Cholesterol Lipid Hypothesis Part I
February 20th, 2023
Is cholesterol the problem with regard to coronary artery disease? Or just a response to the bodies inflammation, autoimmune, dysbiosis and/or infectious issues? Why do we need cholesterol? Is the cholesterol you eat the issue or the type that your body makes? Is it the genetic mutations related to lipoprotein receptors that clear cholesterol? Or a mix of all of the above? We will look at these questions and others over the course of this multi article set a reprise from a few years ago.
Coronary artery disease or atherosclerosis is the medical name given to the disease that leads to a heart attack.
What is atherosclerosis? According to an excellent description by Dr. Attia: "The etymology of atherosclerosis derives from athero-meaning a gruellike substance, and sclerosis-meaning a hardening. This porridge of oxidized sterols, lipids, cholesterol, macrophages, calcium, fibrin, and other cellular materials make up the lesions, or plaques, within the walls of the arteries. Influenced by multiple risk factors, the atherogenic process begins early in life and slowly progresses until the plaque narrows, erodes, or ruptures causing ischemic clinical events (e.g., fatal or non-fatal heart attack or stroke)."
When I was in medical school in the 90's, we were told that cholesterol is the root cause of heart disease and that reducing it will stop the problem. The truth of the matter is far from that simple as I will lay out in the coming article. In fact, lipidology, the study of lipids and therefore atherosclerosis, is one of the most complicated topics that I have tried to understand. Simply putting an adult on a cholesterol lowering drug is a far cry from effective medical management for primary prevention of a cardiovascular event. There has to be more and there is.
I have wanted to dig even deeper into this topic than the previous iteration from a few years ago as I knew that it was incomplete and because it is an issue that is close to my heart. Wanting to know the true root cause of these issues is a primary goal as this disease pervades my family history on my father's side. It is easy to care tremendously about this issue for my little and big pediatric patients alike as the disease process begins in infancy and progresses throughout life making early prevention paramount to long term survival. The first keys to answering this question come from what cholesterol is and the studies that discuss the function of cholesterol and lipids in the human body.
So, let us start there as we have to start somewhere.
Cholesterol is a molecule that is a critical piece of the following vital cellular structures: steroid hormones, all cell membranes throughout the body, bile acids and vitamin D. It is essential and necessary for human survival. We can obtain cholesterol through our diet as a poorly absorbed cholesterol ester when we consume animal products. Cholesterol is also naturally produced in all mammalian cells throughout the body but primarily in the liver in response to low cholesterol levels in the bloodstream. This is the primary source of all cholesterol in the body as dietary cholesterol makes up less than 25% of our cholesterol volume. Plants do not have cholesterol, therefore consuming them has no effect on levels. They have a special plant type sterol called a phyto-sterol which humans do not use. Cholesterol cannot move freely around the blood stream; therefore, it has to be transported around the body in lipoproteins like the LDL or low-density lipoprotein. I like to think of these fatproteins as cholesterol carrying "cars." These cars are going to be critical to understanding heart disease as they travel around our circulation highways with the intent of delivering the cholesterol package to the needed cell membrane, hormone or bile acid.
The lipoprotein cars are combinations of fat and protein that aggregate together to carry molecules called triglycerides and cholesterol. These lipoproteins have the major job of transporting energy as fats called triglycerides around the body to tissues. The cholesterol carrying issue is a secondary event. There are many different types of cars and they are named by the volume of triglycerides that are carried on board. The large lipoproteins are called chylomicrons, buses, and as they lose triglycerides at different cells they shrink and concentrate more cholesterol and become low density lipoproteins, cars. The LDL protein cars are called the bad lipoprotein/cholesterol. Frankly, I find it hard to believe that anything in the body is inherently bad or good! In no way does it make evolutionary sense for God to put a bad thing in our body.
The volume of any particle could convert it to an unbalanced state which makes it unhealthy. That I believe. I think that this is truth. Recent dogma states that the number of these smaller cars or specifically the subtype LDL has a particle number called LDL-P and this number appears to be one of the key measurements in atherosclerotic heart disease risk. The other is the apolipoprotein B level. Apolipoprotein B is a signaling molecule attached to all of the isoforms of LDL making it the newest and potentially best measure of cardiac risk. In heart disease, the elevated volume of LDL particles causes a concentration gradient to exist which leads to the cholesterol containing LDL particles getting into the heart vessel wall, the genesis of a, arterial narrowing event. This appears to be irrefutable based on the literature. The higher your apo B or LDL-P number, the greater your risk of a bad outcome from a heart vessel blockage. Sorry, I am getting ahead of myself.
Let's try and prove whether these lipids are good or bad.
The hypothesis: cholesterol and lipoproteins like LDL are inherently good and necessary unless they become unbalanced either through genetics and/or lifestyle choices.
First off, we need to see why lipoprotein cars and cholesterol were evolutionarily necessary aside from the energy carrying model. I have spent a large percentage of my life studying the immune system and the intestinal microbiome, thus it was not surprising to me to find a link to heart disease.
