The Problematic Paradigm of LDL-C, Part 3

LDL Studies and the Association Between LDL-C and Heart Disease, pt. 2

Previous - Part 2 - LDL Studies and the Association Between LDL-C and Heart Disease, pt. 1

This is the third installment overall in our investigation of lipids and cholesterol, and the second part of our look at studies that compare fat consumption, LDL cholesterol levels, and disease.

Framingham Offspring Analysis

As noted previously, the Framingham Heart Study is a decades-long initiative. The graphics below reflect a follow-up cohort of more than two decades, assessing cardiovascular disease as a function of cholesterol levels. To be clear, those who ultimately suffered cardiovascular disease did in fact have higher levels of LDL-C on average. However, an important note is that this relationship is not retained when stratifying by HDL-C and triglyceride levels. In fact, a person with low LDL-C may be at greatly elevated OR reduced risk depending on these other markers. There is simply no way to know based on LDL-C alone. Conversely, no person with high HDL-C levels is ever at elevated risk, regardless of how high LDL-C levels are. These observations will ultimately serve as much of the backbone for our future exploration of the underlying mechanisms of cardiovascular disease and dyslipidemia.¹

For now, it is sufficient to know that this occurs because low HDL-C and high triglycerides are strong, direct markers of the poor metabolic function that underlies cardiovascular and other chronic disease. One manner by which LDL-C can be elevated is as a downstream effect of that same metabolic dysfunction. In fact, the frequency of metabolic dysfunction in modern populations is the very reason the general association between LDL-C and cardiovascular disease tends to exist. Elevated LDL-C levels don’t portend a rise in cardiovascular disease risk in a person with optimal metabolic markers but they do help suggest increasing metabolic dysfunction when metabolic markers are suboptimal or poor. This phenomenon will be explored in great depth in future posts.

 

            

LEFT: HDL-C levels strongly predict cardiovascular disease, while LDL-C levels lose predictive value in those with good metabolic health. RIGHT: Relative cardiovascular risks for individuals with given levels of LDL-C, HDL-C, and triglycerides. Note the odds ratios (OR) that represent an increase or decrease in disease risk.

 

Studies Comparing LDL-C and Cardiovascular Disease

Additional modern studies confirm the general association between elevated LDL-C levels and increased risk of cardiovascular disease.^2–4 For example, one study found a 25% increased risk of coronary heart disease in those with long-term elevated LDL-C:

“We estimated a relative CHD risk of 1.25 for 16-years of exposure to LDL-cholesterol>190 mg/dL compared with 16 years of LDL-cholesterol<130 mg/dL”²

While another found the risk of cardiovascular disease death to be basically double in men with significantly elevated LDL-C levels.⁴ Interestingly, this same study found that both men and women with above average LDL-C levels suffered the lowest rates of death from all causes, which we will touch on next.

 

Studies Comparing LDL-C and All-Cause Mortality

There may be obvious, logical reasons to be concerned with cardiovascular disease in an individual with a history of such disease, but it perhaps makes less sense to place a myopic focus on heart disease alone in a seemingly healthy population. To that end, the relationship between LDL-C and all-cause mortality does not support the notion that elevated LDL-C is a risk factor for overall death and disease, and if anything supports the opposite – Those with the lowest LDL-C are, in fact, those who suffer the most disease and die the most frequently.^4–11

Yes, the preponderance of evidence suggests that it is those with low, not high, LDL-C levels who are most at risk of adverse health events and death, especially as people age. Take the following data from a massive study of healthy Danish individuals over the age of 50:

 

It is not the individuals with the recommended sub-100 mg/dl LDL-C levels, but those with LDL-C levels in the 130-160 mg/dl range that have the best survival rates.⁸ This finding is common across a number of studies. The reason for this finding may be that lipoproteins are highly involved in cellular repair. In fact, there is really no other manner by which the major components of the cellular repair mechanism – phospholipids and cholesterol that help form and maintain cell structure and function– can move to reach the cells of the body. The trafficking of these components is one of the main functions of the lipoprotein system in the body, so a deficit of this system could very reasonably play a role in susceptibility to cancer, infection, and other disease.

