The answer to that foolish question is certainly going to be “both.” But the finger pointing at the guilty party has wobbled around a good deal in the past few years, and just before Christmas, the American Heart Association came out with a set of dietary recommendations once again apparently putting at least some blame for heart disease on dietary cholesterol. This is a pretty big switch. In the past decade, the recommendations have bounced around a good bit; for example, as late as the 2018 cholesterol management guidelines from the American College of Cardiology and the American Heart Association shifted the emphasis on cholesterol management away from dietary cholesterol.
What, we may ask, is going on? Here’s how the American Heart Association science advisory puts it:
“Historically, nutrition guidelines for reducing cardiovascular disease (CVD) risk and achieving optimal plasma lipoprotein profiles have included recommendations to limit dietary cholesterol. However, contemporary guidelines for CVD risk reduction from the American Heart Association (AHA) and American College of Cardiology (ACC) and the “2015–2020 Dietary Guidelines for Americans” have not issued explicit guidance for dietary cholesterol. Because of the inconsistencies in the evidence base and the inherent difficulty in conducting and interpreting studies to isolate the independent effect of dietary cholesterol on CVD risk, controversy has ensued about whether dietary cholesterol should be a target for CVD prevention and management. (Carson et al “Dietary Cholesterol and Cardiovascular Risk” Circulation. 2019;140:00–00)
From where Doc Gumshoe sits, the AHA is being more than a bit weasely. To answer my previous question, what has been going on is that for several decades, the official positions of the major medical associations emphatically advised limiting the consumption of foods that were high in cholesterol, which specifically included red meat, eggs, and full-fat dairy products. But in the past five years or so, they have effectively backed away from those recommendations, without explaining why they did so. And then, in this past year, the AHA perhaps realized that they may have backed away a bit too far.
What do we know about cholesterol that got us to this point?
More than a century ago, it was determined firmly and clearly, and without “inconsistencies in the evidence base,” that cholesterol was the substance deposited in the walls of human arteries and was the main component in arterial plaque.
It was understood that cholesterol is a simple molecule, solid at body temperature, and not water soluble. It is present in virtually all our tissues, providing structure, and is absolutely essential for life. But, since cholesterol is not water soluble, in order to be transported in our bloodstream, it has to hitch a ride with substances that can be carried around in blood. These are lipoproteins – little particles containing both proteins and lipids, not in any fixed chemical combination, but bundles of varying sizes. Cholesterol attaches to the lipid part of these bundles, and the protein part permits them to be transported in blood.
These particles range in size and density. The low-density, loosely packed bundles, called low-density lipoprotein cholesterol, or LDL-cholesterol, are the ones nicknamed “bad” cholesterol, because they are the ones that are apt to shed the cholesterol molecules themselves, which can attach to the walls of the arteries and even penetrate those walls. But, we have to remember, the LDL-C is absolutely essential to our lives, because those particles are the ones that convey cholesterol to where it’s needed, which is pretty nearly everywhere in our bodies.
The smaller, denser bundles, called high-density lipoprotein cholesterol, or HDL-cholesterol, carries cholesterol back to the liver, where it is taken up by the bile and carried in the bile duct to the colon for excretion in the feces. Therefore, HDL-C is dubbed “good cholesterol.”
It’s worth just mentioning that only about 15% to 20% of the total cholesterol in our bodies enters our digestive systems as cholesterol. The rest we synthesize daily. Some of the foods we eat are more easily transformed into cholesterol, such as solid fats, especially partially hydrogenated fats (transfats). But no matter what we eat or don’t eat, we’ll go on synthesizing cholesterol, because we need it.
"reveal" emails? If not,
just click here...
The balance between LDL-C and HDL-C is a homeostatic mechanism. Those two types of particles have properties beyond their role as cholesterol delivery systems. LDL-C appears to be highly susceptible to oxidative damage, and may also inhibit the synthesis of nitric oxide, which is thought to be one of the body’s natural mechanisms to combat atherosclerosis. And HDL-C has the opposite effect. Its principal lipoprotein, apo A-1, plays a part in preventing particles involved in atherosclerosis from adhering to arterial walls.