I think that this may be the key to unraveling this story: It turns out that the carrier lipoprotein cars like LDL and HDL cholesterol are an ancient part of our innate immune system that have an important function in fighting infection. "HDL's are believed to be a part of the humoral innate immune system, helping mammals to fight against invading pathogens. Indeed, thanks to the different proteins on HDL molecules, HDLs are known to behave as antimicrobial agents protecting animals against different parasites and bacteria." (Montecucco et. al. 2015) There is a linear inverse correlation between HDL concentration in the blood and the risk of infection in humans. (Trinder et. al. 2019) Humans have always used these lipoprotein cars to clear infectious material before they can do inflammatory damage. The evidence to follow will show how these studies makes sense.
The first study was done in 1998 by Dr. C. Iribarren from Kaiser Permanente and was published in the Journal Epidemiology and Infection. They found that there was an inverse relationship between total cholesterol levels and infections that required hospitalization or were acquired in the hospital. In other words, if your cholesterol level gets too low, (see current American College of Cardiology, ACC, recommendations), you can suffer more disease of the infectious type. (Iribarren et. al. 1998)
In 2007, Dr. Shor and colleagues looked at LDL-Cholesterol levels less than 70 mg/dl and disease risk and found that these low levels were associated with increased risks of hematological cancer, fever, and sepsis. (Shor R. et. al. 2007)
In 2019, Dr. Feng and colleagues looked at this picture further. When they analyzed over 7000 patients they found that lower LDL-Cholesterol levels were significantly associated with increased risk of sepsis and admission to ICU in patients admitted for infection. (Feng Q. et. al. 2019) They blamed it on comorbidities of illness, however, other studies and animal models would disagree with this conclusion. See this google search for more exploration: https://www.google.com/search?client=safari&rls=en&q=cholesterol+levels+and+sepsis+risk&ie=UTF-8&oe=UTF-8
Hypothesis: It is possible that driving the lipid level too low will put a subset of patients at risk for negative outcomes from infectious events. Before we look further at the innate immune model, what about the fact that total LDL-C may not be the major risk factor?
"It is true that high total-C is a risk factor for coronary heart disease, but mainly in young and middle-aged men. If high total-C or LDL-C were the most important cause of cardiovascular disease, it should be a risk factor in both sexes, in all populations, and in all age groups. But in many populations, including women, Canadian and Russian men, Maoris, patients with diabetes, and patients with the nephrotic syndrome; the association between t-C and mortality is absent or inverse; or increasing t-C is associated with low coronary and total mortality."(Ravnskov U. 2003)
Let us say for arguments sake that the above is true. What percent of heart attack victims have abnormal cholesterol levels according to the American College of Cardiology at the time of diagnosis? The answer is a shocking 25 - 50 % only!!!! "In a population, a lower LDL level is-on average-associated with a lower risk of heart attack. But about half of all heart attacks occur in people with "normal" cholesterol levels. An individual person may have a whole range of other conditions that could raise the risk. Some of the best-known ones are smoking, diabetes, high blood pressure, obesity, and a lack of physical activity. Other potential contributors include secondhand smoke and air pollution. In addition, there are likely genetic and lifestyle factors that we don't fully understand." (Bhatt D. 2015)
The common link to all of these risk factors is one word, inflammation! This is in no way to say that lipids neither matter nor are not partially causal, because they are. There is just a lot more to this story.
If this is true, why the need to drive down cholesterol so far at all? This is based on studies that show improved outcomes in a select group of patients that have had a previous heart attack and other risk factors including inflammation. Interesting. This may and likely is correct for this subset of people. I think that I am in this category. Strong, very strong family history of early heart disease and other biomarkers like lipoprotein a, an independent risk factor for cardiac mortality with advancing age. More later.
So far, we have established that a large percentage of humans who have cardiac events have normal lipid cholesterol levels at the time of this first event and that lipoprotein levels may have a significant effect beneficially for infection prevention. This simply means that we are still missing a large part of the risk story, but this does not mean that lowering the apolipoprotein B particle volumes in at risk patients is without merit. It is.
Let's go back to why these particles exist in the first place.
Dr. Ravnskov and colleagues published a nice review of the available literature regarding infections and lipoproteins. (Ravnskov U. 2003)
To be continued:
Staying alive despite my genetic risks,
Feingold KR The Effect of Inflammation and Infection on Lipids and Lipoproteins
Canturk Clinical Nutrition Article
Ravnskov QJM Article
Montecucco Handbook of Experimental Pharmacology Article
Trinder Arteriosclerosis, Thrombosis, and Vascular Biologyse
Stone J of American College of Cardiology Article
Bhatt Harvard Heart Letter Article
Feng JAMANetwork Article
Shor Annals of Clinical Laboratory Sc
Grion Eur J Clinical Investigation
Shabana Lipids Health Diseaiences Article