Blood Lipids and Disease Risk
The initial association between cholesterol and cardiovascular disease was born out of the detection of lipid and cholesterol deposits in atherosclerotic lesions during the progression of atherosclerosis.27 Subsequently, studies clarified the role of LDLs in cardiovascular disease development, particularly the role of oxidized LDL (ox-LDL; LDL particles that contain oxidized fatty acids) in infiltrating and damaging arterial walls, and leading to development of lesions and arterial plaques.28,29
Upon exposure of the fatty acid components of LDL particles to free radicals, they become oxidized and structural and functional changes occur to the entire LDL particle. The ox-LDL particle can damage the delicate endothelial lining of the inside of blood vessels.30 Once the ox-LDL particle has disrupted the integrity of the endothelial barrier, additional LDL particles flood into the arterial wall (intima). As oxidized LDL accumulates behind the endothelium, immune cells begin to infiltrate the site to attempt to deal with the oxidized LDL particles. Monocytes differentiate into macrophages, which engulf ox-LDL then express many adhesion molecules that limit their movement. This process results in accumulation of these macrophages rich in adhesion molecules (called foam cells), which contributes to subendothelial plaque burden. Immune cells that have infiltrated the subendothelium also release cytokines, which results in recruitment of more immune cells and LDL particles to the site. This accumulative cycle results in the formation of atherosclerotic plaque deposits, which cause the arterial wall to protrude and disrupt blood flow, a process referred to as stenosis.
Another modification to LDL thought to play a role in the development of atherosclerosis is glycation. LDL can become glycated when a sugar molecule modifies its structure. The reaction is not driven by enzymes and is dependent on the concentration of sugar in the blood, so it is easy to understand why individuals with diabetes have a greater degree of LDL glycation. LDL glycation can play a direct role in the development of atherosclerosis and also makes the LDL molecule more prone to oxidation.31,32
The recognition that modification of LDL is an initiator of endothelial damage allows for a clearer understanding of LDL’s role in the grand scheme of heart disease. Though an elevated number of native LDL particles does not directly endanger endothelial cells, it does mean that there are more LDL particles available to become oxidized (or otherwise modified), which then become more likely to damage endothelial cells.
Lowering serum cholesterol to a more healthful range—total cholesterol about 160–180 mg/dL and LDL cholesterol ideally under 80 mg/dL)— is one of the most frequently used strategies for reducing heart disease risk in persons without coronary heart disease (CHD).33 For young adults (age 20‒39), a 2018 expert panel recommended cholesterol-lowering therapy for those with LDL cholesterol over 160 mg/dL and a history of early-onset atherosclerosis in a close family member. For older adults, cholesterol-lowering therapy should be considered if one has diabetes, an LDL concentration ≥ 190 mg/dL, or increased risk as determined by a risk algorithm.1
Cholesterol and Thyroid Hormones
Thyroid hormones exert significant influence over several aspects of metabolic activity in humans. Lipid and cholesterol synthesis and breakdown are no exception. Thyroid hormones are not only involved in modulating the rate of cholesterol synthesis in the body, they also partly control the rate at which LDL is removed from the blood by influencing the expression of LDL receptors. A similar affect is observed with triglycerides, which are broken down by lipoprotein lipase, an enzyme controlled by cholesterol. The net effect of these relationships is that as people develop hypothyroidism—even subclinical hypothyroidism—their blood lipids often rise.34
In a retrospective study of 406 Chinese individuals who did not smoke and had normal thyroid function according to conventional laboratory parameters, TSH levels exhibited a linear correlation with total cholesterol, non-HDL cholesterol, and triglycerides.35 This means that as TSH levels increased, so did lipid levels. This was the case even within the conventionally established normal TSH range. The authors of this study remarked, "TSH in the upper limits of the reference range might exert adverse effects on lipid profiles and thus representing as a risk factor for hypercholesterolemia and hypertriglyceridemia in the context of CHD."
A review article published in 2015 highlighted numerous ways in which low-normal thyroid function may contribute to atherosclerotic cardiovascular disease.36 For instance, low-normal thyroid function may impair the ability of HDL to prevent the oxidative modification of LDL. Researchers also noted that low-normal thyroid function was linked to lower bilirubin levels, a natural antioxidant. The researchers went on to conclude that “collectively, these data support the concept that low-normal thyroid function may adversely affect several processes which conceivably contribute to the pathogenesis of atherosclerotic cardiovascular disease, beyond effects on conventional lipoprotein measures.”
Given that TSH levels, even within normal ranges, may contribute to an adverse lipid profile, it may be pertinent for anyone who notices their cholesterol or triglyceride levels beginning to rise to also have a more comprehensive thyroid function test. More information about thyroid function testing is available in Life Extension’s Thyroid Regulation protocol.
Measuring Blood Lipids
The determination of relative levels of blood lipids and their lipoprotein carriers is an important step for assessing cardiovascular disease risk, as well as determining appropriate measures for attenuating this risk. Most physicians conduct a routine, fasting blood chemistry panel during a patient's annual physical. This test includes the traditional lipid panel or lipid profile, which measures total cholesterol, HDL, and triglycerides from a fasting blood sample; LDL cholesterol levels are calculated from this data.37 An extended lipid profile may also include tests for non-HDL and VLDL.38
The recognition of some limitations of conventional lipid profile testing has led to the development of advanced lipid testing, which may have an improved prognostic power over conventional lipid panels.
One such advanced lipid analysis technique is nuclear magnetic resonance (NMR) spectroscopy,39 which can directly quantitate LDL particle number. An NMR lipid analysis includes a standard lipid profile, (LDL-C, HDL-C, triglycerides, and total cholesterol) plus the following important measurements:
- LDL particle number
- Number of small LDL particles
- HDL particle number
- LDL particle size
- An analysis of insulin sensitivity based on lipid particle chemistry
Other parameters that can offer insight into cardiovascular risk associated with blood lipids include:
- Lipoprotein (a)
- Lp-PLA2 (which measures activity of an enzyme that can contribute to vascular plaque rupture)
However, as stated elsewhere in this protocol, blood lipids represent only some of the factors that can contribute to cardiovascular risk. Life Extension’s Atherosclerosis and Cardiovascular Disease protocol covers many other factors that can increase risk and which can be measured through blood testing.