**I suspect significant seed oil consumption (canola, soybean, corn, etc.) may also play a role in this relationship, but that’s a long conversation for another day

For this and other reasons, it is highly common for these studies to exclude those with preexisting cardiovascular disease, diabetes, or other disease, and to exclude deaths that occur in the first year or two of follow-up. This seems an obvious choice, in order to avoid or minimize the potential confounding factors we just discussed. However, the predictive value of low LDL-C persists. Consider the findings of a study that excluded those with most underlying disease and those that died in the first year of follow-up:

“All-cause mortality was lower in the groups with TC or LDL-C above the recommended levels…These associations indicate that high lipoprotein levels do not seem to be definitely harmful in the general population”¹⁰

50- to 60-year-olds with LDL-C below 97 mg/dl were more than 50% more likely to have died compared those with higher LDL-C levels. Another study that excluded those with existing cancer diagnosis and those who died within two years of follow-up found “high mortality among older adults with lower TC” and a twenty percent decrease in mortality for those with LDL-C above 130 mg/dl.⁹

Despite efforts to mitigate any potential methodological issues, the common argument against these findings remains the notion that terminal or other serious disease (Usually cancer - Although it is important to note that low LDL-C is associated with other unfavorable outcomes such as stroke as well ^12,13) acts in some way to lower LDL-C, and that this effect confounds the data. To be clear – there is some evidence that individuals with cancer tend to have lower cholesterol levels.¹⁴ However, this makes clear only an association between cancer and low LDL-C levels. The association does not inherently support the second implicit argument – that cancer or other disease causes the decrease in LDL-C. In fact, the argument holds extremely little or no weight whatsoever. As just discussed, it is just as inherently likely that low LDL-C plays a role in the development of cancer than the other way around. Based on the available evidence, this may be the more likely reality.

One major problem with this argument, then, is that it necessarily flies in the face of the belief that low LDL-C levels are something to be desired. Scientists and healthcare professionals who champion very low LDL-C levels always or nearly always write off these findings by the argument outlined above. But even if this were true – if low LDL-C levels are so strongly predictive of future death by cancer or infection that the eventual disease shows up on a cholesterol panel many years in advance – it would necessarily be a cause for concern rather than a cause for celebration. Regardless of the underlying cause, adults with low LDL-C tend to die at a significantly increased rate in the years that follow. It is intellectually incongruent to hand-waive this observation away with the “cancer lowers LDL” argument while also high-fiving the patient for their supposedly optimal health.

The other major problem with this argument is that it is unsupported by the evidence. Again, cancer patients may have lower LDL-C levels. However, the evidence is better that low LDL-C predates and possibly influences the development of cancer than the other way around. On top of the typical measures taken by researchers to minimize any effects of preexisting disease, studies show low LDL-C levels predate an elevated risk of cancer by many years.^15,16 Consider the following statement from the American College of Cardiology, discussing a study demonstrating a strong association between low LDL-C levels and increased cancer incidence an average of 18 years later:

“Researchers reviewed data at four points in time prior to cancer diagnosis and found that LDL cholesterol values were lower in cancer subjects than matched controls at each point of assessment throughout an average of 18.7 years prior to diagnosis (p = .038). The trend for lower LDL-C in cancer patients compared with those who were cancer-free was consistent throughout the duration of the study.”¹⁵

This again suggests that low LDL-C is more likely to influence cancer development than the other way around. It also very strongly suggests that, if it increases the risk of death and can help predict cancer nearly twenty years out, a low LDL-C level needs to be taken seriously as a disease risk rather than celebrated as a sign of health.

NHANES Data

NHANES, the National Health and Nutrition Examination Survey, is a long term CDC tracking project that records the lifestyle habits, health markers and outcomes of thousands of Americans.¹⁷ The most recent set of results, detailing a fifteen year period ending in 2014, demonstrates a very similar relationship between LDL-C and all-cause mortality to that which we’ve already seen in the research. This can be seen below. The top graph shows calculated all-cause mortality risk as a function of LDL-C levels, while the bottom charts show the same risk stratified by LDL-C level and either adjusted for age (left) or adjusted for a variety of risk factors (right). Again, it is quite clear that it is those with low LDL-C levels, rather than those with elevated levels, who proved most likely to die (average age of subjects was 46 years old at the beginning of the tracking period).¹¹     

    

While opinions on the underlying reasons for the relationship differ, it is clear both that individuals with very low LDL cholesterol are at elevated risk of medium-term death and that individuals with high LDL cholesterol tend to be at only minor excess risk of death compared to those with average levels. Furthermore, the relationship between LDL cholesterol and cardiovascular disease is highly dependent on the presence or absence of reasonable metabolic health. This observation will drive much of our future discussion on the nature of lipids and cholesterol. Before diving in, though, we’ll first take a good look at what words like “cholesterol” really mean while explaining the relevant components of the lipid system.

