Part Duo – Deep Thought’s answer to the ultimate question of Life is not 42… It is Complexity

Please allow me to elaborate on cholesterol.  If you are wondering what cholesterol and looking at your time, please read Part Unum before going on any further.  And regarding your time, Douglas Adams has something profound to say about it, “Time is an illusion. Lunchtime doubly so!”

Digression is my profession. Ok, let me warn you, Part Duo is longer and more technical than Part Unum.

The whole controversy around fat intake and heart disease forced me to go back to basics and come up with a better research question to answer the cardiovascular disease issue.

As middle age folk what do we fear the most? Two Ds. We don’t want to Drop dead and/or Degenerate.  And two Cs could potentially cause that: Cardiovascular diseases (include strokes) and Cancer. I deviously did not mention Alzheimer’s disease as it did not fit into my Two Cs diagnosis. But fear of degeneration captures it though. Beware of the bias! These diseases can turn against anyone in a heartbeat if proper care is not taken.

Finally, phew, how can we address/understand these crimes against humanity to improve our Quality of Life (QoL)?  Obviously we must analyze the cardiovascular disease crime scene. Experts have already done that and here is the brief (at least one version of it):

Our fearless detectives of cardiovascular disease analyzed every square inch of the crime scene and carefully looked for evidence. And evidence they found: clogged arteries with plaque (atherosclerosis.) Please note that not all heart diseases are caused by clogged arteries but it is the most common cause. Analysis of plaque revealed presence of cholesterol. They profiled the usual trespassers of that area. Blood carries varying amounts of cholesterol through those arteries and bingo they found their poison: Serum cholesterol. They concluded that elevated levels of serum cholesterol must be the cause of clogged arteries.  They still needed to find the criminal who injected the cholesterol into the innocent victim’s blood.  They looked around and found an accomplice of cholesterol, Mr. Saturated Fat.  Cholesterol – Saturated fat combination is mostly found in animal products (milk, eggs, meat, etc.) Coconut oil has saturated fat but not cholesterol.  Our ever vigilant detectives made another observation: Not all but a lot of victims of this crime were fat (obese). Detectives connected the dots and made a wild assumption: Eating fat must make people fat. You are what you eat. There you have it. Our detectives finally cracked their case and found their killer, fatty foods. Apparently fatty foods, I mean animal products, kill their patrons by cholesterol poisoning.  They called this Lipid Hypothesis. Case closed.

Well not really but that is the simplified version of the cardiovascular disease case. This case has more twists and turns and interpretations and hypotheses than OJ Simpson’s trial in 1990s. But there is one similarity though: Some detectives are still looking for the real killer in both cases.

Actually I gave more credit to our detectives than they deserve in the case description. You see, a Russian scientist named Nikolaj Anitschkow put a bunch of rabbits on high cholesterol diet (I can only imagine how he fed meat to these carrot loving bugs bunnies) in 1913 and demonstrated rabbit arterial intima (similar to human atherosclerosis.) That is how the “cholesterol clogs arteries” hypothesis started. Our detectives did not find cholesterol accidentally, they went looking for it.

Sherlock Holmes said it best, “There is nothing more deceptive than an obvious fact.” Fortunately, not every scientist and physician accepted the diet-heart hypothesis (also known as Lipid Hypothesis) mentioned above. You see, some of these cardiologists were diligent and kept records of their patients’ cholesterol levels. The problem is a significant number of their atherosclerosis patients had low cholesterol levels (well below the so called risky levels established by the detectives) and still suffered from clogged arteries.  Just as an FYI, arteries carry oxygenated blood pumped by the heart and veins carry oxygen-depleted blood from the rest of the body to the heart. Arteries are under more pressure than veins.  Ok, back to cholesterol.

You have to give it to the American researchers and they agreed with the skeptics. Whatever Americans do, they do it in a mega scale and they don’t fool around. The National Heart, Lung, and Blood Institute (NHLBI) of the United States of the America started a cardiovascular cohort study in a small Massachusetts town called Framingham in 1948.  The researchers of NHLBI enrolled 5,209 adults of various ages (almost the entire town) and monitored all kinds of stuff. They named it Framingham Heart Study. How original! This is one of the highly referenced studies in the world and it is still ongoing and they have a third generation of participants in the study now.