So, not only do LDL-C and HDL-C play different roles in cholesterol transport, they do the same with regard to arterial damage. We could say that the nicknames “bad” and “good” cholesterol are fully justified.
Maintaining good levels of HDL-C in the circulation is highly important to cardiac health. Some activities, such as exercise, have a beneficial effect on HDL-C levels. >It’s the view of many cardiologists that the ratio of total cholesterol to HDL-C is more indicative of overall cardiac risk than the total cholesterol value by itself, so, while a TC value of more than 200 is thought to be higher than the optimal range, this can be offset by an HDL-C value higher than 50.
However, despite the necessity of cholesterol in our bodies, for most of the 20th century it was taken for granted that cholesterol was the cause of atherosclerosis and a principal cause of heart attacks (myocardial infarctions, or MIs).
Efforts to reduce the risk of MIs by cutting back on foods rich in cholesterol failed to lead to reliably clinically effective results. In other words, people who significantly reduced their intake of eggs, butter, and beefsteak, did not have fewer MIs – at least, statistically.
It wasn’t until the mid-1990s that a drug, simvastatin, was clearly and definitively demonstrated both to lower cholesterol in the blood and to reduce the incidence of heart attacks. Initially, this beneficial effect was demonstrated only in individuals thought already to be at an elevated risk for heart attacks.
Statins target the formation of cholesterol, termed cholesterol biosynthesis, which takes place mostly in the liver. They inhibit an enzyme labeled HMG-CoA reductase, which is active in cholesterol biosynthesis. However, statins have no effect on cholesterol that enters our bodies as cholesterol – only on the process of cholesterol biosynthesis.
In the years since the results of the trial which demonstrated the effectiveness of simvastatin, several other statins have been developed, approved, and have become widely used. One, atorvastatin, trade named Lipitor, became the world’s all-time best-selling drug, racking up $125 billion in sales in the years before it became a generic.
If heart disease rates had remained at their peak in the years immediately before the widespread use of statins, there would have been about 10 million more deaths attributable to heart disease since then. However, heart disease is still the leading cause of death, both in the US and worldwide. According to the World Health Organization, more than 30% of all deaths on Planet Earth are due to some form of heart disease.
The large decline in the number of heart disease deaths in the US and other developed parts of the world can hardly be attributed to the use of statins alone. Other factors – improved options for the control of hypertension, a reduction in the numbers of tobacco smokers – certainly played a part, but the evidence for the role of statins in that decline is very strong.
Looking for answers to some puzzling questions
While acknowledging the role of elevated cholesterol in cardiac disease, there were still a number of questions to be answered. One of these was what caused MIs in individuals with supposedly “normal” cholesterol. A common factor, unearthed by Paul Ridker, a cardiologist at Brigham and Women’s Hospital and the Harvard Medical School, was that many of these individuals had in their bloodstream high levels of a substance known as C-reactive protein (CRP), which was closely linked with inflammation. Ridker had long suspected that inflammation played at least a principal part in the pathology of serious cardiac events.
A closer look at what actually happens
Paul Ridker followed up his discovery about CRP with a study in which it was shown that treatment with statins not only lowered cholesterol levels, but also lowered levels of this inflammation marker. And in 2008, Ridker presented the results of the JUPITER trial at the New Orleans meeting of the American Heart Association. (Ridker P et al. New Engl J Med 2008;359:2195-2207)
This large trial (17,802 subjects) compared two cohorts of persons, all of whom had normal cholesterol levels. One group of 8,901 subjects received 20 mg. of rosuvastatin daily, and the other, also 8,901, got the placebo. The primary endpoint was incidence of cardiac events consisting of nonfatal myocardial infarction, nonfatal stroke, unstable angina, or death from cardiovascular causes. Subjects receiving rosuvastatin experienced 142 such events, while those on placebo experienced 251 events. Although the reduction was small in terms of absolute risk – about 1.2% ― it was considered highly significant, both statistically and in terms of implications for treatment. As a result of these results, the trial was stopped after a bit less than two years because the sponsors considered it unethical to continue a large cohort of patients on placebo when significant benefit had been demonstrated in the treatment arm.