Part 4 - Lipids and Cholesterol: Who Are the Players and What Are We Really Measuring?

1.           Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor? doi:10.1161/CIRCOUTCOMES.115.002436

2.           Ueda P, Gulayin P, Danaei G. Long-term moderately elevated LDL-cholesterol and blood pressure and risk of coronary heart disease. PLOS ONE. 2018;13(7):e0200017. doi:10.1371/journal.pone.0200017

3.           Mortensen MB, Nordestgaard BG. Elevated LDL cholesterol and increased risk of myocardial infarction and atherosclerotic cardiovascular disease in individuals aged 70–100 years: a contemporary primary prevention cohort. The Lancet. 2020;396(10263):1644-1652. doi:10.1016/S0140-6736(20)32233-9

4.           Gender difference of association between LDL cholesterol concentrations and mortality from coronary heart disease amongst Japanese: the Ibaraki Prefectural Health Study - Noda - 2010 - Journal of Internal Medicine - Wiley Online Library. Accessed August 7, 2022. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2796.2009.02183.x

5.           Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016;6(6):e010401. doi:10.1136/bmjopen-2015-010401

6.           Lu JM, Wu MY, Yang ZM, et al. Low LDL-C levels are associated with risk of mortality in a Chinese cohort study. Endocrine. 2021;73(3):563-572. doi:10.1007/s12020-021-02746-6

7.           Schupf N, Costa R, Luchsinger J, Tang MX, Lee JH, Mayeux R. Relationship Between Plasma Lipids and All-Cause Mortality in Nondemented Elderly. Journal of the American Geriatrics Society. 2005;53(2):219-226. doi:10.1111/j.1532-5415.2005.53106.x

8.           Johannesen CDL, Langsted A, Mortensen MB, Nordestgaard BG. Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study. BMJ. 2020;371:m4266. doi:10.1136/bmj.m4266

9.           Cabrera MAS, de Andrade SM, Dip RM. Lipids and All-Cause Mortality among Older Adults: A 12-Year Follow-Up Study. The Scientific World Journal. 2012;2012:e930139. doi:10.1100/2012/930139

10.         Bathum L, Depont Christensen R, Engers Pedersen L, Lyngsie Pedersen P, Larsen J, Nexøe J. Association of lipoprotein levels with mortality in subjects aged 50 + without previous diabetes or cardiovascular disease: A population-based register study. Scandinavian Journal of Primary Health Care. 2013;31(3):172-180. doi:10.3109/02813432.2013.824157

11.         Liu Y, Liu F, Zhang L, et al. Association between low density lipoprotein cholesterol and all-cause mortality: results from the NHANES 1999–2014. Sci Rep. 2021;11(1):22111. doi:10.1038/s41598-021-01738-w

12.         Ma C, Na M, Neumann S, Gao X. Low-Density Lipoprotein Cholesterol and Risk of Hemorrhagic Stroke: a Systematic Review and Dose-Response Meta-analysis of Prospective Studies. Curr Atheroscler Rep. 2019;21(12):52. doi:10.1007/s11883-019-0815-5

13.         Wang X, Dong Y, Qi X, Huang C, Hou L. Cholesterol Levels and Risk of Hemorrhagic Stroke. Stroke. 2013;44(7):1833-1839. doi:10.1161/STROKEAHA.113.001326

14.         Fiorenza AM, Branchi A, Cardenà A, Molgora M, Rovellini A, Sommariva D. Serum cholesterol levels in patients with cancer. Relationship with nutritional status. Int J Clin Lab Res. 1996;26(1):37-42. doi:10.1007/BF02644772

