How much do we really know about dietary fat and cholesterol, and their relationships to both arterial plaque and cardiovascular disease? During the past several decades, a tremendous amount of new research on these topics has been published within the scientific literature. This research has largely overturned the diet-heart hypothesis, which gained traction during the 1960s and 1970s, and later became accepted as «settled science». The hypothesis makes the following core claims:
To understand the diet-heart hypothesis and its errors, we need to develop a more sophisticated view of cholesterol and its many forms. So the logical first question is, «what is cholesterol?» Cholesterol is a lipid — a type of fat — created by the liver. Cholesterol is absolutely essential to good health. Cholesterol, for example, is the primary precursor not only to vitamin D, but also to all five of the major classes of steroid/sex hormones: progestogens, glucocorticoids, mineralocorticoids, androgens, and estrogen.1 So how does cholesterol travel from the liver to its required destinations throughout the body?
Water and oil, of course, don’t mix. This is because fat is not water-soluble. In the same way, cholesterol, a lipid, is also not water-soluble. To travel around the body, however, cholesterol must be transported through the blood, a water-based medium. This is where high-density lipoprotein (HDL) and low-density lipoprotein (LDL) enter the picture. As lipoproteins, these molecules are combinations of lipids (including cholesterol) and protein. HDL contains proportionally more protein than does LDL. HDL is typically known as «good» cholesterol, whereas LDL is known as «bad» cholesterol, but the story is more complex that these simple names suggest.
In terms of function, LDL and HDL are directional. LDL carries cholesterol from the liver throughout the body, whereas HDL is tasked with reverse cholesterol transport (RCT), meaning it mediates the movement of cholesterol from peripheral cells to the liver for excretion from the body.2 Elevated HDL is a strong protective marker against cardiovascular disease, whereas elevated LDL is typically cited a risk factor for cardiovascular disease — but is LDL really so harmful?
When compared to real-world data, there is a serious problem with the claim that elevated LDL increases one’s risk for cardiovascular disease. In fact, in a statistically significant percentage of cases, people with elevated LDL are actually healthier than those with so-called normal levels. For people over 60, for example, a 2016 study published in the British Medical Journal demonstrated an inverse relationship between LDL count and mortality.3 The study’s lead author, Dr. Malcolm Kendrick, commented, «What we found in our detailed systematic review was that older people with high LDL (low-density lipoprotein) levels, the so-called “bad” cholesterol, lived longer and had less heart disease».4
The reason for this glaring contradiction between what we have been told about LDL and the available evidence has everything to do with LDL particle size. Generally speaking, LDL comes in two sizes — small and large — and only the small version, which is dense and can easily accumulate along the arterial walls, is potentially dangerous. Scientists consider the large version, which they sometimes referred to as buoyant or «fluffy» LDL, to be benign or protective.5
A normal cholesterol test measures cholesterol by volume or concentration (LDL-C). Most doctors consider LDL-C levels between 100 and 129 mg per dL (2.6 and 3.3 mmol/L) to be healthy. Unfortunately, tests that measure LDL concentration reveal nothing about the size of those LDL particles. For example, imagine you fill a drinking glass with almonds to 50% capacity. You then remove the almonds and fill the same glass to 50% capacity with tiny cumin seeds. In both cases, the glasses were 50% full, but if you count the number of individual almonds and the number of individual cumin seeds, you will of course have many more cumin seeds.
There is another test, known as LDL-P, which measures the number of LDL particles. If your LDL-P score is high, it indicates that you likely have a large amount of small LDL particles. LDL-C and LDL-P are sometimes concordant, meaning when one is high, so is the other. Discordant LDL scores, however, are also common. In other words, you can have low LDL-P while having high LDL-C; or you can have low LDL-C while having high LDL-P.6 Nevertheless, the focus should be on LDL-P, because as LDL-P increases, so does one’s risks for heart disease, obesity, hypertension, insulin resistance, high triglycerides, and low HDL.7, 8 In fact, the prevalence of small-particle LDL predicts heart disease at over three times the rate of large-particle LDL.9
The LDL-C test still provides useful information, but LDL-P should be the default cholesterol test used by doctors. In 2007, Crowell et al. analyzed data from the Framingham Offspring study and determined that LDL-P is nearly twice as predictive of cardiac events as LDL-C.10 In Part 2 of this newsletter series, we’ll examine specific foods and strategies for minimizing small-particle LDL.
