Cholesterol

Originally contributed here: https://philosophicalvegan.com/posting.php?mode=edit&f=7&p=47839

Please note, this article is a work in progress

What is Cholesterol?

(Ference et al., 2017, p. 2461).

Cholesterol is a type of plasma lipid and an organic molecule produced by the liver that serves critical roles in steroid hormone production, acts as a precursor to bile acids, and is used along the cell membrane to provide rigidity [1]. Cholesterol and other plasma lipids (triglyceride, phospholipid, free fatty-acids) are transported by lipoproteins, of which there are seven main types corresponding to their respected densities: high-density lipoproteins (HDL), low-density lipoproteins (LDL), very-low-density lipoproteins (VLDL), intermediate density lipoproteins (IDL), lipoprotein a (LPa), chylomicrons, and chylomicron remnants. All of which are atherogenic (cause heart disease) except HDL [2][3]. However, this article will focus on LDL because of its clinical significance to heart disease risk.

According to a paper published by the European Heart Journal(2017),

 "In most people, LDL particles constitute ∼90% of circulating apoB-containing lipoproteins in fasting blood (Figure 1)

Worth noting is the term 'LDL', 'LDL-C' and 'LDL cholesterol' are not interchangeable.

Ference et al (2017) posits that in clinical practice, rather than measuring the exact amount of plasma LDL within each LDL particle, it is usually estimated based on the concentration to assess the total amount of cholesterol contained within LDL particles; going forward, this will be referred to as LDL-C [4].

LDL vs HDL

Despite cholesterol being an aforementioned integral component of organic systems, the worry from various health authorities is having too much of it within the blood over a prolonged period, which is a disorder known as hypercholesterolemia. While all apoB-containing lipoproteins may play a role in atherosclerosis (heart disease), the most studied are LDL and HDL. To put simply, LDL is known as the "bad" cholesterol, and HDL can be thought of as the "good" cholesterol. HDL carries cholesterol back to the liver, while LDL carries it out where it can be deposited inside the coronary arteries [5]. A simplified explanation of the view is to imagine a pipe being slowly clogged and restricting flow, in this case, blood, to vital organs, eventually leading to a cardiac event (including but not limited to stroke, myocardial infarction, vascular thrombosis) or death. The problem occurs when there is consistent exposure of blood vessels to high levels of LDL, especially in the presence of low HDL, where they can infiltrate the inner lining of the arterial wall, become oxidized, and taken up by macrophages, initiating a cascade of inflammatory events that results in foam cell formation and deposition of plaque along the inner lining of the artery walls [6].

How Do We Know LDL-C Causes ASCVD?

Here we see various criteria for causation of LDL on ASCVD from table 1 of the paper.

In 2017, the European Society of Cardiology released a massive consensus paper concluding that LDL-C causes atherosclerotic cardiovascular disease (ASCVD). The analysis found the following:

 "Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. [7]

Genetic Research Provides Strong Evidence For Causation

As explained on page 2463, a mendelian randomization study is a genetic study in which participants are naturally randomized based on if they have an LDL-C raising or lowering genetic mutation. This allows an unbiased estimate that separates cholesterol from other confounding factors such as smoking. As mentioned, familial hypercholesterolemia (FH) is a genetic condition where a loss of function of the LDL receptor leads to markedly increased levels of LDL-C. As it turns out, these individuals have a significantly elevated lifetime risk of the disease and, in some instances, may die in their teens and twenties of heart disease (Ference et al., 2017, p. 2462). Furthermore, those who inherit the FH mutation as compared to unaffected siblings provide substantial grounds for a causative effect; the authors explain,

  “The fact that siblings who inherit an FH mutation have markedly elevated plasma LDL-C levels and a corresponding dose-dependent markedly elevated lifetime risk of ASCVD as compared to their unaffected siblings provides powerful evidence that LDL causes ASCVD” [8]"

Contrastingly, genes that lower LDL-c, also correspondingly lower the lifetime risk of CVD [9].

What is the Optimal Range For LDL?

Evidence from Fernández-Friera et al., 2017[10] and O'Keefe et al., 2004[11] show that when LDL is above 50-70mg/dL plaques form, and below this, the disease does not occur.

Rejection of Consensus

People who do not accept or downplay the role of cholesterol in heart disease are not taken seriously by the scientific community and are sometimes referred to by experts as "cholesterol denialists"[12]Such critics have been described as "dangerous" and "irresponsible" by medical experts [13]. Statin noncompliance is linked to recurring events and has been described as "An Internet-Driven Cult With Deadly Consequences"[14] [15] [16]. The most significant critics of the lipid hypothesis, or cholesterol as a cause of heart disease, are the International Network of Cholesterol Skeptics (TINCS), who often rail against the use of statin medications. Professor Rory Collins (2018) of Oxford University has criticized many of these individuals, especially when they espouse pseudoscientific claims against the use of life-saving statin medications. He has said this is no different to denying smoking:

 "The claims that blood LDL cholesterol levels are not causally related to cardiovascular disease (which is really in the same realm as claiming that smoking does not cause cancer) are factually false," (Rory Collins The Guardian, n.p).

When the director of TINCS Uffe Ravonskov was asked why he believes this, he said that the experts only say cholesterol is damaging to heart health because

  "the vast majority are paid generously by the drug companies."

[17]

Does Low LDL Cause Cancer and Higher All-Cause Mortality?