Can you guess what they found after 30 years of probing? Well, let me describe the experiment first. The researchers created a bunch of sub groups by age brackets and gender and collected cholesterol levels of these people and kept a record of how long the participants survived and whether they developed cardiovascular disease or not.

Ok, can you guess now?  You know it is a trick question, right? The simple answer is they found jack squat. No smoking gun and could not establish a relationship between cholesterol levels and heart disease. What is more interesting is that some people with high cholesterol levels never developed clogged arteries beyond what is considered normal. Hot diggity damn! If the glove doesn’t fit you must acquit.  We are onto something here. It was not an obvious slam dunk case. It was complicated and still is to-date. Deep Thought knew that. Skeptics are right (It is strange how often skeptics seem to get things right) and Elvis is not dead.

You don’t believe me? Fine, don’t take my word for it. Please look at the data yourself. I gathered these data points from various reports using my hand ruler and the standard disclaimer applies: The numbers presented here are close enough but not the actual numbers from Framingham reports.

Here is a chart showing serum cholesterol distribution of men aged between 30 and 49 years from the Framingham report published in 1979. Remember NHLBI started collecting this data in 1948.


Here is how to read the above chart. The green line in the chart represents cholesterol level of men who did not develop coronary heart disease and the red line represents cholesterol level of the unlucky men who developed coronary heart disease over the next 30 years. Here is a very simple way to understand this chart. If both lines completely overlap each other, then cholesterol level has no impact (at least from these studies) on developing heart disease in the future. The farther the mean of these distributions are the higher the correlation between cholesterol and heart disease. By the way, mmol/L (millimoles per liter) is a unit used widely around the globe but a few countries (US, France, etc.) use the mg/dL (milligrams per deciliter) unit.  1 mmol/L is about 38.7 mg/dL.  For example, if you have a total cholesterol level of 190 that translates to about 5 mmol/liter on the x-axis in the chart. Okey dokey.

Let us interpret it. Among the healthy cohort (the green line), approximately 38% of the male participants (in the 30 to 49 age bracket) had their total cholesterol level between 3.5 and 4.5 mmol/L (135 to 174 mg/dL) at the beginning of the study. About 6% of the participants had their cholesterol level between 5.5 and 6.5 mmol/L (213 to 251 mg/dL.) Similarly, among the participants who developed heart disease (the red line), approximately 31% of the male participants had their total cholesterol level between 3.5 and 4.5 mmol/L (135 to 174 mg/dL) at the beginning of the study.

Are you not going nuts right about now? What the above chart is telling us is that the participants (men aged between 30 and 49 years) who developed heart disease on average had a slightly higher total cholesterol level than those who did not. I am not even sure if the difference is compelling. Whooptidooda! What does it mean? It means Hoo-ah! (Scent of a Woman) It means nothing. You can get heart disease even if you have your total cholesterol between 135 and 174 mg/dL or you are an Iron Man and you get nothing even if you have your cholesterol level above 210. Hoo-ah!

Oh, let us not leave it at that. Let us milk the data a little more. After all we love data. Here is a similar chart for men between the ages of 50 and 62 years.


The above chart does not need any explanation but I get pleasure out of stating the obvious. Apparently above the age of 50 for men, cholesterol level does not mean squat. Your cholesterol level does not say anything about your risk of heart disease if you are above the age of 50 assuming other markers such as blood pressure, diabetes, etc., are in check.

I know you want to see some mortality data. Ok, may be not you but the evil dark lord Sauron wants to see it. Here is a chart that shows mortality rate of men over a 30 year period. Oh and these men were between the ages of 31 and 39 when the study first started collecting data. The study collected mortality data of these men for the next 30 years (i.e., the men turned between 61 and 69 years old – at least the survivors.)