The subjects in the JUPITER trial had baseline LDL-cholesterol levels of 108 mg/dL and CRP levels of 4.2/4.3 mg/L. Those LDL-C levels are considered reasonably good in patients with no established cardiac risk factors. However, CRP levels greater than 4.0 mg/L are now considered elevated and associated with significant risk.
The JUPITER trial cannot be said definitely to demonstrate that lowering CRP was the determining factor in reducing the numbers of signal cardiac events. Treatment with rosuvastatin not only reduced CRP from the baseline level to about 1.8 mg/L, but also lowered the LDL-C levels from a pretreatment 108 mg/dL to 55 mg/dL, so the benefit may have in part been due to the LDL-C reduction. But the reduction in that marker of inflammation was certainly an eye-opener.
In further analysis of the JUPITER trial results, Ridker came to the conclusion that elevated CRP levels signal more heart disease risk than do elevated LDL-C levels, although the highest risk is in patients in whom both of those are elevated. CRP levels below 1 mg/L are related to low risk, between 1 and 3 mg/L to medium risk, and higher than 3 mg/L to higher risk. The chart below traces the relationship between LDL-C and CRP levels and cardiac risk over an 8-year period.
Here’s another way of looking at the way cholesterol and inflammation (as shown by CRP levels) have a causal relationship with cardiac events.
According to the data behind that chart, a person could have a relatively high level of LDL cholesterol, such as greater than 160 mg/dL, and not be affected by a high level of cardiac risk. A person with elevated levels of CRP, indicating systemic inflammation, would be likely to have a higher level of cardiac risk even if his/her LDL cholesterol level was moderate, lower than 130 mg/dL. But if both the LDL cholesterol and the CRP levels were in the highest range, the cardiac risk would be apt to be very high indeed.
The LDL-C levels considered as low in these graphics are based on the guidelines promulgated by the National Cholesterol Educational Program (NCEP) Adult Treatment Panel III in 2001, which used 130 mg/dL as the cutpoint for borderline high LDL-C. More recently, many clinicians have argued for a target LDL-C reading of about 100 mg/dL in individuals with no specific cardiac risk factors, and below 70 mg/dL in persons with one or more risk factors. Thus, the data above could be criticized as minimizing the risk presented by elevated levels of LDL-C.
Although the data as presented strongly suggests that inflammation is a greater risk factor for heart disease than elevated cholesterol, it is far from presenting satisfactory vindication for the supporters of the view that inflammation is the whole story and cholesterol is a mere ruse cooked up by the pharmaceutical industry as a way to push their products.
Interaction between cholesterol and inflammation
We can accept the data showing the link between cholesterol and inflammation, on the one hand, and serious cardiac events such as heart attacks and strokes on the other hand. The statistical link is evident. But how exactly does inflammation cause these cardiac events? And why is it that the cholesterol that lodges in our arteries becomes the blood clots that cause strokes and myocardial infarcts?
At about the same time that Paul Ridker was doing his preliminary investigations , another Brigham and Women’s/Harvard cardiologist, Peter Libby, learned that cholesterol didn’t just swim around in the bloodstream. It actually worked its way into the arterial wall. This appeared to constitute a kind of insult to the arterial wall and provoked an inflammatory response, which in turn resulted in the formation of blood clots. It was these blood clots that, at least in some cases, blocked coronary arteries, causing heart attacks, and also blocked cerebral arteries, causing strokes. Peter Libby coined the term “vulnerable plaque” for plaque affected by inflammation that was prone to clot formation.
Libby demonstrated that the interior walls of blood vessels are made from smooth muscle cells which are lined with the endothelial cells that are in direct contact with the circulating blood. These endothelial cells act as sentries. If they detect the presence of anything other than blood cells in the blood stream, they summon white blood cells, which are the immune system’s front-line guardians. Naturally occurring adhesion molecules could attract the white blood cells and get them to stick to the endothelium lining the arteries. This action triggered an inflammatory response in the arteries, and the release of a cytokine called interleukin-1 (IL-1). IL-1 had been discovered in the late 1970s, and which had been found to cause fever in laboratory animals. IL-1, classified as a pyrogen (a fever-causing agent) is c