Pathophysiology

Cardiovascular disease (CVD) remains the leading cause of death and a major cause of disability in Western countries, and it is also becoming increasingly common in developing countries.1

Control of lipid levels is one of the most effective strategies for CVD prevention. Epidemiologic data have demonstrated the crucial role of dyslipidemia, especially hypercholesterolemia, in the development of CVD.1 Randomized clinical trials conducted over the past 20 years have consistently demonstrated that the aggressive reduction of LDL-C levels in the blood reduces CV risk in the settings of secondary prevention and high-risk primary prevention.2,3

Familial hypercholesterolemia (FH) represents a particularly difficult-to-treat type of hypercholesterolemia in the US.

Heterozygous FH (HeFH)4,5

  • Heterozygous FH is a genetic disorder (1 inherited FH-causing mutation) that affects about 1 in 250 people and increases the likelihood of having coronary heart disease at a younger age.
  • One of the main signs of HeFH is LDL-C levels over 190 mg/dL in adults and over 160 mg/dL in children.
  • For these patients, exercising and healthy eating habits are important; but often not enough to reduce LDL-C to a healthy/safe level.
  • Finding and treating the disorder early can reduce heart disease risk by up to 80%. Statin or other therapy in childhood is often required, sometimes starting by age 8-10.

Homozygous FH (HoFH)4-6

  • In very rare cases (~1 in 160,000-300,000 people worldwide, or ~1,300 people in the US), a person can have two FH-causing mutations in both copies of the same gene.
  • This is a life-threatening disease originally characterized by cholesterol levels >500 mg/dL, extensive xanthomas, and marked premature and progressive ASCVD.
  • People with HoFH have extremely high levels of cholesterol and can have CV events in childhood. Treatment is needed immediately.

Pathophysiology/Genetics

Atherosclerosis is a leading cause of death and loss of productive years of life worldwide.7 Research supporting the role of cholesterol in arterial plaque formation has led to the cholesterol hypothesis for atherosclerosis.

Of course, LDL-C has been widely studied and 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 heavily 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 and other APOB-containing lipoproteins, cholesterol from them can enter the intima and accumulate.8,9 As LDL-C increases, the retention of plaque and risk of atherosclerosis increase.10

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.11-13

In FH, the three main known genetic mutations are classified as:

  • Defects in the LDL receptor (most common)
  • Defects in apolipoprotein B (APOB)
  • Defects in proprotein convertase subtilisin/Kexin type 9 (PCSK9)

Each of these mutations leads to impairment of LDL receptors and a consequent reduction in uptake of LDL-C, with subsequent high LDL-C concentration.14

References

  1. Agabiti Rosei E, Salvetti M. Management of hypercholesterolemia, appropriateness of therapeutic approaches and new drugs in patients with high cardiovascular risk. High Blood Press Cardiovasc Prev. 2016;23:217-230.
  2. Ridker PM. LDL cholesterol: controversies and future therapeutic directions. Lancet. 2014;384:607-617.
  3. Ridker PM, Amarenco P, Brunell R, et al. Evaluating bococizumab, a monoclonal antibody to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: Rationale and design of the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) Lipid Lowering and SPIRE Cardiovascular Outcomes trials. Am Heart J. 2016;178:135-144.
  4. Centers for Disease Control and Prevention (CDC). Familial Hypercholesterolemia. Reviewed March 20, 2020. Accessed March 26, 2021. https://www.cdc.gov/genomics/disease/fh/FH.htm
  5. Cuchel M, Bruckert E, Ginsberg H, et al. Homozygous familial hypercholesterolaemia: New insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014;35:2146–2157.
  6. Regeneron [press release]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc; Feburary 11, 2021. FDA approves first-in-class Evkeeza™ (evinacumab-dgnb) for patients with ultra-rare inherited form of high cholesterol. https://investor.regeneron.com/news-releases/news-release-details/fda-approves-first-class-evkeezatm-evinacumab-dgnb-patients
  7. Bandeali S, Farmer J. High-density lipoprotein and atherosclerosis: The role of antioxidant activity. Curr Atheroscler Rep. 2012;14:101-107.
  8. Tabas I, Williams KJ, Bore´n J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007;116:1832-1844.
  9. Nordestgaard BG, Zilversmit DB. Large lipoproteins are excluded from the arterial wall in diabetic cholesterol-fed rabbits. J Lipid Res. 1988;29:1491-1500.
  10. 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.
  11. Zheng C, Khoo C, Furtado J, Sacks FM. Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense LDL phenotype. Circulation. 2010;121:1722-1734.
  12. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol. 2014;11:563-575.
  13. Farnier M. PCSK9: From discovery to therapeutic applications. Arch Cardiovasc Dis. 2014;107:58-66.
  14. Vaezi Z, Amini A. Familial Hypercholesterolemia. IN: StatPearls. Treasure Island (FL): StatPearls Publishing; January 1, 2021.
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