Emerging research into underappreciated aspects of cholesterol biochemistry has revealed that levels of cholesterol account for only a portion of the cardiovascular risk profile, while the properties of the molecules responsible for transporting cholesterol through the blood, called lipoproteins, offer important insights into the development of atherosclerosis.
In fact, the size and density of lipoproteins are important factors for cardiovascular risk – for example, large, buoyant LDL (“bad cholesterol”) particles are much less dangerous than small, dense LDL particles; likewise large, buoyant HDL (“good cholesterol”) particles offer greater vascular protection than smaller, more dense HDL. The development of advanced lipid testing strategies that take the importance of lipoprotein particle size into consideration, such as the Vertical Auto Profile (VAP) or NMR (nuclear magnetic resonance) tests, allows a far deeper assessment of cardiovascular risk than a conventional lipid profile utilized by most mainstream medical practitioners.
Furthermore, metabolic processes, such as oxidation and glycation, modify the functionality of lipoproteins, transforming them from cholesterol transport vehicles into highly reactive molecules capable of damaging the delicate endothelial cells that line our arterial walls. This endothelial damage both initiates and promotes atherogenesis. Scientifically supported natural interventions can target the formation of these modified lipoproteins and help avert deadly cardiovascular diseases such as heart attack and stroke.
The pharmaceutical industry has been very successful in promoting cholesterol reduction with statin drugs as essentially the most important strategy for reducing cardiovascular risk. However, although the use of pharmaceutical treatment has saved lives, Life Extension has long recognized that optimal cardiovascular protection involves a multifactorial strategy that includes at least 17 different factors responsible for vascular disease.
Life Extension believes that innovative strategies for decreasing vascular risk should incorporate thorough cholesterol and lipoprotein testing, as well as strategic nutrient and pharmaceutical intervention, for optimal health effects and vascular support.
The Blood Lipids: Cholesterol and Triglycerides
CHOLESTEROL is a wax-like steroid molecule that plays a critical role in metabolism. It is a major component of cellular membranes, where its concentration varies depending on the function of the particular cell. For example, the membrane of liver cells contains fairly large fractions of cholesterol (~30%).1
The cholesterol in cell membranes serves two primary functions. First, it modulates the fluidity of membranes, allowing them to maintain their function over a wide range of temperatures. Second, it prevents leakage of ions (molecules used by the cell to interact with its environment) by acting as a cellular insulator.2 This effect is critical for the proper function of neuronal cells, because the cholesterol-rich myelin sheath insulates neurons and allows them to transmit electrical impulses rapidly over distances.
Cholesterol has other important roles in human metabolism. Cholesterol serves as a precursor to the steroid hormones, which include the sex hormones (androgens and estrogens), mineral-corticoids, which control the balance of water and minerals in the kidney, and glucocorticoids, which control protein and carbohydrate metabolism, immune suppression, and inflammation. Cholesterol is also the precursor to vitamin D. Finally, cholesterol provides the framework for the synthesis of bile acids, which emulsify dietary fats for absorption.
TRIGLYCERIDES are storage lipids that have a critical role in metabolism and energy production. They are molecular complexes of glycerol (glycerin) and three fatty acids.
While glucose is the preferred energy source for most cells, it is a bulky molecule that contains little energy for the amount of space it occupies. Glucose is primarily stored in the liver and muscles as glycogen. Fatty acids, on the other hand, when packaged as triglycerides, are denser sources of energy than carbohydrates, which make them superior for long-term energy storage (the average human can only store enough glucose in the liver for about 12 hours worth of energy without food, but can store enough fat to power the body for significantly longer).
Lipoproteins: Blood Lipid Transporters
Lipids (cholesterol and fatty acids) are unable to move independently through the blood stream, and so must be transported throughout the body as lipid particles. The lipid particles that transport cholesterol in circulation are called lipoproteins. Contained within these lipoproteins are one or more proteins, called apolipoproteins, which act as molecular “signals” to facilitate the movement of lipid-filled lipoproteins throughout the body. Lipoproteins can also carry fat-soluble antioxidants, like CoQ10, vitamin E, and carotenoids, which protect the transported lipids from oxidative damage. This is why vitamin E and CoQ10 have performed so well in cardiovascular studies – because they prevent the oxidative modification of LDL particles, which in turn protects the blood vessel lining from damage. This will be discussed in greater detail in forthcoming sections in this protocol.