15.         LOW LDL CHOLESTEROL IS RELATED TO CANCER RISK. American College of Cardiology. Accessed December 14, 2022. https://www.acc.org/about-acc/press-releases/2012/03/25/15/15/http%3a%2f%2fwww.acc.org%2fabout-acc%2fpress-releases%2f2012%2f03%2f25%2f15%2f15%2fldl_cancer

16.         Knekt P, Reunanen A, Aromaa A, Heliövaara M, Hakulinen T, Hakama M. Serum cholesterol and risk of cancer in a cohort of 39,000 men and women. J Clin Epidemiol. 1988;41(6):519-530. doi:10.1016/0895-4356(88)90056-x

17.         NHANES - National Health and Nutrition Examination Survey Homepage. Published December 9, 2022. Accessed December 14, 2022. https://www.cdc.gov/nchs/nhanes/index.htm

The Problematic Paradigm of LDL-C, Part 2

LDL Studies and the Association Between LDL-C and Heart Disease, pt. 1

Previous - Part 1 - The Development of the Lipid-Heart and Diet-Heart Hypotheses

With a background understanding of how and why the lipid-heart and diet-heart hypotheses began to develop, we’ll now look at the research of the time, followed by more recent examples, that both do and do not support the general thesis of the LDL-disease paradigm. As mentioned in the previous installment, one significant study to be published during the rise of Keys, the AHA, and the general cholesterol paradigm was the Framingham study. An ongoing effort that persists to this day, the initial results were reported in 1957 and detailed a general relationship between cholesterol levels and future cardiac events. We’ll start with Framingham before examining several other lines of research concerned with the relationships between saturated fat, cholesterol levels, and heart disease.

Framingham

The Framingham Heart Study is an ongoing cardiovascular disease project that has been tracking, and continues to track, heart disease for the last several decades. The first published results, a 4-year follow up of middle-age Americans, were made available in 1957. Among the published results was a comparison of total cholesterol levels and atherosclerotic heart disease in men over the age of 45. A couple relevant notes – Frist, science in the 1950s tended to use “people” as a synonym for “middle-age white men who smoked a lot.” That’s not meant to discredit the results, just a note of interest. Second, this study predated the technique and practice to specifically measure LDL cholesterol, and instead used the slightly less meaningful total cholesterol. We’ll define and describe all the relevant terms in a coming section, but for now total cholesterol can be thought of as LDL-C plus HDL-C plus a small contribution from triglycerides.

What these results showed was simply that the men with total cholesterol over 260 mg/dl suffered more frequent heart disease during the 4-year follow up than those with lower cholesterol (for reference, standard guidelines today typically recommend a total cholesterol below 200mg/dl). Similar patterns were noted for elevated blood pressure and obesity. While not a specific measure of LDL cholesterol and not as “scientific” as modern research (this was simply a measuring and counting exercise), the pattern was nonetheless unmistakable – those men with elevated total cholesterol were more likely to suffer future heart disease. At a time when the lipid-heart hypothesis was still gaining credence, these results were instrumental in cementing its place in medical and public consciousness.^1,2

Minnesota Coronary Experiment

While the Framingham study was only observational, the Minnesota Coronary Experiment was a well-designed randomized controlled trial, or RCT. This means that subjects were “controlled” for a long period of time in their dietary habits, with results being tracked over time. In this case, the study was conducted on some 10,000 Minnesota mental health patients, whose diet and life were easily controlled, measured, and tracked. Half of the subjects ate food cooked and served with highly saturated fats like butter, while the other half consumed the same food cooked and served with generally unsaturated fats like corn oil and margarine.

What also made the MCE experiment notable was that it the brainchild of Ancel Keys, who designed the study in an effort to validate his beliefs that saturated fat consumption drove cholesterol levels and heart disease. In 1973, after five years of intervention and tracking, data was published demonstrating that the intervention (unsaturated fat) group did indeed have lower LDL-cholesterol levels (LDL-C measures were now common, unlike during the initial Framingham results). While LDL-C levels had fallen only 4 mg/dl in the saturated fat group, they had fallen 32 mg/dl on average in the intervention group. Perhaps Keys was right! This did in fact seem to validate, to at least some degree, the notion that saturated fat consumption influenced cholesterol levels.

