Pathophysiology

Atherosclerosis is a leading cause of death and loss of productive years of life worldwide.1 Research supporting the role of cholesterol in arterial plaque formation has led to the cholesterol hypothesis for atherosclerosis.

Low-density lipoprotein-cholesterol (LDL-C) has been widely studied. Research has confirmed that LDL-C and other apoB-containing lipoproteins, such as very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and lipoprotein (a), are involved in atherosclerosis. A key event in plaque formation is the accumulation of these lipoproteins in the arterial intima. Because of the size of LDL-C and other apoB-containing lipoproteins, cholesterol from them can enter the intima and accumulate.2 As LDL-C increases, the retention of plaque and risk of atherosclerosis increase.3

Levels of another source of cholesterol—high-density lipoprotein-cholesterol (HDL-C)—are inversely associated with atherosclerotic risk due, in part, to reverse cholesterol transport. HDL-C is thought to scavenge cholesterol from peripheral vessels and transport it to the liver for excretion. HDL-C has also demonstrated beneficial effects on platelet and endothelial function, coagulation, inflammation, and interactions with triglyceride-rich lipoproteins.4

While triglycerides are not directly atherogenic, they are a biomarker of cardiovascular (CV) risk due to their association with atherogenic remnant particles and apoC-III, a proatherogenic protein found on all classes of plasma lipoproteins. Several triglyceride-rich lipoproteins, including VLDL and chylomicron remnants, appear to promote atherogenesis independently of LDL-C.In addition, high triglycerides are associated with increased VLDL production and delayed VLDL clearance, resulting in higher risk of plaque formation.5,6

To avoid the atherogenic cascade, triglyceride-rich lipoproteins must be cleared from the bloodstream and metabolized by the liver before endothelial accumulation.5,6 Lowering LDL-C reduces plaque deposition, plaque rupture, and thrombus formation—the cause of several types of CV events—and helps maintain the structural integrity of the blood vessel. Statins and certain other drugs have been clearly shown to reduce LDL-C in the blood through decreasing the liver’s production of cholesterol. Other data have also shown the synergistic effects of statins and non-statin agents, such as ezetimibe (inhibits intestinal cholesterol absorption) or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, to further reduce cholesterol.7-9

LDL-C is removed from the blood when it binds to LDL receptors, mainly on hepatocytes. The complex is internalized into an endosome that then splits in two, one part of which carries the cholesterol and fuses to a lysosome for degradation and the other part that delivers the LDL receptor back to the cell surface to remove more LDL-C from the blood.7-9

Research over the past decade has characterized the role of PCSK9 in regulating LDL-C. PCSK9 binds to LDL receptors at a different site from LDL-C, and all three are internalized into the hepatocytes. When PCSK9 is bound, the LDL receptor does not return to the surface, and all three components of the complex are degraded by the lysosome. When the LDL receptor does not return to the surface, the result is a reduction of LDL-C clearance from the blood.10-13

Inhibition of PCSK9—and the resulting preservation of LDL receptors—has become an important therapeutic target. Monoclonal antibodies to PCSK9 have significantly reduced LDL-C in patients taking statins, people with statin intolerance, and individuals with familial hypercholesterolemia.10,12,14-16

References

  1. Bandeali S, Farmer J. High-density lipoprotein and atherosclerosis: the role of antioxidant activity. Curr Atheroscler Rep. 2012;14:101-107.
  2. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473:317-325.
  3. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38:2459-2472.
  4. Goldstein JL, Ho YK, Basu SK, Brown MS. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci USA. 1979;76:333-337.
  5. Talayero BG, Sacks FM. The role of triglycerides in atherosclerosis. Curr Cardiol Rep. 2011;13: 544-552.
  6. Ooi EM, Barrett PH, Chan DC, Watts GF. Apolipoprotein C-III: understanding an emerging cardiovascular risk factor. Clin Sci (Lond). 2008;114:611-624.
  7. Zheng C, Khoo C, Furtado J, Sacks FM. Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense low-density lipoprotein phenotype. Circulation. 2010;121:1722-1734.
  8. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol. 2014;11:563-575.
  9. Farnier M. PCSK9: From discovery to therapeutic applications. Arch Cardiovasc Dis. 2014;107:58-66.
  10. Seidah NG, Awan Z, Chrétien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014;114:1022-1036.
  11. Awan Z, Baass A, Genest J. Proprotein convertase subtilisin/kexin type 9 (PCSK9): lessons learned from patients with hypercholesterolemia. Clin Chem. 2014;60:1380-1389.
  12. Desai NR, Sabatine MS. PCSK9 inhibition in patients with hypercholesterolemia. Trends Cardiovasc Med. 2015;25:567-574.
  13. Norata GD, Tibolla G, Catapano AL. Targeting PCSK9 for hypercholesterolemia. Annu Rev Pharmacol Toxicol. 2014;54:273-293.
  14. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489-1499.
  15. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500-1509.
  16. Weinreich M, Frishman WH. Antihyperlipidemic therapies targeting PCSK9. Cardiol Rev. 2014;22:140-146.
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