Four main classes of lipoproteins exist, and each has a different, important function:
Amongst its myriad of functions, the liver has a central role in the distribution of cellular fuel throughout the body. Following a meal, and after its own requirements for glucose have been satisfied, the liver converts excess glucose and fatty acids into triglycerides for storage, and packages them into VLDL particles for transit to fat cells. VLDLs travel from the liver to fat cells, where they transfer triglycerides/fatty acids to the cell for storage. VLDLs carry between 10 and 15% of the total cholesterol normally found in the blood.3
As VLDLs release their triglycerides to fat cells, their cholesterol content becomes proportionally higher (which also causes the VLDL particle to become smaller and denser). The loss of triglycerides causes the VLDL to transition to a low-density lipoprotein (LDL). The LDL particle, which averages about 45% cholesterol, is the primary particle for the transport of cholesterol from the liver to other cells of the body; about 60-70% of serum cholesterol is carried by LDL.4
During the VLDL to LDL transition, an apolipoprotein buried just below the surface of the VLDL called ApoB-100, becomes exposed. ApoB-100 identifies the lipoprotein as an LDL particle to other cells. Cells which require cholesterol recognize ApoB-100 and capture the LDL, so that the cholesterol it contains can be brought into the cell. Each LDL particle expresses exactly one ApoB-100 molecule, so measurement of Apo-B100 levels serves as a much more accurate indicator of LDL number than LDL-C (LDL cholesterol) level.
Because of the correlation between elevated blood levels of cholesterol carried in LDL and the risk of heart disease, LDL is commonly referred to as the “bad cholesterol”. LDL is, however, more than just cholesterol, and its contribution to disease risk involves more than just the cholesterol it carries.
All LDL particles are not created equal. In fact, LDL subfractions are divided into several classes based on size (diameter) and density, and are generally represented from largest to smallest in numerical order beginning with 1. The lower numbered classes are larger and more buoyant (less dense); size gradually decreases and density increases as the numbers progress. Smaller, denser LDLs are significantly more atherogenic for two reasons; they are much more susceptible to oxidation,5,6,7 and they pass from the blood stream into the blood vessel wall much more efficiently than large buoyant LDL particles.8 A more comprehensive lipid test, such as The Verticle Auto Profile (VAP) Test or NMR (nuclear magnetic resonance), allows for assessment of the size and density of LDL particles, a feature that dramatically increases the prognostic value and sets these advanced tests apart from conventional lipid tests. If an individual is found to have a greater number of small dense LDLs they are said to express LDL pattern B and are at greater risk for heart disease than an individual with more large buoyant LDL particles, which is referred to as pattern A.
HDLs are small, dense lipoprotein particles that are assembled in the liver, and carry about 20-30% of the total serum cholesterol.9 Cholesterol carried in the HDL particle is called “good cholesterol,” in reference to the protective effect HDL particles can have on cardiovascular disease risk. HDL particles can pick up cholesterol from other tissues and transport it back to the liver for re-processing and/or disposal as bile salts. HDL can also transport cholesterol to the testes, ovaries and adrenals to serve as precursors to steroid hormones. HDLs are identified by their apolipoproteins ApoA-I and ApoA-II, which allow the particles to interact with cell surface receptors and other enzymes.
The movement of cholesterol from tissues to the liver for clearance, mediated by HDLs, is called reverse cholesterol transport. If the reverse cholesterol transport process is not functioning efficiently, lipids can build up in tissues such as the arterial wall. Thus, reverse cholesterol transport is critical for avoiding atherosclerosis. Interestingly, a link between the male hormone testosterone and reverse cholesterol transport has been discovered – testosterone enhances reverse cholesterol transport.10 Though it is known that testosterone decreases levels of HDL, it also improves HDL function. This effect is mediated by a protein in the liver called scavenger receptor B1 that acts to stimulate cholesterol uptake for processing and disposal. Testosterone beneficially increases scavenger receptor B1.11 Testosterone also increases the activity of an enzyme called hepatic lipase, another facilitator of reverse cholesterol transport.12
Aging men experience a decline in testosterone levels, as well as a simultaneous increase in heart disease risk, which suggests that these phenomena may be related. Indeed, studies have shown that men with even slightly lower testosterone levels were over three times as likely to exhibit signs of early coronary artery disease.13 In order to maintain optimal reverse cholesterol transport efficiency, aging men should strive to maintain a free testosterone in the youthful range of 20 – 25 pg/ml. Those men interested in learning more about the link between heart disease and declining testosterone levels and ways to boost testosterone naturally should read Life Extension’s Male Hormone Restoration protocol.