You may be already asking the next relevant question – what about disease and death? After all, lower cholesterol is supposed to portend protection from heart disease. Well, that data was simply not published at the time. In fact, it remained unpublished for decades. Only in the last decade, with the death of Keys and his primary co-researcher, were these results made public by his collaborator’s son, who “rescued” the raw data from his father’s personal computer.

The findings may explain why data on death and disease was never published by Keys. That extra 30 mg/dl drop in LDL-C had not in fact saved lives, but was actually associated with a 22% increase in all-cause mortality. Had these results seen the light of day in the early 70s, they may have helped influence a different nutritional landscape in the years that followed. Instead, the data only on LDL lowering, on top of the Framingham results and multifaced efforts to demonize saturated fat, helped end any and all reasonable debate on the nature of heart disease. The fraudulent efforts of Keys, beginning years earlier with a fabricated relationship between fat consumption and disease, continued, as did the now-entrenched notion that saturated fat must be avoided to prevent heart disease.^3,4

Other Early Studies

The MCE was not the only large trial of the time designed to prove the diet-heart and lipid-heart hypotheses and, believe it or not, was not the only one to hide its undesirable results.

The Sydney Diet-Heart Study was another large RCT designed to explore the effects of replacing saturated fats with unsaturated vegetable oils. The results of the SDHS were also slated to be published in 1973. Instead, all that was published was the following:

“It is concluded that because of multiple changes in lifestyle men who have had myocardial infarction are not a good choice for testing the lipid hypothesis” ⁵

After seven years (and who knows how much effort and money) of designing and tracking dietary intervention in a population chosen by the researches, all they decided to publish was an excuse that their chosen population was inappropriate for studying the topic at hand.

Again, the full results eventually became public and, again, they likely betray the reason the researchers chose to hide them in the first place. The SDHS, like the MCE, was not designed to seek objective truth, but to validate a subjective truth that had already been pre-ordained. So when the data showed that the interventional vegetable oil group was 70% more likely to suffer cardiovascular disease and 62% more likely to die, the researches chose to blame their methodology instead.⁶

This is not to say that every study found an increased rate of death and disease in subjects replacing saturated fat. The Oslo Diet Heart Study was perhaps the most prominent study that did not confirm the (hidden) results of the MCE and the SDHS. Instead, 206 heart attack patients consuming a self-selected diet were compared to 206 similar patients consuming a controlled diet rich in unsaturated vegetable oil. The results? In 11 years, the self-selected diet group saw 102 cardiovascular disease deaths and 5 from other disease, while the vegetable oil group saw 88 cardiovascular disease deaths and 12 from other disease, for an approximately 14 percent decrease in cardiovascular mortality and a 7 percent decrease in all disease-related mortality.⁷

With Framingham and Oslo published and promoted and the MCE and SDHS covered up, the inescapable scientific conclusion of the time confirmed what Keys, the AHA, the government, and many doctors of the time already believed – saturated fat must be minimized in order to lower cholesterol levels and prevent death and disease.

** This part is purely my opinion: The Oslo study is absolutely horrible. Why? Because there is no real control group. The MCE and SDHS, for example, controlled the diet of both groups. This means that total calorie consumption, total sugar and carbohydrate consumption, nutrient density, etc. were all roughly equal between the two groups, and the difference in fat could be better assessed as the reason for any differences. Oslo didn’t do that. They simply let the control group eat whatever they wanted and made no effort to track it, while tracking every aspect of the intervention diet. So while the interventional high-vegetable oil group suffered slightly less disease, there isn’t really anything relevant to compare it to. This is a common problem even in modern science, where a population will go from a self-selected diet to one that’s fully controlled. Low-fat, low-carb, vegan, keto, whatever…but the researchers don’t control for calories. So any difference they find after the intervention could, in theory, be attributable to a decrease in calories rather than the dietary pattern the researchers are trying to assess. Because those in the Oslo study went from a self-selected “heart attack diet” to one entirely controlled by the researchers, it is entirely possible that the reduction in disease mortality was due to the intended intervention itself, but… it could also be due a reduction in calories or sugar or something else, and we have no possible way to know that. The increased mortality of the vegetable oil groups in the better-designed MCE and SDHS lend credence to the theory that vegetable oil is not the reason for the decreased mortality in the Oslo study. In fact, it may be the case that the vegetable oil is still causing excess disease, but that this effect is more than counterbalanced by the reduction in disease caused by a decrease in calories, sugar, or any change the researchers aren’t measuring or reporting.

