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L15 CVS Lipoproteins (as risk factors for heart disease)

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aliasesL15 CVS Lipoproteins (as risk factors for heart disease)

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Overview

This lecture covers how blood lipoproteins are measured and used in cardiovascular disease (CVD) risk assessment, the metabolic pathway that interconverts chylomicrons, VLDL, LDL and HDL, and the evidence that LDL, Lp(a) and HDL each contribute to (or protect against) atherosclerotic heart disease. It works through the mechanism of foam cell formation, current and emerging drugs to lower LDL and Lp(a), and ways to raise HDL.

Blood Lipid Testing and CVD Risk

Cholesterol carried in lipoproteins is measured in a blood lipid test and used in CVD risk assessment.

  • Optimal levels: total cholesterol < 4.0 mmol/L, triglycerides < 1.7 mmol/L, HDL cholesterol > 1.0 mmol/L, LDL cholesterol < 2.0 mmol/L, cholesterol/HDL ratio < 4.0.
  • For those at high CVD risk (including diabetes), the recommended target LDL is 1.8 mmol/L.
  • At lower risk (5-15%), a 40% reduction in LDL should be targeted.
    (Cardiovascular Disease Risk Assessment and Management for Primary Care, NZ, 2018)

Lipoprotein Metabolism Pathway

Key enzymes:

  • LPL (lipoprotein lipase): acts at the capillary endothelium.
  • HL (hepatic lipase): acts at the liver surface.

Steps (adapted from Brewer 2004, N. Engl. J. Med. 350:1491-1494):

  1. The liver secretes VLDL (carrying apoB, apoC-II, apoE).
  2. Dietary lipid enters as chylomicrons from the GI tract, also carrying apoB, apoC-II, apoE.
  3. LPL acts on chylomicrons and VLDL, depleting their triacylglycerol core and producing remnants (chylomicron remnants and VLDL remnants).
  4. HL converts the VLDL remnant to LDL.
  5. LDL is taken up by the liver via the LDL receptor, LRP or SR-BI, or enters the arterial wall.
  6. In the arterial wall, LDL is oxidised and taken up by macrophages via scavenger receptors, forming a cholesterol pool (foam cell precursor).
  7. HDL arm: nascent HDL (lipid-poor apoA-I) is converted by LCAT to mature (alpha) HDL carrying free cholesterol (FC), cholesteryl ester (CE) and apoA-I. Mature HDL interacts with ABCA1 on both arterial-wall macrophages and hepatocytes, driving cholesterol efflux from the macrophage and uptake/excretion by the liver (as bile acids, free cholesterol and phospholipid secreted to the GI tract).
  8. Apo(a), secreted by the liver, attaches to a VLDL/LDL particle in the circulation to form Lp(a) (elaborated below).

LDL and Foam Cell Formation

LDL promotes atherogenesis because it has high affinity for the arterial wall and carries lipids that are easily oxidised, which promotes inflammation and thrombosis. Sequence:

  1. LDL particles cross the vascular endothelium.
  2. LDL becomes oxidised LDL beneath the internal elastic lamina.
  3. Oxidised LDL and cell adhesion molecules recruit monocytes.
  4. Monocytes differentiate into macrophages, releasing IL-1 and MCP-1.
  5. Macrophages take up oxidised LDL via scavenger receptors.
    6-7. Lipid-laden macrophages accumulate, forming foam cells.
  6. Foam cells undergo apoptosis.

Associated smooth muscle mitogens drive smooth muscle proliferation and migration. This produces fatty streaks (pale/streaked areas visible on the arterial intima, e.g. in the abdominal aorta) which can progress to coronary stenosis (an example case showed 99% stenosis of the LCX following an inferior MI).

Evidence for LDL as a CVD Risk Factor

  • Many large clinical trials (Framingham, 4S, WOSCOPS) show elevated LDL-C is an independent risk factor for heart disease.
  • Statin intervention lowers CVD risk.
  • Individuals with familial hypercholesterolaemia (LDL receptor mutations) develop premature CVD.

Reducing LDL

Lifestyle: diet, weight loss, exercise.

Drugs:

  • Statins (HMG-CoA reductase inhibitors): lower cholesterol synthesis and upregulate the LDL receptor; well proven to reduce CVD risk; have benefits beyond cholesterol lowering, such as anti-inflammatory properties.
  • PCSK9 antibodies (e.g. alirocumab): used for statin non-responders; PCSK9 is a protease that degrades the LDL receptor, so inhibiting it increases LDL receptor availability.
  • For homozygous familial hypercholesterolaemia: MTP inhibitors (e.g. lomitapide) and apoB antisense drugs (e.g. mipomersen), both of which reduce hepatic lipoprotein secretion.

Lipoprotein(a) [Lp(a)]

Structure: Lp(a) = apo(a) + LDL. Apo(a) is disulphide-linked to the apoB-100 of an LDL particle. Apo(a) consists of a chain of kringle domains (KIV1-KIV10, KV) followed by a protease-like domain. The KIV2 domain occurs as a variable number of repeats, coded for by the LPA gene: more repeats corresponds to lower Lp(a) levels. Apo(a) is secreted by the liver, and Lp(a) forms by attachment to LDL/VLDL in the circulation.

Lp(a) is markedly more atherogenic than LDL: one estimate puts its atherogenicity at approximately 6-fold that of LDL on a per-particle basis (point estimate 6.6, 95% CI 5.1-8.8) (Björnson et al 2024).

