The Straight Dope on Cholesterol by Peter Attia

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The Straight Dope on Cholesterol by Peter Attia

Rating: 8/10

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High-Level Thoughts

Peter Attia's multi-part series on what you should know about cholesterol may as well be a short book, so I took notes on it as if it were one. Enjoy! 

Summary Notes

"Cholesterol, a steroid alcohol, can be free or unesterified (UC as we say, which stands for unesterified cholesterol) which is its active form, or it can exist in its esterified or storage form which we call a cholesterol ester (CE). The diagram above shows a free (i.e., UC) molecule of cholesterol. An esterified variant (i.e., CE) would have an attachment where the arrow is pointing to the hydroxyl group on carbon #3, aptly named the esterification site."

"cholesterol can only be produced by organisms in the Animal Kingdom it is termed a zoosterol."

"About 25% of our daily intake of cholesterol roughly 300 to 500 mg comes from what we eat (called exogenous cholesterol), and the remaining 75% of our intake of cholesterol  roughly 800 to 1,200 mg  is made by our body (called endogenous production)"

"Cholesterol is required by all cell membranes and to produce steroid hormones and bile acids."

"Every cell in the body can produce cholesterol"

"Of this made or synthesized cholesterol, our liver synthesizes about 20% of it and the remaining 80% is synthesized by other cells in our bodies"

"the body works very hard (and very smart) to ensure cellular cholesterol levels are within a pretty narrow band"

"Excess cellular cholesterol will crystalize and cause cellular apoptosis"

"Plasma cholesterol levels (which is what clinicians measure with standard cholesterol tests) often have little to do with cellular cholesterol, especially artery cholesterol, which is what we really care about"

"Much (> 50%) of the cholesterol we ingest from food is esterified (CE), hence we dont actually absorb much, if any, exogenous cholesterol (i.e., cholesterol in food)"

"One of the biggest misconceptions out there (maybe second only to the idea that eating fat makes you fat) is that cholesterol is bad. This could not be further from the truth. Cholesterol is very good! In fact, there are (fortunately rare) genetic disorders in which people cannot properly synthesize cholesterol. Once such disease is Smith-Lemli-Opitz syndrome (also called SLOS, or 7-dehydrocholesterol reductase deficiency) which is a metabolic and congenital disorder leading to a number of problems including autism, mental retardation, lack of muscle, and many others."

"Cholesterol is one of the main building blocks used to make cell membranes (in particular, the ever-important lipid bilayer of the cell membrane)."

"Beyond cholesterols role in allowing cells to even exist, it also serves an important role in the synthesis of vitamins and steroid hormones, including sex hormones and bile acids."

"Re-absorption of the cholesterol we synthesize in our body is the dominant source of the cholesterol in our body. That is, most of the cholesterol in our body was made by our body."

"A molecule is said to be hydrophobic (also called nonpolar) if it repels water, while a molecule is said to be hydrophilic (also called polar) if it attracts water."

"Think of your veins, arteries, and capillaries as the waterways or rivers of your body."

"If a molecule is hydrophilic, it can be transported in our bloodstream without any assistance  sort of like swimming freely in the river  because it is not repelled by water. Conversely, if a molecule is hydrophobic, it must have a transporter to move about the river because the plasma (water) wants to repel it."

"Sugar and salt will easily dissolve in water. They are, therefore, hydrophilic. Oil does not dissolve in water. It is, therefore, hydrophobic. By extension, a molecule of glucose (sugar) or sodium and chloride ions (salt), because of their chemical properties which I wont detail here, will travel through plasma without assistance. A lipid will not."

"cholesterol doesnt exist in our bloodstream without something to carry it from point A to point B."

"The proteins that traffic collections of lipids are called apoproteins. Once bound to lipids they are called apolipoproteins, and the protein wrapped vehicle that transports the lipids are called lipoproteins."

"Apoprotein A-I (abbreviated apoA-I), which is composed of alpha-helicies, form lipoproteins which are higher in density. (The A class designation stems from the fact that apoAs migrate with alpha-proteins in an electrophoretic field). Conversely, apoprotein B (abbreviated apoB), which is predominantly composed of beta-pleated-sheets, form lipoproteins which are lower in density. (The B class designation stems from the fact that apoBs migrate with beta-proteins in an electrophoretic field.)"

"Virtually all apoB in our body is found on low-density lipoprotein  LDL, while most apoA-I in our body is found on high-density lipoprotein  HDL."

"It is the LDL particle that is the ultimate delivery vehicle of cholesterol back to the liver in a process now called indirect reverse cholesterol transport. However, under certain circumstances the LDL will penetrate and deliver its cholesterol load to the artery walls. THIS IS EXACTLY WHAT WE DONT WANT TO HAPPEN."

