Friend or Foe? High HDL Cholesterol

High Density Lipoprotein Origin: liver Content: 18-25% TC content 45-55% Protein 2-7% TG 20-30% Phospholipids Density: (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 HDL 3. (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 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.