Mechanisms of harm:

  • Atherogenic: Lp(a) drives the same foam-cell-forming cascade as LDL (endothelial crossing, oxidation, macrophage uptake, foam cell formation).
  • Immunogenic: oxidised phospholipids (OxPLs) carried on Lp(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans.

Epidemiology and evidence:

  • Lp(a) levels are genetically inherited; about 20% of the population has levels elevated above the desirable level (<50 mg/dL).
  • Support for Lp(a) as a CVD and aortic valve stenosis (AVS) risk factor comes from meta-analyses, studies of risk at extreme levels, UK Biobank data, genetic association studies, and AVS-specific studies.
  • A 2022 AHA scientific statement concluded Lp(a) is an independent and causal risk factor for atherosclerotic cardiovascular disease, acting via atherogenesis, inflammation and thrombosis, and is predominantly a monogenic risk determinant, with approximately 70-90% of interindividual variability in Lp(a) levels genetically determined.

Three slides in this section (the 2010 European Heart Journal consensus statement, the 2022 AHA scientific statement, and the Journal of Clinical Lipidology article on phenotypic mimics of FH) are screenshots of printed article covers with no extractable text layer; their content above was transcribed from the rendered images rather than from slide text.

Diagnostic pitfall: high Lp(a) levels can give the appearance of familial hypercholesterolaemia, because the cholesterol carried by Lp(a) is measured as LDL cholesterol in a standard lipid test.

Reducing Lp(a):

  • Statins are ineffective at lowering Lp(a) and may actually increase it.
  • PCSK9 inhibitors (which prevent degradation of the LDL receptor) do lower Lp(a).
  • Lp(a) apheresis, oestrogens and niacin all lower Lp(a) but are not ideal therapies.
  • While awaiting a specific effective therapy, an elevated Lp(a) level (>50 mg/dL) should provide incentive to manage other risk factors.
  • Emerging therapies: apo(a) antisense and siRNA drugs in Phase III trials (e.g. (Lp(a))HORIZON and OCEAN(a)); small molecule inhibitors of Lp(a) assembly (Eli Lilly) in Phase II; investigational in vivo CRISPR/Cas gene editing (e.g. CTX320, shown to durably reduce Lp(a) in non-human primates after a single dose).

HDL and CVD Risk

Evidence for HDL being protective:

  • Many large clinical trials show low HDL-C is a CVD risk factor.
  • Individuals with Tangier disease (ABCA1 mutations) have extremely low HDL and develop premature CVD.

Evidence against HDL being protective:

  • Genetic association studies (Voight 2012) do not support a causal protective role.
  • Intervention trials with CETP inhibitors (torcetrapib, dalcetrapib, anacetrapib) all failed to show benefit.

Case study - Tangier disease: female, age 42, severe HDL deficiency, minor stroke at age 40, father died of MI at 62, paternal uncle with CAD. Lipid results: total cholesterol 3.5 mmol/L (ideal <5.5), triglycerides 1.5 mmol/L (ideal <2.2), HDL cholesterol 0.04 mmol/L (ideal 1.00-2.20, markedly low), LDL cholesterol 2.8 mmol/L (ideal <3.5), cholesterol/HDL-C ratio 87.5 (ideal <5.5, markedly elevated).

Increasing HDL: exercise, weight loss, lipid-lowering drugs (statins, fibrates, niacin), alcohol (not ideal), dietary saturated fat (also not ideal).

Take Home Message

  • LDL, Lp(a) and HDL levels are all important in assessing risk of developing coronary artery disease (CAD).
  • Non-optimal levels should be treated with lifestyle changes and/or drugs.
  • Abnormal lipoprotein levels may run in families (genetics).

Self-test

  1. What is measured in a standard blood lipid test, and what are the optimal values for total cholesterol, LDL, HDL and the cholesterol/HDL ratio?
  2. Describe the steps of the lipoprotein metabolism pathway from VLDL/chylomicron secretion through to LDL formation, naming the enzymes involved at each step.
  3. Describe how HDL removes cholesterol from arterial-wall macrophages and returns it to the liver.
  4. Describe the steps of foam cell formation in the arterial wall, starting from LDL crossing the endothelium.
  5. List three lines of evidence that LDL is a causal risk factor for heart disease.
  6. Distinguish the mechanism of action of statins from that of PCSK9 inhibitors in lowering LDL.
  7. Describe the structure of an Lp(a) particle and explain what determines an individual’s Lp(a) level.
  8. Explain the two mechanisms by which Lp(a) is thought to promote cardiovascular disease.
  9. Why can elevated Lp(a) produce a lipid profile that mimics familial hypercholesterolaemia?
  10. Distinguish the evidence that supports HDL being protective against CVD from the evidence against it.
  11. A 42-year-old woman presents with a history of minor stroke, a father who died of MI at 62, and a lipid profile showing severely low HDL cholesterol with a very high cholesterol/HDL ratio. What condition does this suggest, and what is the underlying molecular defect?
  12. List three approaches to increasing HDL levels, noting any that raise HDL but are not recommended.
  13. Explain why statins are not an effective treatment for elevated Lp(a), and name a drug class that does lower it.
  14. A patient has high LDL, high Lp(a) and low HDL. Using the metabolic pathway, explain why each of these findings independently increases atherogenic risk.

Answers

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