HDL a negative risk factor? or cholesterol efflux??

Although the data on HDL being protective of atherosclerotic disease is pretty consistent, there are negative studies, and the data on medications which dramatically improve HDL levels (eg, the cholesteryl ester transfer protein --CETP --inhibitors, such as torcetrapib) are clinically disappointing. there have been several explanations for this. for example, some HDL particles are "pro-inflammatory" and elicit an atherosclerotic response (which may be related to apolipoprotein C-III). a new article in NEJM highlights another angle -- that the issue is not the HDL number, but HDL's functionality in the reverse transport of cholesterol, as measured by the cholesterol efflux capacity (see lipids HDL efflux capacity vs amt NEJM 2014 in dropbox, or DOI: 10.1056/NEJMoa1409065). This article looks at the Dallas Heart Study, where they measured HDL levels, HDL particle concentrations, and cholesterol efflux capacity in 2924 adults free of cardiovascular disease and followed people a median of 9.4 years, assessing the primary endpoint of nonfatal MI, nonfatal stroke, coronary revascularization, or cardiovascular death.  results:

--median age 42; 43% male; 49% Black, 30% White; 30% hypertensive; 10% diabetic; 28% smoking; baseline total cholesterol 177, triglycerides 96, LDL 104, non-HDL 127, HDL 47, HDL particle concentration 32.8 mmol/L, Lp(a) 48, hs-CRP 2.7, coronary-artery calcium >10 Agatston units 19%. (ie, a pretty young and healthy crew)
--HDL cholesterol had significant correlations with: BMI, waist-to-hip ratio, visceral and truncal fat, adiponectin, leptin, insulin resistance, and CRP. 35% of variance of HDL was atributable to these other risk factors
--HDL particle concentration correlated with only waist-to-hip ratio, adiponectin and leptin levels; cholesterol efflux capacity correlated only with adiponectin and only to a small degree only. 3% of efflux capacity was attributable to other risk factors.
--132 patients had primary cardiovascular events over the 9.4 years.
--there was an inverse trend for baseline HDL to be associated with cardiovascular events, though even less pronounced when controlling for other risk factors.
--there was an inverse association between HDL particle concentration, adjusting for both the cardiac risk factors and HDL level (HR 0.53, 0.31-0.89)
--there was a graded inverse relationship between cholesterol efflux capacity and cardiovascular endpoints, comparing 4th vs 1st quartlile having HR 0.44 (0.27-0.73), without attenuation by other cardiac risk factors, HDL level, and HDL particle concentration.
--adding cholesterol efflux capacity to the traditional cardiac risk factors significantly improved the risk-prediction indexes.

so, what does this all mean?
--function is more important than just being there. it has been shown that there nonfunctional HDLs, as noted above. cholesterol efflux capacity, as shown in this study, is likely the most important functional role of HDL, though HDL also has antioxidant properties, decreases blood viscosity, improves endothelial function, and inhibits platelets.
--as commented on in the NEJM article, there is an assay for cholesterol efflux capacity which is now scalable to large numbers of patients (though i highly doubt it is commercially available, and i would wait for more large studies before ordering it anyway).
--I am always concerned that the newest article that comes out negates the trove of prior findings. the reality is that this Dallas Study was of very healthy people, there were not a lot of cardiac events (132 in 2924 patients followed almost 10 years -- only 4.4% !!), and so many previous articles have found that HDL is protective in population studies. and every article I've seen which looks at cardiac clinical outcomes has found that the cholesterol/HDL ratio is more predictive of events than the LDL (i've seen at least 6 such studies).  so, there is a really good reason that the Framingham Risk Score and others  incorporate the total cholesterol and HDL in their risk models.  The negative press on HDL is largely based on the negative intervention studies (eg with the CETP inhibitors, or with niacin, both of which probably create collateral damage on the vascular system).
--bottom line for now: until a commercial, inexpensive assay becomes available which reliably predicts atherosclerotic events better than HDL levels, we should continue measuring HDL levels and incorporating them into our cardiac risk assessment.