Part 3 - LDL Studies and the Association Between LDL-C and Heart Disease, pt.2

 

 

 

1.           Framingham Heart Study. In: Wikipedia. ; 2022. Accessed December 14, 2022. https://en.wikipedia.org/w/index.php?title=Framingham_Heart_Study&oldid=1126493920
2.           Dawber TR, Moore FE, Mann GV. II. Coronary Heart Disease in the Framingham Study. Am J Public Health Nations Health. 1957;47(4 Pt 2):4-24.
3.           Frantz ID, Dawson EA, Ashman PL, et al. Test of effect of lipid lowering by diet on cardiovascular risk. The Minnesota Coronary Survey. Arteriosclerosis. 1989;9(1):129-135. doi:10.1161/01.atv.9.1.129
4.           Ramsden CE, Zamora D, Majchrzak-Hong S, et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ. 2016;353:i1246. doi:10.1136/bmj.i1246
5.           Woodhill JM, Palmer AJ, Leelarthaepin B, McGilchrist C, Blacket RB. Low Fat, Low Cholesterol Diet in Secondary Prevention of Coronary Heart Disease. In: Kritchevsky D, Paoletti R, Holmes WL, eds. Drugs, Lipid Metabolism, and Atherosclerosis. Advances in Experimental Medicine and Biology. Springer US; 1978:317-330. doi:10.1007/978-1-4684-0967-3_18
6.           Ramsden CE, Zamora D, Leelarthaepin B, et al. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ. 2013;346:e8707. doi:10.1136/bmj.e8707
7.           Leren P. The Oslo Diet-Heart Study. Circulation. 1970;42(5):935-942. doi:10.1161/01.CIR.42.5.935

The Problematic Paradigm of LDL-C, Part 1

The Development of the Lipid-Heart and Diet-Heart Hypotheses

The lipid-heart and diet-heart hypotheses. The average person may not know them by their name, but certainly everybody knows them in some capacity or another. Quite simply, their combined assertion is this: consuming dietary fat and cholesterol causes cholesterol levels in the blood to rise, and these rising levels of cholesterol are the primary factor in the development of heart disease. Put even more simply – eat too much fat, risk a heart attack.

This singular basic message has formed the backbone of nutrition and dietary advice for decades, for as long as most who will read this have been alive. One would be forgiven if, somewhere along a road lined with high-school health classes, heart-healthy checkmarks, and ubiquitous advertisements for low-fat yogurt and statins, that these ideas were settled science existing in a space far beyond any credible doubt. But what makes the longevity of these twin concepts so notable is both the absence of strong evidence to support the assertions, and the incredible simplicity of the model that allows them to persist unabated nonetheless.

The simplicity is apparent and approachable – eating fat and cholesterol causes cholesterol to accumulate in the bloodstream, where it…. gets stuck, basically. The mechanics of WHY cholesterol behaves this way are less apparent and rarely explained, but it seems the basic idea presented to the public is simply that cholesterol is a sticky substance that, in large amounts, inevitably attaches itself to the walls of the arteries and blocks the normal flow of blood. Obviously, things are not this simple. Likely surprising to many, cholesterol does not exist “in” the bloodstream at all, but in carrier “boats” called lipoproteins, and so the basic construct by which it sticks to the blood vessels needs at least some greater level of detail. In fact, it requires a much greater level of detail, which will be explored over the course of this series of posts.

But before exploring the realities of cholesterol and the failures of the lipid-heart and diet-heart hypotheses, one needs to understand where these parallel concepts came from and the factors that allowed them to thrive.

Some 70 years ago, as it is today, heart disease was a common killer in western society. Autopsies of young soldiers killed in action found significant atherosclerosis, artery-clogging deposits that contained, among other things, a waxy substance known as cholesterol. In an era that still saw doctors recommending their preferred brand of cigarette, the heavy rates of smoking among these young soldiers and the population at large didn’t jump off the page as an obvious candidate in the search for the heart-stopping culprit.