Blood Lipids and Lipoproteins 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.14 Subsequently, studies have elucidated a 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.15,16
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 oxidized LDL (ox-LDL) particle can damage the delicate endothelial lining of the inside of blood vessels.17 Once the ox-LDL particle has disrupted the integrity of the endothelial barrier additional LDL particles flood into the arterial wall (intima). Upon recognition of the presence of the ox-LDL within the intima, immune cells (macrophages) respond by engulfing it in an effort to remove it. But, the immune cells have then become too enlarged (by engulfing multiple ox-LDL particles) to escape back through the endothelial layer and become trapped within the intima, where they continually release cytokines, causing oxidative and inflammatory reactions to occur, resulting in the oxidation of additional native LDL particles and recruitment of more immune cells. 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.
The recognition that ox-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 an “optimal” range (total cholesterol 160 – 180; LDL-C 50-99) is one of the most frequently used strategies for reducing heart disease risk in persons without CHD.18 This approach, however, only addresses a portion of the risk. The actual predictive power of high LDL cholesterol for cardiovascular risk is likely much more complex, and has been the subject of several investigations. (Standard therapy for those at increased risk for heart disease is to keep LDL below 70 mg/dl.)
The Multifactorial Pathology of Vascular Disease
Analysis of the decline in CHD death rates from 1980 to 2000 by mathematical modeling highlighted the need to address multiple risk factors to protect against the end result of heart disease - mortality. In this study, cholesterol reduction accounted for only 34% of the reduction in death rate in individuals with heart disease. To put this into context, the same model estimated that reductions in systolic blood pressure were responsible for 53% of the death rate reduction, and smoking cessation accounted for 13%.19 In another comprehensive review of studies of CHD risk factors, non-HDL cholesterol increased the risk of CHD less than either elevated C-reactive protein (CRP; a marker of systemic inflammation) levels or high systolic blood pressure.20 In the Copenhagen Heart Study, which tracked 12,000 participants for 21 years, high cholesterol was the 6th most relevant risk factor for developing CHD in both men and women; diabetes, hypertension, smoking, physical inactivity and no daily alcohol intake (light alcohol consumption is heart-healthy) presented larger risks for the disease.21 The controversial JUPITER trial, which examined prevention of CHD by statin drugs in persons with very low LDL-C (but elevated hs-CRP) supported the conclusion that non-LDL-C risk factors (such as inflammation) represent enough risk for CHD to warrant treatment, even if lipids are within low-risk ranges.22
In order to reduce risk, there must be a systematic approach and understanding of the multiple factors of cardiovascular risk and atherosclerosis. Optimal cholesterol management is important for risk reduction, but so are the multiple risk factors that Life Extension has long identified. Accordingly, efforts to lower cholesterol to mitigate cardiovascular risk will only be met with optimal success if paired with measures to reduce other risk factors such as inflammation, oxidation, hypertension, excess plasma glucose, excess body weight, fibrinogen, excess homocysteine, low vitamin K, insufficient vitamin D, hormone imbalance; etc. Mainstream medicine is quick to point out that 10-15% of patients with coronary heart disease have no apparent major risk factors.23
Life Extension members are well aware of the need to address every risk factor for heart disease to improve outcome. The 17 Daggers of Arterial Disease graphic has been published in Life Extension Magazine and illustrates the risk factors that Life Extension has identified as being critical to address in order to maintain optimal vascular health.
Blood Lipid Measurement
The determination of the relative levels of the blood lipids and their lipoprotein carriers is an important step for assessing cardiovascular disease, 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 classic lipid panel or lipid profile, which measures total cholesterol, HDL, and triglycerides from a fasting blood sample; levels of LDL-C are calculated from this data.30 An extended lipid profile may also include tests for non-HDL and VLDL.