"The final important point I want to make about cholesterol transport is that it goes BOTH ways. Lipoprotein particles carry triglycerides and cholesterol from the gut and liver to the periphery (muscles and adipocytes  fat cells) for energy, cellular maintenance, and other functions like steroid creation"

"Historically this process of returning cholesterol to the liver was thought to be performed only by HDLs and has been termed reverse cholesterol transport, or RCT"

"This RCT concept is outdated as we now know LDLs actually perform the majority of RCT. While the HDL particle is a crucial part of the immensely complex RCT pathway, a not-so-well-known fact is that apoB lipoproteins (i.e., LDLs and their brethren) carry most of the cholesterol back to the liver. In other words, the bad lipoprotein, LDL, does more of the cleaning up (i.e., taking cholesterol back to the liver) than the good lipoprotein, HDL!"

"The problem, as well discuss subsequently, is that LDLs actually do the bad stuff, too  they dump cholesterol into artery walls."

"What becomes critical to understand for our subsequent discussions is that the apoB particles have the potential to deliver cholesterol into an artery wall (the problem were trying to avoid), and 90-95% of the apoB particles are LDL particles. Hence, it is LDL particle number (LDL-P or apoB) that drives the particles into the artery wall. Thus, physicians need to be able to quantify the number of LDL particles present in a given individual. For decades there was no way of doing that. Then LDL-C (read on) became available and it served as a way (not entirely accurate, but nonetheless a way) of quantitating LDL particles."

"Lp(a) is an LDL-like particle but with a special apoprotein attached to it, aptly called apoprotein(a), which is actually attached to the apoB molecule of a standard LDL particle. Think of Lp(a) as a special kind of LDL particle. As well learn later in this series, Lp(a) particles are bad dudes when it comes to atherosclerosis"

"Therefore LDL-C can be estimated knowing just TC, HDL-C, and TG, assuming LDL-C matters (hint: it doesnt matter much in many folks)."

"Unfortunately, especially in an insulin resistant population (i.e., the United States), both TG content within lipoproteins and the exchange of TG for cholesterol esters between particles is very common, and using this formula can significantly underestimate LDL-C. Worse yet, LDL-C becomes less meaningful in predicting risk, as I will address next week."

"I now use the HDL, Inc. [now (circa 2017) True Health Diagnostics] test exclusively for reasons I will explain later."

"the number and size of the lipoprotein particles is perhaps the earliest warning sign for insulin resistance."

"If you were only allowed to know one metric to understand your risk of heart disease it would be the number of apoB particles (90-95% of which are LDLs) in your plasma. In practicality, there are two ways to do this: Directly measure (i.e., not estimate) the concentration of apoB in your plasma (several technologies and companies offer such an assay). Recall, there is one apoB molecule per particle; Directly measure the number of LDL particles in your plasma using NMR technology."

"If this number is high, you are at risk of atherosclerosis. Everything else is secondary."

"Does having lots of HDL particles help? Probably, especially if they are functional at carrying out reverse cholesterol transport, but its not clear if it matters when LDL particle count is low. In fact, while many drugs are known to increase the cholesterol content of HDL particles (i.e., HDL-C), not one to date has ever shown a benefit from doing so."

"Does having normal serum triglyceride levels matter? Probably, with normal being defined as < 70-100 mg/dL, though its not entirely clear this is an independent predictor of low risk."

"Does having a low level of LDL-C matter? Not if LDL-P (or apoB) are high, or better said, not when the two markers are discordant."

"atherosclerosis  the accumulation of sterols and inflammatory cells within an artery wall which may (or may not) narrow the lumen of the artery"

"statistically speaking, this condition (atherosclerotic induced ischemia or infarction) is the most common one that will result in the loss of your life. For most of us, atherosclerosis (most commonly within coronary arteries, but also carotid or cerebral arteries) is the leading cause of death, even ahead of all forms of cancer combined. Hence, its worth really understanding this problem."

"The sine qua non of atherosclerosis is the presence of sterols in arterial wall macrophages. Sterols are delivered to the arterial wall by the penetration of the endothelium by an apoB-containing lipoprotein, which transport the sterols. In other words, unless an apoB-containing lipoprotein particle violates the border created by an endothelium cell and the layer it protects, the media layer, there is no way atherogenesis occurs."

"we know that the most successful pharmacologic interventions demonstrated to reduce coronary artery disease are those that reduce LDL-P and thus delivery of sterols to the artery"

"So why does having an LDL-P of 2,000 nmol/L (95th percentile) increase the risk of atherosclerosis relative to, say, 1,000 nmol/L (20th percentile)? In the end, its a probabilistic game. The more particles  NOT cholesterol molecules within the particles and not the size of the LDL particles  you have, the more likely the chance a LDL-P is going to ding an endothelial cell, squeeze into the sub-endothelial space and begin the process of atherosclerosis."

