Sunday, September 16, 2012

The Lipid Hypothesis: Blood Lipids and Ratios

Reverse Cholesterol Transport and The Total:HDL-C Ratio

Total cholesterol is an old risk factor for CVD and is quite an odd risk factor as it’s made up of cholesterol in LDL (LDL-C), HDL (HDL-C), IDL (IDL-C) and VLDL particles (VLDL-C), with LDL-C, IDL-C and VLDL-C being considered bad and HDL-C being considered good.   Surely if you consider LDL-C bad and HDL-C good then you should look at them separately or a ratio of them.

The reason HDL is thought to be good is because it transports cholesterol back to the liver (reverse cholesterol transport) and has antioxidant and anti-inflammatory effects [1]. 

The process of reverse cholesterol transport goes like this: 
  1. HDL transports cholesterol out of cholesterol rich macrophages (foam cells).
  2. Cholesterol ester transfer protein (CETP) exchanges the cholesterol in HDL particles with triglycerides in VLDL particles.  This lowers HDL-C and changes the VLDL particles into (small, dense) LDL particles
  3. The triglycerides in the HDL particle are degraded to fatty acids and glycerol via hepatic lipase, while the cholesterol in the LDL particle is transported to the liver and taken up by the LDL receptor often to be used for bile production 

A high Total:HDL-C ratio suggests the process of using and clearing cholesterol is inefficient, and is a stronger risk factor than total cholesterol, LDL-C, HDL-C or triglycerides.

“So what would the total-to-HDL cholesterol mean? The longer LDL stays in the blood, the more two things happen: it is exposed to oxidants, and as its limited supply of antioxidants run out, the polyunsaturated fatty acids in its membrane oxidize, leading to the further oxidation of its proteins and cholesterol; it is exposed to cholesterol ester transfer protein (CETP), which transfers cholesterol from HDL to LDL, thus boosting the total-to-HDL cholesterol ratio.” - Chris Masterjohn [1]

OR (10% increase)


A meta-analysis of cohort studies found that "the ratio total/HDL cholesterol was the strongest predictor of IHD mortality (40% more informative than non-HDL cholesterol and more than twice as informative as total cholesterol)" [4]

The Total:HDL-C ratio seems to be a pretty good risk factor (much better than total cholesterol) and the lipid hypothesis should probably be modified to suggest that: 'reducing the total cholesterol: HDL cholesterol ratio in an individual or in a population group will lead to a reduction in the risk of suffering a new event of coronary heart disease'

* In the second reference the likely reason why the Total:HDL-C ratio had a higher risk than the LDL-C:HDL-C ratio is because total cholesterol also includes IDL-C and VLDL-C (which may be worse than LDL-C, not sure).  non-HDL-C would be better than LDL-C to use for this reason.  Also, because total cholesterol and HDL-C is measured in standard blood tests you don't have to make approximate calculations that may or may not be accurate.

Testing the Modified Lipid Hypothesis

Once again, this modified lipid hypothesis is still a hypothesis.  While it may be true most of the time it still needs to be tested to see whether things that lower/raise the ratio actually decrease/increase the risk of CVD.  Previously I mentioned that phytosterols, replacing SFA with MUFA/PUFA or carbs, grain fibre and low fat diets reduce total cholesterol but don't reduce CVD.  Because these things reduce LDL-C proportionally more than HDL-C they also reduce the Total:HDL-C ratio, thus once again showing the importance of testing hypotheses and not assuming that just because something reduces the Total:HDL-C ratio it will therefore reduce CVD.  In addion, niacin and CETP inhibitors reduce the Total:HDL-C ratio, but don't reduce CVD

Niacin is vitamin B3, but when used in pharmacological doses (~100x the RDI) it’s considered a drug.  Niacin lowers total cholesterol, LDL-C and triglycerides and raises HDL-C, thereby lowering the Total:HDL-C ratio.  But niacin doesn't reduce CVD and may increase the risk of stroke [5]

CETP has gained some attention and is considered to be atherogenic because it generally increases LDL-C and decreases HDL-C, therefore increasing the Total:HDL-C ratio.  However, the relationship between genetic variations that reduce CETP expression and rates of CHD is inconsistent, some variants increase the risk, while others decrease the risk [6].  For example, one study found people with an HDL-C of 41-60mg/dl and a heterozygous mutation for CETP deficiency had 43% more cardiac events.  The authors of the study described CETP deficiency as “an independent risk factor for CHD” [7].  Although this hasn’t stopped pharmaceutical companies from developing CETP inhibitors.  In RCTs CETP inhibitors have resulted in more deaths than placebo.  This is probably because HDL cholesterol doesn’t protect against atherosclerosis, HDL particles do, and a way in which HDL particles protect against atherosclerosis is by carrying vitamin E and CETP transfers vitamin E to HDL particles [8] 

Further Reading:
(1) The Total-to-HDL Cholesterol Ratio -- What Does It Mean?

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