Here is how to read it. The cohort of men with cholesterol level less than 182 mg/dL (4.7 mmol/L) at the start of the study is represented by the top blue line with diamond points. Apparently 85% of the men from the less than 182 mg/dl cholesterol level cohort were still alive after 30 years in 1979. Similarly, men in the greater than 263 mg/dL (>6.8 mmol/L) cohort did a little worse and approximately 68% of these men were still alive in 1979. So, what this tells us is that if men below the age of 40 have high cholesterol level then they are at a higher risk of suffering from a heart disease. But please note that the difference between the top group and the bottom group is only 17% after 30 years.

Here is another chart but for older men.


Woo-Ah! Here is how to read it. Initial cholesterol level had no impact on mortality rate of men between the ages of 56 and 65 over the next 30 years (i.e., they collected mortality data of this group till the participants turned between 86 and 95 years old.)  Amazing isn’t it. There is almost no difference. In other words, men above the age of 50 should not worry too much about their cholesterol level assuming other markers are in check.

I know what you are thinking. What about women? Good news is that women tend to have better mortality curves than men and the scientific community believes that sex hormones, especially estrogen plays a beneficial role in managing women’s heart health. However, unfortunately, issues do crop up for women after menopause and usually women develop heart complications a decade later than men. I read an article talking about an estrogen trial on men. Researchers injected various doses of estrogen to manipulate cholesterol levels in men but unfortunately, a lot of complications arose (no shit Sherlock) and the researchers had to abandon the estrogen study on men.

Here is the mortality rate chart for women between the ages of 31 and 39.


As you can see women fared much better than men and the mortality rate difference among women after 30 years between the low and the high cholesterol level sub groups is a mere 8%.

Here is the strange part, even after hundreds of studies such as Framingham Heath Study, majority of the detectives (physicians) still believe in the cholesterol hypothesis. What do they have against cholesterol? Why so much hatred? Can’t we all get along?

Let us get to know our antagonist then and gather some intelligence on cholesterol (it will get fairly technical from here on.)

Cholesterol is a complex organic molecule (also known as a Lipid (fat)) with an alcohol group (-OH) attached to it and it is a modified steroid. Oh yeah, we run on steroids baby! Fats are not soluble in blood and cholesterol is no different.  Chemists call alcohol group an “ol”. For example, if you add an alcohol group to ethane and make moonshine, they call it ethanol. If you blend alcohol to gasoline, they call it Gasohol. So, if you ever come across a drunken obnoxious Ass, you can call him an “Assol”. You are just following the scientific nomenclature.

In any case, please take a look at the mug shot of cholesterol, the public enemy number 1:


Here are some facts about this deadly killer:

  1. Cholesterol is found in all animal cell membranes and it is vital to our survival. Our liver synthesizes most of our cholesterol and the process is fairly complex – takes more than 30 intermediate steps to produce final cholesterol. Wonder why our bodies spend so much energy to make such a deadly poison.
  2. Cholesterol is needed for our bone structure, muscles, digestion, hormone production, brain function, nerve endings, just to name a few.
  3. Cholesterol plays an important role in the synthesis of a lot of hormones, vitamin D, and bile acids. Cholesterol level goes up if our body does not produce enough hormones, vitamin D, bile acid etc., to rebalance our system (very important point to remember.)
  4. Cholesterol plays an important role in stress management. Our body produces cortisol when we are under stress (low blood glucose, etc.) and cholesterol is needed for that. Cortisol helps reduce inflammation.
  5. We synthesize about 1 gram of Cholesterol every day in our bodies (estimate for a 150 lb (68 kg) human male) and a 150 lb human male carries around 35 grams of Cholesterol all together.
  6. Almost 25% of cholesterol resides in the brain. Cholesterol is essential for our nervous system and plays a major role in the creation of our synapses.
  7. Here is the most important point: Most of the ingested cholesterol is esterified (a fatty acid is attached) and this form of cholesterol is poorly absorbed by the body. The absorption of ingested cholesterol in gastrointestinal tract varies from person to person and it can range anywhere between 20% and 60% of what is consumed (another reason why a standard diet recommendation does not work for everyone.) And human body is very smart and it actually compensates for the additional cholesterol ingested from foods by synthesizing less of its own. It is very important to understand this point. Consumption of cholesterol does not dramatically increase blood cholesterol level (there will be some increase in cholesterol level in the blood in the first few hours after food intake but our liver automatically adjusts for this change.) This is the main reason why most cholesterol tests are done after a 12 hour fast to determine our natural serum cholesterol levels.