"there is some evidence that particle-for-particle Lp(a) is actually even more atherogenic than LDL (though we have far fewer of them)."

"The common denominator is that both sets of patients in (1) and (2) have high LDL-P. What Im going to attempt to show you today is that once adjusted for particle number, particle size has no statistically significant relationship to cardiovascular risk. But first, some geometry."

"at the same concentration of cholesterol within LDL particles, assuming the same ratio of CE:TG, it is mathematically necessary the person on the right, case #2, has more particles, and therefore has greater risk."

"Only when you do this can you see that the relationship between size and event vanishes. The only thing that matters is the number of LDL particles  large, small, or mixed."

"Around Q42006 (i.e., last 3 months of 2006), one of these variables began to deviate from the others. The details arent important, but the point is one variable began to suggest home prices would fall while the others all pointed to a continued rise. Prior to Q42006 these parameters were said to be concordant  they all predicted the same thing  either up or down. By 2007, they became discordant  one variable said the sky was falling while others said everything was fine."

"When all of the variables are concordant, their accuracy is prophetic, as was the case from the mid-1990s until late 2006. When some variables become discordant with each other, especially variables that were historically concordant with each other, really bad stuff happens,"

"while other factors are likely to be involved the pathogenesis of atherosclerosis (e.g., endothelial health, normal versus abnormal inflammatory response) the primary driver of atherosclerosis is the number of apoB trafficking lipoproteins in circulation, of which LDL particles are the vast majority."

"LDL-P is driving atherosclerotic risk, not LDL-C. If LDL-P and LDL-C were equally bad even when discordant you would expect the blue line to be as steep as the red line (and both to be steeper than the black line). But this is not the case."

"In fact, though not statistically significant, the highest risk group has high LDL-P and actually has low LDL-C (Ill give you a hint of why, below) while the lowest risk group has low LDL-P and not-low LDL-C."

"The highest risk and lowest risk groups are those with discordant LDL-C and LDL-P. The high risk group has high LDL-P and low LDL-C, while the lowest risk group has high LDL-C with low LDL-P."

"the discordance between LDL-P and LDL-C is exacerbated in patients with metabolic syndrome."

"In the patients without metabolic syndrome, LDL-C under-predicts cardiac risk 22% of the time, consistent with the population data I have shown you earlier. However, when you look at the patients with metabolic syndrome, you can see that 63% of the time their risk of cardiac disease is under-predicted. Again, not a typo."

"These data were collected from nearly 2,000 patients with diabetes who presented with perfect standard cholesterol numbers: LDL-C < 70 mg/dL; HDL-C > 40 mg/dL; TG <150 mg/dL. However, only in 22% of cases were their LDL-P concordant with LDL-C. That is, in only 22% of cases did these patients have an LDL-P level below 700 nmol/L. Remember, LDL-C < 70 mg/dL is considered VERY low risk  the 5th percentile. Yet, by LDL-P, the real marker of risk, 35% of these patients had more than 1,000 nmol/L and 7% were high risk. When you do this analysis with the same group of patients stratified by less stringent LDL-C criteria (e.g., <100 mg/dL) the number of patients in the high risk group is even higher. The real world tragedy: 90-95% of physicians, including cardiologists, would bet their own lives that persons with an LDL-C < 70 mg/dL have no atherosclerotic risk."

"LDL-C fails to even reasonably predict cardiovascular disease in a patient population sick enough to show up in the hospital with chest pain or outright myocardial infarction."

"With respect to laboratory medicine, two markers that have a high correlation with a given outcome are concordant  they equally predict the same outcome. However, when the two tests do not correlate with each other they are said to be discordant. LDL-P (or apoB) is the best predictor of adverse cardiac events, which has been documented repeatedly in every major cardiovascular risk study. LDL-C is only a good predictor of adverse cardiac events when it is concordant with LDL-P; otherwise it is a poor predictor of risk. There is no way of determining which individual patient may have discordant LDL-C and LDL-P without measuring both markers. Discordance between LDL-C and LDL-P is even greater in populations with metabolic syndrome, including patients with diabetes."

"if indeed LDL-P is always as good and in most cases better than LDL-C at predicting cardiovascular risk, why do we continue to measure (or calculate) LDL-C at all?"

"After two years the niacin group, as expected, had experienced a significant increase in plasma HDL-C (along with some other benefits like a greater reduction in plasma triglycerides). However, there was no improvement in patient survival. The trial was futile and the data and safety board halted the trial. In other words, for patients with cardiac risk and LDL-C levels at goal with medication niacin, despite raising HDL-C and lowering TG, did nothing to improve survival. This was another strike against the HDL hypothesis."

"This study found, consistent with the trials Ive discussed above, that any genetic polymorphism that seems to raise HDL-C does not seem to protect from heart disease. That is, patients with higher HDL-C due to a known genetic alteration did not seem to have protection from heart disease as a result of that gene. This suggests that people with high or low HDL-C who get coronary artery disease may well have something else at play."