Among the less conspiratorial claims made by TINCS, is to point out that high LDL cholesterol in old age has a longevity advantage, while low LDL shortens lifespan. Ravonskov's finding is not novel. The 30-year follow up of the Framingham Heart Project found that for people over the age of 50, higher LDL was protective,[18]. In 2016, The Center for Evidence-Based Medicine (CEBM) responded to Ravonskov's claims of high LDL being protective. They pointed out that it is privy to extreme bias, such as reverse causation, meaning that it might not be that low LDL causes illness, but that illness causes low LDL[19]. Multiple lines of evidence show that this does appear to be the case. Randomized controlled trials of LDL lowering treatments reduce cardiovascular disease mortality without leading to increased cancer risk [20]. Furthermore, a genetic study in the elderly also refutes Ravonskov's claim, as those over 60 with genetically high LDL had a higher risk of mortality, and those with genetically low LDL had a lower risk, as expected [21]. Finally, another mendelian randomization trial demonstrated that despite observations there was a significantly increased risk of cancer in those with an LDL below the tenth percentile (in comparison to those with values above the 66th percentile), genetically predicted lower serum LDL was not associated with the incidence of cancer, underscoring that lower LDL is not causal, but likely part of the pathophysiology of cancer. [22] A few other problems with Ravonskov's observations are that they did not consider the duration of exposure to high LDL and survivorship bias. This highlights the unreliability of cross-sectional and other population studies like Ravonskov's and the importance of randomized genetic research for addressing cholesterol and whether or not it causes heart disease.

LDL: HDL Ratio Negates Negative Effects?

Skeptics may claim that cholesterol feeding increases HDL, and therefore the risk is attenuated. This is also a false claim as cholesterol feeding has been shown to increase the HDL to LDL ratio in an unfavorable direction [23]

Large Buoyant LDL particles are benign?

Another false claim offered by skeptics is the claim that the large buoyant LDL subfraction is non-atherogenic. Previous cohort studies have demonstrated this to be false as large LDL increases heart disease risk by 44%, while small LDL increases risk by 63% [24].

While it has been consistently shown that small dense LDL and the total cholesterol to HDL ratio do indeed correlate well with CVD risk, in no way does this indicate that sdLDL is inherently more atherogenic or that HDL and cholesterol are the central dictators of cardiovascular disease risk. Accordingly, most studies show that while sdLDL shows a significant univariate association with CHD risk, it is seldom an independent predictor after multivariate adjustment for triglycerides and HDL. This suggests that "the increased risk associated with smaller LDL size in univariate analyses is a consequence of the broader pathophysiology of which small, dense LDL is a part (e.g. high triglycerides, low HDL cholesterol, increased LDL particle number, obesity, insulin resistance, diabetes, metabolic syndrome)." [25]. Furthermore, a recent mendelian randomization observed the effects of various lipoprotein subfractions on CVD risk and provided additional support that sdLDL is not inherently more atherogenic, with the authors concluding, "LDL and VLDL subfractions appear to have nearly uniform effects on CAD across particle size. Therefore, the results do not support the hypothesis that small, dense LDL particles are more atherogenic." [26]

Dietary Cholesterol

Which Foods Contain Cholesterol?

Only foods of animal origin contain appreciable amounts of dietary cholesterol. For this reason, the average dietary intake of dietary cholesterol in vegans would be expected to be zero at all times. However, this does not necessarily mean that vegans do not have to worry about dyslipidemia, as other factors can raise cholesterol.

Does Dietary Cholesterol Raise Serum Cholesterol?

The three main factors that increase LDL cholesterol are dietary cholesterol, saturated fatty acids, and trans-fatty acids[27]. Eating cholesterol from food (dietary cholesterol) increases cholesterol in the blood (serum cholesterol). In scientific research, this is usually done with egg feeding as they contain a high amount of dietary cholesterol. However, most cholesterol feeding studies have found either a weak or no correlation, or only an association in specific individuals. Often these individuals are deemed "hyper-responders." This variability has led many to conclude that the relationship is weak or non-existent. With countless blogs and videos all over the internet, including some experts mistakenly concluding dietary cholesterol does not affect serum cholesterol. One of the proponents of this misinformation is Chris Kresser, an acupuncturist, and an online blogger. Kresser references a 2005 study looking at cholesterol feeding that found eggs raised cholesterol in insulin sensitive, but not in the diabetic or obese participants[28]. However, upon further investigation of the subject characteristics table, those that had low baseline serum cholesterol had an increase, while those who had a high baseline did not find an increase. In other words, the higher the baseline cholesterol, the less of an impact eating more had. In addition, a meta-analysis of forty studies from the American Journal of Clinical Nutrition found a similar finding; dietary cholesterol only raised serum cholesterol in those with a dietary intake under 900mg/dL [29]

Hegsted Equations and Meta-Regression Analyses

Interestingly, this is predicted by a mathematical equation called the Hegsted equation. The Hegsted equation is a way to predict the expected change in serum cholesterol from added dietary cholesterol and is remarkably consistent[30]. The relationship between dietary and serum cholesterol is a non-linear hyperbolic curve meaning it would be expected to level off. Simply, the higher the starting cholesterol is, the less of an impact eating more will have. Importantly, for this reason, decreasing dietary cholesterol would have a stronger impact.

Hegsted equation curve illustrated by Hopkins et al. (2015)

Article originally written by Riley MacIntyre May 30th 2020, 4pm