Here is the key question then: If ingested cholesterol does not really impact our blood cholesterol level then why are our detectives blaming fatty foods for cardiovascular disease? If cholesterol is so bad then why does every freaking cell in the animal world need this poison? Is it possible that variations in cholesterol levels in our blood may not be the cause but a symptom for cardiovascular disease? Is there a slim shady hiding among cholesterol globules creating the havoc? Will the real slim shady please stand up?

We need to understand one important property of cholesterol and fat before we ask our detectives our questions. Cholesterol and fat are non-polar (i.e., they do not mix with water/blood.) So, our liver came up with an ingenious design to transport these suckers around. A water loving lipoprotein that can swim in blood! Liver packages cholesterol, fat (in the form of triglycerides or TAGs) and any other stuff our cells need (Vitamin D, etc.) in these lipoprotein capsules and ships them around.

Alrighty then, now we can ask our heart detectives the questions we raised above.  They had to come up with an answer. And as any good detective would do they started profiling cholesterol in the blood again. To their amazement they found different types of these globules containing different levels of cholesterol floating around and they named them as follows:

  1. Chylomicron (pronounced Kylo-micron. No relation to Kylo ren, son of Leia and Han Solo) – These suckers are fat and they come in 1000 nm sizes.
  2. Very Low Density Lipoprotein (commonly known as VLDL) – They come in 50 to 90 nm sizes.
  3. Intermediate Density Lipoprotein (IDL): About 30 to 35 nm in size.
  4. Low Density Lipoprotein (LDL) – About 20 to 30 nm in size.
  5. High Density Lipoprotein (HDL) – About 5 to 10 nm in size.

Our detectives went to town and found that the fat slob, Chylomicron, actually carries mostly Triglycerides (fatty acids get converted into triglycerides during storage and transportation and I don’t know why) from intestines to various parts of our body. The composition of a Chylomicron globule is as follows: 90% TAGs, 8% phospholipids and 2% Cholesterol.   Note that the actual composition is not as precise as I mentioned here but I am providing a midpoint estimate.  Since fat is not soluble in blood, Chylomicrons transport our digested fatty acids around in our body. Here is the most important point, Chylomicrons were not found in the plaque (the finger prints left at the crime scene.) But our detectives found LDLs and VLDLs in the plaque. There you have it. They pounded the table this time and started celebrating, “We got ‘em.”  The real culprits are these VLDLs and LDLs, they screamed.

But for some reason I don’t have much faith in these detectives. So, let us do some background checks on our culprits.

As you know our body needs fat and cholesterol to maintain and repair our cells. So, our main repair shop, liver, packages some TAGs, Cholesterol, Vitamin D and a few other trace stuff in these VLDL globules and transports them to various parts of our body through blood. The purpose of these VLDLs is to transfer TAGs and Cholesterol, to various cells. As cells absorb TAGs and Cholesterol, our VLDLs shrink in size and become Intermediate Density Lipoproteins (IDLs) and further transfer of TAGs and Cholesterol to cells allows them to shrink further and become Low Density Lipoproteins (LDLs). One point to note is that VLDLs start out with a lot more TAGs than Cholesterol. So, the two key differences among VLDLs, IDLs, and LDLs is the amount of Cholesterol present in these globules and size of these globules. As you can imagine, VLDLs and IDLs lose a lot more TAGs than Cholesterol, so LDLs carry more Cholesterol as % of total stuff in them than VLDLs. The process is a lot more complicated and a number of proteins, enzymes, and hormones play important roles in all of this but we got the big picture.