Around the same time, a University of Minnesota physiologist named Ancel Keys presented to the World Health Organization his theory that the consumption of fat (saturated fat from animal products in particular) was the primary factor in the development of cardiovascular disease. To support this claim, Keys hand-selected six countries, from a complete dataset of about two dozen, that allowed him to draw the most pronounced connection between increasing fat consumption and increasing heart disease. This extremely biased methodological error, in which Keys dismissed all available data contradicting his beliefs, led him to be publicly refuted in his original attempt at promoting his idea.¹

2

However, other factors were also developing that would eventually assist Keys in his effort to demonize the consumption of saturated fat. In 1911, while attempting to use vegetable oil as a base for soapmaking, the company Proctor and Gamble inadvertently discovered that they could create a partially solid product that reasonably resembled butter at room temperature. Vegetable oils, previously used primarily as industrial lubricants, were suddenly an appealing option for the creation of a cheap, shelf-stable, butter-like compound that could be marketed as a cooking product. Thus was born Crisco, an industrially-produced product with little saturated fat.³

For the next couple of decades, sales grew steadily as P&G marketed their butter-replacement product as a cheaper, easier cooking alternative. However, their big moment came in 1948 with their large donation to a fledgling non-profit known as the American Heart Association. On the back of this cash influx, the AHA, presided over at this time by Dr. Paul Dudley White, would go from an organization with little influence or notoriety to the largest non-profit in the nation in just more than a decade.^4,5

In 1955, during the AHA’s rise to prominence, President Dwight D. Eisenhower, himself a heavy smoker, suffered a heart attack that would be instrumental in shaping the American dietary paradigm. His personal doctor, the same Dr. White who presided over the AHA during the Crisco partnership and who was himself unsurprisingly opposed to saturated fat consumption, entrusted the role of the President’s personal nutrition advisor to the like-minded Ancel Keys. Eisenhower bought in to the “prudent diet” approach being offered by Keys, whose relationship with the popular president helped push him and his ideas forward in the American consciousness.^6,7

Now in lockstep with the President, Keys and the ever-growing AHA led a national charge to erase the menace of heart disease from American society. Within years of President Eisenhower’s heart attack, Keys was featured on the cover of TIME magazine as an expert on diet and heart health, while the AHA formalized guidance that saturated fat consumption should be strictly limited for the prevention of heart disease. These guidelines, based on effectively no clinical evidence, did not yet push for the elimination of all fat from the diet, arguing that the replacement of saturated fat with polyunsaturated fats such as Crisco would do the trick. As we will see in the next section, clinical trials launched after the fact were meant to validate the guidelines already put in place, but failed notably in this endeavor.

Unfortunately for President Eisenhower, the prudent diet approach assigned by Keys was ineffective, as he would go on to suffer multiple additional heart attacks, a stroke, and develop diabetes before his death from obstructive coronary disease. Now, much of this declining health is again likely attributable to smoking, but it is without question that the public face of America’s new low-fat diet experiment fell well short of resounding success.

Meanwhile, scientists such as John Yudkin advocated not for a low-fat, but instead a low-sugar approach to dietary intervention. In the mid-1960s, a series of studies pointing towards sugar as the primary driver of cardiovascular disease helped, briefly at least, keep alive the fat vs sugar debate. In an effort to combat the impact of these studies the research director of the Sugar Research Foundation, John Hickson, paid two Harvard scientists to author editorials in the New England Journal of Medicine that would discredit the research and exonerate sugar as a disease-causing agent. One of these scientists would become an administrator for the USDA, while the other would lead the Kellogg’s-funded nutrition foundation at Harvard.^8,9

Efforts such as these, combined with the growing prominence of Keys and his like-minded followers, the influence of the AHA, and the full resolve of the US government, helped cement the lipid-heart and diet-heart hypotheses as the standard dietary paradigm. While evidence was still extremely limited, one major observational study had now confirmed a general association between cholesterol and heart disease (the Framingham study, which we’ll examine in detail in the next section), with the promise of more and better research to come being promoted by Keys and others. While some of these research efforts would ultimately do more to discredit than to confirm the attack on saturated fat and LDL cholesterol levels, they would not do so until such notions were firmly entrenched in the minds of scientists, health care professionals, and the general public.