For most of the 20th century, most researchers viewed atherosclerosis as a «cholesterol storage» disease, meaning arterial plaque, derived from circulating cholesterol, accumulates along the walls of the arteries, leading to increased blood pressure and, eventually, blockages. While this is true, it’s only part of the story. «Over the last quarter century», explains Harvard cardiologist Dr. Peter Libby, «the concept that inflammation plays a primordial role in atherogenesis has gained ascendency».11
The new understanding of atherosclerosis maintains that initial plaque build-up causes the arterial walls to thicken, but not to narrow. The accumulation of plaque, however, triggers an inflammatory immune response whereby leukocytes (white blood cells tasked with protecting the body from infectious disease and foreign invaders), for yet unknown reasons, attack the plaque deposits, thus triggering the development of fibrous lesions (a form of scar tissue). According to this view, stenosis (the narrowing of the arteries) is not the result of plaque accumulation per se, but of the repeated rupturing and healing of these lesions.
In 2016, writing for the Journal of the American College of Cardiology, Libby et al. summarized the current state of cardiovascular disease research, and the scientific community’s increasing acknowledgement of the holistic nature of the disease, as follows: «Recent research provides new insight into the integrative biology of inflammation as it contributes to ischemic cardiovascular disease. These results have revealed hitherto unsuspected inflammatory signaling networks at work in these disorders that link the brain, autonomic nervous system, bone marrow, and spleen to the atherosclerotic plaque and to the infarcting myocardium. A burgeoning clinical literature indicates that such inflammatory networks—far from a mere laboratory curiosity—operate in our patients and can influence aspects of ischemic cardiovascular disease that determine decisively clinical outcomes».12
As discussed above, inflammation contributes heavily to the clogging of the arteries. Reactive oxygen species, also known as free radicals, are among the primary causes of systemic inflammation. In 2008, Bonomi et al., in a study published by Histology and Histopathology, described the «consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein in the vascular wall».13 Reactive oxygen species (ROS), they went on to explain, «are key mediators of signaling pathways that underlie vascular inflammation in atherogenesis, starting from the initiation of fatty streak development, through lesion progression, to ultimate plaque rupture».14
In 2017, Katoor et al., publishing in Genetics and Genomics, further emphasized the role of ROS species in atherosclerosis and other vascular diseases. «Atherosclerosis», they wrote, «is now considered a chronic inflammatory disease. Oxidative stress, induced by [the] generation of excess reactive oxygen species has emerged as a critical, final common mechanism in atherosclerosis».15
ROS species are kept in check by antioxidants. Therefore, sufficient levels of circulating antioxidants are critical to maintaining clean, unclogged arteries. Glutathione is a tripeptide molecule that has the unique ability to recycle antioxidants. Normally, when antioxidants neutralize reactive oxygen species (free radicals), they become inert. Since glutathione can «recycle» these inert antioxidants, making them viable again, it is known as «the master antioxidant».
In studies of cardiac patients, glutathione levels are severely depleted compared to those observed in healthy people. For example, in a study of New York Heart Association patients, Class I structural cardiac disease patients exhibited 21% reduced glutathione, while Class II to IV patients exhibited 40% reduced glutathione.16 Liposomes are the best delivery vehicle for oral glutathione because they bypass proteolytic degradation within the GI tract. Liposomal glutathione, therefore, is one of the best nutraceutical products for preventing clogged arteries.
Homocysteine is an intermediate product in the normal biosynthesis of two amino acids — methionine and cysteine. Homocysteine is always present in the blood, but at elevated levels, it represents a major risk factor for many conditions, including various forms of cardiovascular disease. Since the early 1990s, for example, elevated homocysteine has been recognized as a risk factor for atherosclerotic vascular disease and hypercoagulability (collectively, we refer to these two conditions as the clogging of the arteries).17
Until recently, there was disagreement within the scientific community as to whether or not homocysteine is an independent risk factor for coronary artery disease (CAD). In 2014, however, a team of researchers analyzing data from 3,065 patients concluded that homocysteine is in fact an independent CAD risk factor.18 Reducing homocysteine is therefore one of the critical strategies for preventing arterial plaque.