"unpublished data from the MESA trial found that the correlation between HDL-C and HDL-P was only 0.73, which is far from good enough to say HDL-C is a perfect proxy for HDL-P."

"A rise in HDL-C seems to disproportionately result from an increase in large HDL particles. In other words, as HDL-C rises, it doesnt necessarily mean HDL-P is rising at all, and certainly not as much."

"for increases in HDL-C at low levels (i.e., below 40 mg/dL) the increase in small particles seems to account for much of the increase in total HDL-P, While for increases over 40 mg/dL, the increase in large particles seems to account for the increase in HDL-C. Also note that as HDL-C rises above 45 mg/dL, there is almost no further increase in total HDL-P  the rise in HDL-C is driven by enlargement of the HDL particle  more cholesterol per particle  not the drop in small HDL-P."

"Large HDL particles may be less protective and even dysfunctional in certain pathological states, whereas small to medium-sized HDL particles seem to confer greater protection through the following mechanisms: Greater antioxidant activity Greater anti-inflammatory activity Greater cholesterol efflux capacity Greater anti-thrombotic properties"

"The punch line: a serum HDL-C level has no known relationship to this complex process of RCT. The last thing a HDL does is lose its cholesterol. The old concept that a drug or lifestyle that raises HDL-C is improving the RCT process is wrong; it may or may not be affecting that dynamic process. Instead of calling this RCT, it would be more appropriately called apoA-I trafficking of cholesterol."

"I, and many others far more knowledgeable, would argue that if statins and other drugs were used to lower LDL-P (and apoB), instead of LDL-C, their efficacy would be even greater. The same is true for dietary intervention."

"authors found that an increase in the number of HDL particles and smaller HDL particles decreased the risk of cardiovascular disease."

"the problem with the HDL hypothesis is that its using the wrong marker of HDL. By looking at HDL-C instead of HDL-P, these investigators may have missed the point. Just like LDL, its all about the particles."

"50% of people with heart disease have normal traditional lipid values."

"What do I mean by this? Most risk calculators (e.g., Framingham) take their inputs (e.g., age, gender, LDL-C, HDL-C, smoking, diabetes, blood pressure) and calculate a 10-year risk score. If youve ever played with these models youll quickly see that age drives risk more than any other input."

"First, there are no long-term studies  either in primary or secondary prevention  examining the exact question we all want to know the answer to with respect to the role of dietary intervention on cardiovascular disease. There are short-term studies, some of which I will highlight, which look at proxies for cardiovascular disease, but all of the long-term studies (looking at secondary prevention), are either drug studies or multiple intervention studies (e.g., cholesterol-lowering drug(s) + blood pressure reducing drug(s) + dietary intervention + exercise + )."

"Second, everything we have learned to date on the risk relationship between cardiovascular disease and risk markers is predicated on the assumption that a risk maker of level X in a person on diet A is the same as it would be for a person on diet B."

"Since virtually all of the thousands of subjects who have made up the dozens of studies that form the basis for our understanding on this topic were consuming some variant of the standard American diet (i.e., high-carb), it is quite possible that what we know about risk stratification is that this population is not entirely fit for extrapolation to a population on a radically different diet"

"25% of total energy in the form of sugar is not as extreme as you might think. For a person consuming 2,400 kcal/day this amounts to about 120 pounds/year of sugar, which is slightly below the average consumption of annual sugar in the United States."

"What was most interesting about this study was the clear difference between the 3 groups that was not solely a function of fructose load. In other words, the best outcome from a disease risk standpoint was in the glucose group, while the worst outcome was not in the all-fructose group, but in the 50/50 (technically 55/45) mixed group. This is a very powerful indication that while glucose and fructose alone can be deleterious in excess, their combination seems synergistically bad."

"It is very difficult to make the case that when carbohydrates in general, and sugars in particular, are removed or greatly reduced in the diet, insulin resistance is not improved, even in the presence of high amounts of saturated fats. When insulin resistance improves (i.e., as we become more insulin sensitive), we are less likely to have the signs and symptoms of metabolic syndrome. As we meet fewer criteria of metabolic syndrome, our risk of not only heart disease, but also stroke, cancer, diabetes, and Alzheimers disease goes down."

"The consumption of sugar (sucrose, high fructose corn syrup) increases plasma levels of triglycerides, VLDL and apoB, and reduces plasma levels of HDL-C and apoA-I."

"The removal of sugar reverses each of these."

"The consumption of fructose alone, though likely in dose-dependent fashion, has a similar, though perhaps less harmful, impact as that of fructose and glucose combined (i.e., sugar)."

"The addition of fat, in the absence of sugar and starch, does not raise serum triglycerides or other biomarkers of cardiovascular disease."

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