The lipid-heart and diet-heart hypotheses, weak and unsupported as they may be, were here to stay.

Part 2 – LDL Studies and the Association Between LDL-C and Heart Disease, pt.1

 

1.               1957_Yerushalmy_Hilleboe_Fat_Diet_Mortality_Heart_Disease.pdf. Accessed December 12, 2022. http://library.crossfit.com/free/pdf/1957_Yerushalmy_Hilleboe_Fat_Diet_Mortality_Heart_Disease.pdf
2.               Deep Nutrition: Why Your Genes Need Traditional Food - Catherine Shanahan, M.D. - Google Books. Accessed December 12, 2022. https://books.google.com/books?hl=en&lr=&id=1fs3DAAAQBAJ&oi=fnd&pg=PP1&dq=deep+nutrition+cate+shanahan&ots=YNQWfUTs9a&sig=tVMLoLV8CQ34Lhsq4Rduo__tQdg#v=onepage&q=deep%20nutrition%20cate%20shanahan&f=false
3.               MSEd LWB. This Is How Crisco Is Really Made. Mashed. Published July 9, 2020. Accessed December 12, 2022. https://www.mashed.com/224919/this-is-how-crisco-is-really-made/
4.               History-of-the-American-Heart-Association.pdf. Accessed December 12, 2022. https://www.heart.org/-/media/Files/About-Us/History/History-of-the-American-Heart-Association.pdf
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The Problematic Paradigm of LDL-C, Introduction

 

As was mentioned in this blog’s introductory post, much of what will be written on here will be expansive pieces on health and nutrition, designed to be both in-depth but also accessible to somebody with no background in topics related to health, physiology, or nutrition. Future topics will likely include, among others – why epidemiology (ie. observational study) is mostly junk science, why meat is certainly not causing cancer, why animals are not driving climate change, various aspects of chronic disease, the relationships between extreme exercise and health, why vegetables oils will lower your cholesterol but probably also contribute to killing you, why vegetables aren’t all they’re cracked up to be, and why your health will likely improve if you eat a bunch of them anyway.

However, the first topic that will be explored, likely over the course of the next 2-3 months, is cholesterol and cardiovascular disease. Cardiovascular disease is probably the most prominent chronic disease in the modern consciousness and the disease at which most dietary and nutrition advice has been aimed over the last several decades. Simply put, I believe the bulk of that advice has been and remains erroneous and actively harmful to those subscribing to its tenants, and has been far more effective at promoting massive commercial and pharmaceutical interests than it has at improving health or preventing disease.

I have already written a lengthy paper on the subject of lipid metabolism, cholesterol, and cardiovascular disease, which can be found here. However, this paper almost certainly suffers from the aforementioned problem of inaccessibility. My hope here, over the next several weeks, is to explain in lay terms the paper’s thesis and its implications for cardiovascular disease and human nutrition. I intend for this to be a roughly ten-part series on all things cholesterol, beginning with the necessary background information before walking through the behavior and mechanics of lipids and the dietary choices that drive these observations. This introductory post will serve as a table of contents of sorts, with part 1 coming shortly.

Part 1 - The Development of the Lipid-Heart and Diet-Heart Hypotheses 

Part 2 - LDL Studies and the Association Between LDL-C and Heart Disease, Pt. 1

Part 3 - LDL Studies and the Association between LDL-C and Heart Disease, Pt. 2

Part 4 - Lipids and Cholesterol: Who Are the Players and What Are We Really Measuring?

Part 5 - An Energy Delivery Model: Triglyceride Production and Utilization

Part 6 - An Energy Delivery Model: The Consequences of Poor Triglycerides Utilization

Part 7 - An Energy Delivery Model: Efficient Triglyceride Uptake and an Increased Energy Demand

Part 8 - An Energy Delivery Model: The Contrasting Presentations of Elevated LDL-C

Part 9 - An Energy Delivery Model: The Downstream Consequences of an Impaired Energy Delivery System

Part 10 - Other Factors in the Development of Atherosclerosis

Part 11 - The Effects of Diet on Markers of Cardiovascular and Metabolic Health

Part 12 - The Effects of Diet on LDL-C, As Told By Energy Delivery