High HDL Cholesterol
Friend or Foe?
High Density Lipoprotein
 Origin: liver
 Content:
 18-25% TC content
 45-55% Protein
 2-7% TG
 20-30% Phospholipids
 Density: 1.063-1.210 (highest density lipoprotein)
 Particle size: small
 Function:
 Reverse cholesterol transport from peripheral cells to liver
Reverse cholesterol transport
 Apo A-1 is produced by the liver and intestines and the building block for
nascent HDL.
 HDL particles accept free cholesterol from peripheral cells through ATP
binding cassette A1 (ABCA1).
 Including plaques in artery walls
 Lecithin cholesterol acetyl transferase (LCAT) converts free cholesterol to
cholesteryl esters to form the core of HDL3. (LCAT is activated by Apo A-1).
 HDL removes triglycerides from VLDL,IDL, or LDL in exchange for
cholesterol esters via CETP(cholesterol ester transfer protein).
 Transferred esters can then be taken up by the liver and eliminated through
scavenger receptors or delivered by HDL itself.
Hyperalphalipoproteinemia
 An elevated concentration of apo A-1 and apo A-II
 Associated with low levels of VLDL and TG
 HDL ≥60 is positevly associated with a decreased risk of coronary heart
disease per NCEP ATPIII.
 Factors that elevate HDL concentrations
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Chronic alcoholism
Oral estrogen replacement therapy
Aerobic exercise
Niacin(high dose), Fibrates, Statins
Deficiency of CETP
Is “Good” Cholesterol always Good?
 Very high levels of HDL cholesterol have paradoxically been
reported to be atherogenic
 Torcetrapib: CETP inhibitor developed by Pfizer for
hypercholeterolemia.
 Inhibition of CETP increases HDL particle size
 61% increase in HDL levels
 Development halted in 2006 when phase III studies showed
excessive all cause mortality.
The IDEAL and EPIC Studies
 Study designed to assess the relationship of HDL-C, HDL
particle size, and apoA-1 with the occurrence of CAD.
 Post-hoc analysis of 2 studies February of 2008
 IDEAL: higher HDL-C (>70mg/dL) proved a significant major
cardiac event risk factor after adjustment for other variables.
 EPIC: HDL particle size(>9.53) showed an increased risk, after
adjustment for apoA-1 and apoB levels. ApoA-1 was associated
with an overall decreased risk.
Theories
 Researchers have speculated that since the exchange of cholesterol
esters between HDL and peripheral cells is bidirectional, very
large HDL particles that are enriched in cholesterol become
cholesterol donors instead of acceptors
 Larger HDL particles can turn proinflammatory, thereby inducing
a proatherogenic lipoprotein profile. This may have been the case
in torcetrapib trials. Although patients on torcetrapib had
significant elevations in HDL-C, the agent did not induce the
expected regression of atherosclerosis
 Too many HDL particles may correlate with low functioning HDL
Conclusions
 Healthy lifestyle changes don’t contribute to raising large-particle HDL.
None of the existing treatments that raise HDL have been associated
with problems found with torcetrapib.
 Interventions that primarily raise plasma HDL-C but do not alter apoA-I
levels may not have any beneficial effects on atherosclerosis and may
increase the risk of atherosclerosis when achieving very high HDL-C
levels and HDL particle size
 ApoA-1 may be the most important cardioprotective factor.
 Size matters
 Large HDL may be detrimental (inconclusive)
 Pt’s with small LDL particle size are more at risk for CAD
Final Thoughts
 Lifestyle modifications continue to be the safest intervention
for raising HDL-C. Patients who need to raise their HDL
levels should be counseled on the benefits of participating in
routine aerobic exercise, defined as five 30-minute sessions
per week; smoking cessation; and dietary modifications such
as reducing intake of saturated and trans fatty acids and
increasing intake of monounsaturated and polysaturated fatty
acids.