For many years, epidemiologic data have convinced me and many others that HDL protects against atherosclerotic cardiovascular disease. The question is how? The dominant paradigm has long been that HDL removes cholesterol from sites of its accumulation in arteries, reverse cholesterol transport, a concept which goes hand in hand with the view that the accumulation of cholesterol or some fraction thereof in the arteries causes atherosclerosis.
Insights from Phase III Trials of Torcetrapib and Dalcetrapib
The simple idea that more HDL is better was unequivocally refuted by the failure of two inhibitors of the protein cholesteryl ester transfer protein (CETP), torcetrapib and dalcetrapib, to prevent cardiovascular events. Subjects taking torcetrapib had a 72% increase in HDL and a 25% decrease in LDL (due to concurrent statin therapy), yet still had 60% excess cardiovascular morbidity and mortality, resulting in premature termination of the study.
The study involving dalcetrapib was halted early because it was determined that there was virtually no chance of a positive outcome, despite increasing serum HDL by 31% to 40%. In a recent consensus statement from the National Lipid Association, leaders in the clinical research community concluded that therapy resulted in loss of some undetermined function of normal HDL, or development of “large dysfunctional HDL molecules.” 
Increased blood viscosity caused by large HDL molecules is indeed the explanation for the failure of CETP inhibitor trials. The aforementioned consensus statement on the role of HDL in cardiovascular disease by the National Lipid Association failed to mention blood viscosity.
Lipid Particle Size and the Stickiness of Red Blood Cells
Erythrocytes can approach each other to within 7.9 nm due to electrostatic repulsion caused by sialic acid in the erythrocyte cell membrane . Molecules which are large enough to simultaneously bind two erythrocytes, such as LDL and fibrinogen, foster erythrocyte aggregation and increase blood viscosity . Increased blood viscosity causes atherosclerosis by promoting thrombosis.
Normal HDL is too small to simultaneously bind two erythrocytes, and by competing with LDL for erythrocyte binding, decreases blood viscosity.
Erythrocyte aggregates are familiar to clinical laboratorians as the variable measured in the erythrocyte sedimentation rate. The bonds which form these aggregates are reversible and weak, forming in areas of slow blood flow. For an analogy that is easy to understand, a similar phenomenon is seen in the condiment ketchup. While ketchup is still, intermolecular bonds form and its viscosity increases. However, shake the bottle, and the viscosity of the ketchup decreases and it flows more quickly.
Inhibitors of CETP increase HDL particle size so that they too foster erythrocyte aggregation and increase blood viscosity. Torcetrapib, 120 mg per day, increased HDL particle size from 8.4 to 9.1 nm, and 120 mg twice daily increased particle size from 8.4 to 9.7 nm . Post-hoc analysis of data from the EPIC-Norfolk study show that the odds ratio for a major coronary event progressively increases with HDL particle sizes of 8.6 nm and greater, being 4 times higher for HDL particle sizes of more than 10.07 nm .
The larger the particle diameter, the more stable the erythrocyte aggregate will be because the repulsive force between erythrocytes decreases with the square of the intervening distance, according to Coulomb’s law. Normal HDL particles approach the maximum size, which will not increase the risk of cardiovascular disease, and it is difficult to improve on what evolution has wrought.
Consistent with a therapy-associated increase in blood viscosity, torcetrapib caused a 5-mm increase in systolic blood pressure. It should be noted that increased blood viscosity directly increases total peripheral resistance and systolic blood pressure.
Torcetrapib therapy was also associated with increased non-cardiovascular mortality, speaking to a defect in this treatment modality more fundamental than accelerated atherogenesis. In particular, mortality from cancer and infections were increased, despite there being no increase in the number of neoplasia or infections. Increased blood viscosity and decreased blood flow is a fundamental defect which would increase mortality from any disease.
Studies of two other CETP inhibitors, anacetrapib and evacetrapib, continue. This is testament to the appeal of the over-simplistic and incorrect notion that the accumulation of lipid in arteries causes atherosclerosis.
The opposite effects of LDL and HDL on blood viscosity have been confirmed many times. According to the scientific method, the less likely a prediction is to be true by chance, the stronger is the evidence in favor of the hypothesis if the prediction is confirmed. I submit that the prediction that an increase in the concentration of any component of blood will decrease viscosity is bold, and confirmation is strong evidence in favor of the hypothesis that increased blood viscosity causes atherosclerosis.
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