So to summarize, our liver transports TAGs and Cholesterol in VLDLs to rest of the body for maintenance. And once the work is done, LDL receptors on our liver catch the shrunken LDLs (also known as LDL remnants) and absorb them back into the liver. The liver then can store the contents of the captured LDL or use it to make hormones or bile acids, etc.

Ok then, what about HDLs? HDLs are also produced by liver and they do exactly the opposite of LDLs. They capture TAGs, cholesterol, and phospholipids from cells and either transport back to the liver or transfer cholesterol to VLDLs in exchange for TAGs and phospholipids. Think of HDLs as sponges of cholesterol and TAGs. Eventually, HDLs also return back to the mother ship, liver. Commonly held belief is that HDLs can scoop up cholesterol out of artery walls and may even reduce the risk of atherosclerosis.  Keep in mind that we don’t know this for a fact and it is our best guess at this time. This whole HDL scooping up cholesterol from plaque walls does not make a lot of sense to me as some experts don’t think cholesterol is permeable through the endothelial walls of our arteries. But let us leave that to our experts to debate.

Another important observation: People with high total cholesterol but with relatively high HDL levels fared better than people with low total cholesterol but very low HDL levels.

Now you know why our detectives call HDL the “good” Cholesterol and LDL the “bad” cholesterol. But is LDL really bad? It is just doing its job of transporting essential building blocks to our cells.

Clearly, LDLs can’t be the villains. Our detectives had to get back to profiling again and this time they took a much closer look at the plaque and said, “Aha! Finally, we got it this time. You see LDLs are not the bad guys but Oxidized LDLs and Glycated LDLs are the creeps.” What the…? How can we be sure that they got it this time? Our detectives must have learned their trade from Inspector Lestrade and not Sherlock Holmes. What a pity!

Interestingly, not all heart patients had high LDLs as mentioned earlier. Our tenacious Ds (our detectives) got back to work again to figure out how and why the LDL oxidation occured. Inflammation was identified as a potential cause but we don’t have any clarity on the causes of inflammation. After a lot of screening and profiling again they found another culprit. TAGs this time! You are darn right! This one has been there all along and they circled back to it.

Our detectives’ current hypothesis is that presence of high TAGs and or oxidized LDLs caused by inflammation is the root cause for cardiovascular disease.

Here is a quick summary of our detectives’ progress on cardiovascular disease over the last half a century:

  1. 50 years ago they thought fat caused the cardiovascular disease for sure.
  2. 30 years ago it was total cholesterol and they were pretty sure of it.
  3. 20 years ago it was LDL.
  4. 10 years ago it was Oxidized and/or Glycated LDLs.
  5. Now it is a combination of Triglycerides (TAGs) and/or oxidized LDLs from inflammation.

What do you think are the odds that we will have another hypothesis in 10 years?

Here is my interpretation on LDLs (I am not a trained physician (not even untrained physician) but that never stopped me from giving out opinions): The level of cholesterol or TAGs in our system is more of a symptom than a cause. A lot of Lipid Hypothesis skeptics share this view. So, this is nothing new and I am not breaking any new ground here. I simply agree with the skeptics in this case. Here is my issue with the Lipid Hypothesis: Any number of reasons could cause high cholesterol levels in our bodies. For example, high level of LDLs in our blood stream could be due to failure of LDL receptors on our liver to capture the darn things. Or maybe our body cells do need all the TAGs and cholesterol because of some unknown autoimmune disease. Or maybe we have some hormonal imbalance and that causes our bodies to store excess fat and require all the TAGs. Or we have severe vitamin D deficiency and our body is producing more cholesterol to kick start the vitamin D production.

