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Lipid Distribution and Blood Viscosity

The roles of lipoproteins in atherosclerosis and other cardiovascular diseases (CVD) are often oversimplified.  Total cholesterol and low-density lipoprotein (LDL, the "bad" cholesterol) levels are typically viewed as factors for increased risk of CVD, while high-density lipoprotein (HDL, the "good" cholesterol) levels are negatively correlated with cardiovascular risk.  While this generalized view of risk factors has been commonly accepted within the medical community for some time, there has been a recent paradigm shift in thought.  A newer and increasingly well-accepted theory suggests that LDL deposits in the arterial walls become oxidized, initiating an inflammatory cascade that triggers formation of vascular lesions.1  This theory is not without its flaws, but it supports the central thesis that lipids are linked to cardiovascular diseases.  The most recent research emphasizes that not all types of cholesterol are equal.  Cholesterol screening and cardiovascular risk assessment may be improved by determining lipoprotein subclass profiles because LDL and HDL molecules vary in size and structure, thus affecting their function in the body. 2,3

A study published in JAMA in 1988 demonstrated that lipid profiles containing more small, dense LDL particles were linked with a threefold increased risk of myocardial infarction, regardless of age, sex, and relative weight.4 Another study published in the American Journal of Cardiology, conducted by researchers at the University of Pittsburgh, showed a strong correlation between small LDL particles and coronary artery calcification (CAC) (p < 0.01), a noninvasive predictor of coronary atherosclerosis and myocardial infarction.  This relationship was not seen with medium and large LDL particle sizes.5, 6 The same study also found a correlation with CAC for all very low-density lipoprotein (VLDL) subclasses, which are larger and contain more triglycerides than LDL.5 Most VLDL is metabolized to an intermediate density lipoprotein (IDL) which is subsequently broken down into LDL.  Results found in these studies suggest that LDL molecules as well as all sizes of VLDL cholesterol are positively associated with CAC while HDL had an inverse association with CAC.5  Although these findings provide insights for clinicians, there remains a controversy within the medical profession as to whether measuring lipid subclasses can effectively help direct treatments.  The majority of these treatments are targeted towards LDL, triglycerides, or total cholesterol as a whole.  Measuring lipid subclasses is also more cumbersome and costly than traditional cholesterol testing methods.  

Theories regarding LDL as a primary causative factor of CVD are, in part, driven forward by industry stakeholders in the market for cholesterol-lowering drugs such as statins, while ignoring the site-specific nature of atherosclerotic lesions.  If lipids and lipoproteins were the core cause of plaque formation, one would expect to see atherosclerotic plaques uniformly distributed throughout the body.  This is not the case, however, as clinical evidence has shown an affinity for atherosclerotic lesions within the proximal aorta, coronary arteries, carotid arteries, distal aorta, iliac, renal, and distal arteries of the leg.7,8 These areas are most prone to high turbulence and the abrasive forces of hemodynamic shearing which is actually determined by the viscosity of blood.  The thickness and stickiness of the blood itself is mediated by an array of factors including lipoproteins.

Lipoproteins and triglycerides in the blood have profound effects on blood flow.  A study published in Atherosclerosis by Seplowitz et al. found that VLDL caused greater increases in blood viscosity than LDL in vitro.3 Conversely, Rosenson et al. found that HDL has a negative relationship with blood viscosity at low and high shear, regardless if viscosity was corrected for hematocrit.2  Another study published in the journal Metabolism showed that whole blood viscosity was positively correlated with LDL (r = 0.443, p = 0.021) and inversely correlated with LDL size (r = -0.429, p = 0.029) at a shear of 1000 inverse seconds.9 This supports the previously cited evidence that all sizes of VLDL and certain subclasses of LDL encourage the development of coronary disease risk while HDL does just the opposite.5  What does this mean?  The idea that bad cholesterol causes cardiovascular disease and good cholesterol helps prevent it may be explained by their opposing effects on blood viscosity.

Elevated  blood viscosity is an independent predictor of stroke, carotid intima-media thickness (CIMT), and carotid atherosclerosis.9 In addition to detailed lipid profile screening, blood viscosity measurement serves as a comprehensive biomarker for cardiovascular health and blood flow.  The diverse types, sizes, and concentrations of lipids in circulation can trigger different hemodynamic responses (i.e. movement of blood through the body) which affect blood viscosity and cardiovascular outcomes.  A deeper consideration of blood flow parameters, rather than a lipid or inflammation theory alone, provides a more comprehensive explanation for the development of cardiovascular diseases.   The field of hemodynamics represents the new paradigm shift for understanding, diagnosing, and treating cardiovascular diseases.


References:

1. Libby, P., et al., Inflammation in atherosclerosis: transition from theory to practice. Circ J, 2010. 74(2): p. 213-20.

2. Rosenson, R.S., S. Shott, and C.C. Tangney, Hypertriglyceridemia is associated with an elevated blood viscosity: triglycerides and blood viscosity. Atherosclerosis, 2002. 161(2): p. 433-439.

3. Seplowitz, A.H., S. Chien, and F.R. Smith, Effects of lipoproteins on plasma viscosity. Atherosclerosis, 1981. 38(1-2): p. 89-95.

4. Austin, M.A., et al., Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA, 1988. 260(13): p. 1917-21.

5. Mackey, R.H., et al., Lipoprotein subclasses and coronary artery calcium in postmenopausal women from the healthy women study. Am J Cardiol, 2002. 90(8A): p. 71i-76i.

6. Wexler, L., et al., Coronary artery calcification: pathophysiology, epidemiology, imaging methods, and clinical implications: a statement for health professionals from the American Heart Association. Circulation, 1996. 94(5): p. 1175-1192.

7. Lowe, G.D., Different Locations of Atherosclerosis–Different Risk Factors, Different Therapies? Pathophysiology of haemostasis and thrombosis, 2005. 33(5-6): p. 262-266.

8. Malek, A.M., S.L. Alper, and S. Izumo, Hemodynamic shear stress and its role in atherosclerosis. JAMA 1999. 282(21): p. 2035-42.

9. Slyper, A., et al., The influence of lipoproteins on whole-blood viscosity at multiple shear rates. Metabolism, 2005. 54(6): p. 764-8.

 

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