in plasma LDL-C and the risk of ASCVD.34,4550 The remarkable consistency among these studies, in addition to biological and experimental evidence, provides compelling evidence that LDL-C is causally associated with the risk of ASCVD, and that lowering LDL-C reduces the risk of ASCVD proportionally to the absolute achieved reduction in LDL-C.2,51

Furthermore, Mendelian randomization studies have demonstrated that long-term exposure to lower LDL-C levels is associated with a much lower risk of CV events as compared with shorter-term exposure to lower LDL-C (as achieved, for example, in randomized trials).48,52 These data provide strong support for the concept that LDL particles have both a causal and cumulative effect on the risk of ASCVD. Therefore, the effect of LDL-C on the risk of ASCVD appears to be determined by both the absolute magnitude and the total duration of exposure to LDL-C.2 The clinical benefit of lowering LDL-C is determined by the reduction in circulating LDL particles as estimated by ApoB, which is usually mirrored by a reduction of cholesterol carried by those particles.2,53 Therefore, the clinical benefit of therapies that lower LDL-C by reducing LDL particle mass will be proportional to the absolute reduction in LDL-C, because—on average—the reduction in LDL-C and LDL particles will be concordant.34,50,54,55 In contrast, the clinical benefit of therapies that lower LDL-C by a mechanism that may dramatically modify their composition may not be proportional to the observed absolute reduction in LDL-C, but instead would be expected to be proportional to the absolute change in LDL particle concentration as measured by a reduction in ApoB.2,53

5.3.2 Triglyceride-rich lipoproteins and risk of atherosclerosis TG-rich VLDL particles and their remnants carry most of the circulating TGs. Therefore, the plasma TG concentration reflects the concentration of circulating ApoB-containing TG-rich lipoproteins. Elevated plasma TG levels are associated with an increasing risk of ASCVD, but this association becomes null after adjusting for non- HDL-C, an estimate of the total concentration of all ApoB-containing lipoproteins.45 Similarly, lowering TG with fibrates reduces the risk of CV events by the same amount as LDL-C-lowering therapies when measured per unit change of non-HDL-C,50 suggesting that the effect of plasma TGs on ASCVD is mediated by changes in the concentration of TG-rich lipoproteins as estimated by non-HDL-C.

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Table 6 Physical and chemical characteristics of human plasma lipoproteins

Density (g/mL) Diameter (nm) TGs (%) Cholesteryl esters (%) PLs (%) Cholesterol (%) Apolipoproteins

Major Others

Chylomicrons <0.95 80100 9095 24 26 1 ApoB-48 ApoA-I, A-II, A-IV, A-V VLDL 0.951.006 3080 5065 814 1216 47 ApoB-100 ApoA-I, C-II, C-III, E, A-V IDL 1.0061.019 2530 2540 2035 1624 711 ApoB-100 ApoC-II, C-III, E LDL 1.0191.063 2025 46 3435 2226 615 ApoB-100 HDL 1.0631.210 813 7 1020 55 5 ApoA-I ApoA-II, C-III, E, M Lp(a) 1.0061.125 2530 48 3546 1724 69 Apo(a) ApoB-100 Apo = apolipoprotein; HDL = high-density lipoprotein; IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; Lp(a) = lipoprotein(a); PLs = phospholipids; TGs = triglycerides; VLDL = very low-density lipoprotein.

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