You may say, “Hold on Faker dude. What about HDL levels?” Here is my take on that. Let us simplify the whole cholesterol and TAGs circulation process in our body and compare it to a grocery delivery and waste recovery system. Imagine your liver as the grocery store, blood as roads and VLDLs and LDLs as transport vehicles delivering the groceries (in our case, cholesterol and TAGs) around our neighborhood (various cells) and HDLs as waste collecting trucks of used/unused cholesterol and TAGs (not really waste but let us go with this analogy) and returning them to the grocery store (liver.) Wow! That was a long sentence and I hope you got the big picture here. Let us assume that some of the stuff VLDLs deliver around gets consumed in the system. Then in theory there must be an optimal ratio between how much gets delivered and how much gets recycled back. Let us assume that the ratio is 2:1. I am making this ratio up. So, how would you interpret a high LDL+VLDL to HDL ratio? For some reason, we are recycling less cholesterol through our HDLs than we are feeding our system. Does that mean that there is something wrong with the LDLs or we have a problem in our system somewhere? Why are our cells asking for more VLDLs and LDLs? Why does the liver think it needs to produce more cholesterol and TAGs? Are we simply losing LDLs in our system and if so how and why?  What does it even mean by having higher total cholesterol? All our biochemical reactors can’t possibly require the same amount of cholesterol and TAGs. So, how can anyone say that everyone’s total cholesterol level has to be less than 200 mg/dl (5.17 mmol/l)? By the way, safe limits for total and LDL cholesterol levels set by our doctors have been falling for the past 30 years.

I think HDL and LDL levels in our serum are markers/symptoms for our overall health. Low HDL and high LDL levels suggest a potential problem in our plumbing. Artificially increasing or decreasing these levels don’t fix the problem. Granted some fraction of the population may get benefited by simply reducing the amount of LDL produced because that fraction’s system is producing too much cholesterol for various reasons (this is where statins come into play.) But statins can’t be a fix for all.

Ok, as you can tell we can come up with 50 different arguments for or against the Lipid Hypothesis but I realize that we can’t test our arguments ethically. So, what can we do about it?

Don’t panic! We already learned a lot. So, let us quickly summarize what we know.

  1. Human body is very complex and hundreds of different parts have to function properly to have a healthy life.
  2. We do not have a Tricorder (Start Trek’s health scanner) to identify our problems. Trial and error seems to be the best course of action to figure out some of our problems.
  3. Our detectives (doctors) are reasonably good at dealing with accidents but not so good at avoiding these accidents. Not all of our doctors are in touch with minor issues in our bodies such as hormonal imbalances and various biochemical interactions as these fields are still evolving. Unfortunately, today’s minor issues can become major issues in a decade or two (like in Sam’s case.)
  4. There is no simple explanation for cardiovascular disease.
  5. Consumption of fat and cholesterol may not be the root cause of cardiovascular disease. This is not a medical advice.
  6. Varying levels of LDLs and HDLs in our system may simply be markers for our overall cardiovascular health.
  7. Men below the age of 50 with high cholesterol level and other health issues should seek profession help for sure.
  8. Men and women above the age of 50 have a little to worry about cholesterol level alone. Of course, one must pay attention to other symptoms and assess the risk.
  9. Female sex hormone (estrogen) seems to protect women from heart disease. Don’t mess with hormone therapies without proper guidance and professional consultation.
  10. We are still not entirely sure how the plaque is built in our arterial walls. It is very important for us to be open minded and look for all potential causes. We should not just focus on a few familiar variables and theories.

By the way, both heart disease and strokes fall under cardiovascular disease classification.  When atherosclerosis happens in the coronary arteries, it is called a heart disease. If the same thing happens at the base of the neck in the carotid arteries, then blood supply to a part of the brain gets cut off and the patient suffers a stroke. But let us quickly discuss two types of strokes: Ischaemic stroke and Haemorrhagic stroke.  A small blood clot getting clogged in a small artery in the brain causes Ischaemic stroke. If the artery bursts that causes a Haemorrhagic stroke. Obviously this is an overly simplified explanation but root causes for both heart disease and strokes are similar.

Wow! A lot of information to digest. Let us figure out what we can do about these diseases and how we can optimize our Quality of Life (QoL) in Part Tres.