The recognition of the relative risks of the different subclasses of lipoprotein particles has led to the development of advanced lipid testing, which may have an improved prognostic power over conventional lipid panels in its ability to assess additional risk factors for CHD (such LDL particle size, VLDL remnants, lipoprotein(a), or ApoB). The Vertical Auto Profile (VAP) Test is a comprehensive advanced lipid test that uses advanced techniques to separate and quantify lipoproteins from a blood sample. The standard VAP can directly measure LDL-C levels; can subclassify LDLs by particle size and density, and HDL, VLDL subclasses, as well as apolipoprotein B-100 (ApoB).
A comparison between standard lipid tests and the VAP test is provided in the table below.
Other lipid tests include: 1) A gradient gel technique developed by Berkeley HeartLab,31 which, while not as comprehensive as the VAP test, is able to quantify all seven LDL subclasses. 2) Nuclear magnetic resonance (NMR) spectroscopy,32 which determines much of the same information as the other two techniques (VAP and Berkeley), but it is the only one test that can quantitate LDL particle number (though this is not necessarily an advantage over the VAP test, since this is functionally the same as directly quantitating ApoB-100).
Conventional Approaches to Managing Blood Lipids and Lipoproteins
Reduction of total- and LDL-cholesterol (and/or triglycerides) by conventional medical therapies usually involves inhibiting cellular cholesterol production in the body, or preventing the absorption/reabsorption of cholesterol from the gut. By reducing the availability of cholesterol to cells, they are forced to pull cholesterol from the blood (which is contained in LDL particles). This has the net effect of lowering LDL-C. Therapies which increase the breakdown of fatty acids in the liver or lower the amount of VLDL in the blood (like fibrate drugs or high-dose niacin)33 also result in lower serum cholesterol levels. Often, complementary strategies (such as statin to lower cholesterol production plus a bile acid sequesterant to lower cholesterol absorption) are combined to meet cholesterol-lowering goals.
Reduction of cellular cholesterol production is the most frequent strategy for reducing cardiovascular disease risk, with HMG-CoA reductase inhibitors (statins) being the most commonly prescribed cholesterol-lowering treatments. Statins inhibit the activity of the enzyme HMG-CoA reductase, a key regulatory step in cholesterol synthesis. Since cholesterol levels in cells are tightly controlled (cholesterol is critical to many cellular functions), the shutdown of cellular cholesterol synthesis causes the cell to respond by increasing the activity of the LDL receptor on the cell surface, which has the net effect of pulling LDL particles out of the bloodstream and into the cell. Statins may also reduce CHD risk by other mechanisms, such as by reducing inflammation.34
Statins may induce serious side effects in some individuals; most common being muscle pain or weakness (myopathy). The prevalence of myopathy is fairly low in clinical trials (1.5-3.0%), but can be as high as 33% in community based studies and may rise dramatically in statin users who are active (up to 75% in statin-treated athletes.)35,36 Occasionally, statins may cause an elevation of the liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT). These enzymes can be monitored by doing a routine chemistry panel blood test. Additionally, by inhibiting HMG-CoA reductase (an enzyme not only required for the production of cholesterol, but other metabolites as well), statins may also reduce levels of the critically important antioxidant molecule CoQ10.
Lowering cholesterol absorption from the intestines reduces LDL-C in a different fashion; by preventing uptake of intestinal cholesterol, cells respond by making more LDL receptor, which pulls LDL particles out of the blood stream. Ezetimibe and bile acid sequestrants (colesevelam, cholestyramine, cholestopol) are two classes of prescription treatment that work in this fashion. Ezetimibe acts on the cells lining the intestines (enterocytes) to reduce their ability to take up cholesterol from the intestines. While ezetimibe does reduce LDL levels, the results of several major trials37,38,39 failed to show the benefit of ezetimibe as part of a combination therapy for reducing risk of cardiovascular disease, and it may actually increase the risk of atherosclerosis if prescribed to patients already on statins for reasons that are not clear.40 Bile acid sequestrants bind to bile acids in the intestine, which reduces their ability to emulsify fats and cholesterol. This has the net effect of preventing intestinal cholesterol absorption. Bile acid sequestrants may also increase HDL production in the liver, which is usually inhibited by the reabsorption of bile acids.41