What causes heart disease?

Heart disease artery plaque

A few weeks back I wrote an article about the drug class known as “PCSK9 inhibitors”, and how they seem to lower the risk of a heart attack, and how there is even preliminary evidence to support the notion that they prolong life. The article wasn’t particularly popular among some readers of this blog, presumably because it was construed as supporting the LDL hypothesis (i.e. the commonly held notion that it’s a cholesterol transport molecule called “Low Density Lipoprotein”, or “LDL” for short, that causes heart disease).

For those who are unaware, the LDL hypothesis basically says that heart disease happens because LDL somewhow ends up in the arterial wall, after which it is oxidized, which starts an inflammatory reaction that gradually leads to the hardering of arteries and eventually to bad things like heart attacks and strokes.

As I’ve written about before on this blog, the LDL hypothesis is bunk. There is by now a wealth of evidence showing that LDL has little to do with heart disease, such as this systematic review from BMJ Evidence Based Medicine, which showed that there is no correlation whatsoever between the amount of LDL lowering induced by statins and other LDL lowering drugs, and the benefit seen on cardiovascular disease risk (if indeed any benefit is seen – it often isn’t).

Dr Malcolm Kendrick, the person I primarily turn to when I want to understand anything to do with heart disease, has just come out with an excellent new book, in which he goes in to significant detail about why the LDL hypothesis is wrong, and what the mass of evidence shows actually causes heart disease. The book is well worth a read for anyone with an interest in understanding heart disease (which I assume is everyone who follows this blog).

The ultra-short elevator pitch version of what he argues in the book is that heart disease is what happens when damage to the arterial wall occurs at a faster rate than repair can happen. That’s why everything from sickle cell disease to diabetes to high blood pressure to smoking to rheumatoid arthritis to cortisone treatment to the cancer drug Avastin increases the risk of cardiovascular disease – they all either increase the speed at which the arterial wall gets damaged or slow down its repair. It’s why heart disease (more correctly called “cardiovascular disease”) only affects arteries (which are high pressure systems) and not veins (which are low pressure systems), and why atherosclerosis (the hardening of the arteries that characterizes heart disease) primarily happens at locations where blood flow is extra turbulent, such as at bifurcations.

This alternative to the LDL hypothesis is known as the “thrombogenic hypothesis” of heart disease. It’s actually been around for a long time, first having been proposed by German pathologist Carl von Rokitansky in the 19th century. Von Rokitansky noted that atherosclerotic plaques bear a remarkable similarity to blood clots when analyzed in a microscope, and proposed that they were in fact blood clots in various stages of repair.

Unfortunately, at the time, von Rokitansky wasn’t able to explain how blood clots ended up inside the artery wall, and so the hypothesis floundered for a century and a half (which is a little bit ironic when you consider that no-one knows how LDL ends up inside the artery wall either, yet that hasn’t hindered the LDL hypothesis from becoming the dominant explanation for how heart disease happens). We now know the mechanism by which this happens: cells formed in the bone marrow, known as “endothelial progenitor cells”, circulate in the blood stream and form a new layer of endothelium on top of any clots that form on the artery wall after damage – thus the clot is incorporated in to the arterial wall.

In spite of the fact that probably at least 99% of cardiologists still believe in the LDL hypothesis, the thrombogenic hypothesis is actually supported far better by all the available evidence. While the LDL hypothesis cannot explain why any of the risk factors listed above increases the risk of heart disease, the thrombogenic hypothesis easily explains all of them.

One of the things Malcolm Kendrick mentions in his new book is the molecule Lipoprotein(a), a.k.a. Lp(a). It has been found to correlate far better with risk of heart disease than LDL does. Interestingly, it is in fact identical to LDL, with one small difference – it has an extra protein, called Apo(a), bound to its surface. This gives it a function that is quite different from LDL. As mentioned, LDL transports cholesterol in the blood stream. What Lp(a) does instead is to stabilize blood clots. Why does this matter?

Because whenever the arterial wall is damaged, a blood clot forms to prevent you bleeding out. The arterial wall then, as mentioned, rebuilds itself on top of the blood clot, and the clot is gradually degraded and absorbed by the body. People with high levels of Lp(a) have more stable blood clots, which means that their blood clots are absorbed more slowly. In other words, arterial wall repair happens more slowly, so people with high Lp(a) have more atherosclerosis and therefore more heart disease.

What does all of this have to do with PCSK9 inhibitors?

PCSK9 inhibitors work by increasing the expression of the LDL receptor on the surface of liver cells. The traditional LDL hypothesis explanation for how PCSK9 inhibitors reduce heart disease is that the increased expression of the LDL receptor results in increased uptake of LDL from the blood stream and therefore lower levels of LDL in the body. There is, however, a tantalizing alternate explanation for how PCSK9 inhibitors reduce heart disease, that fits perfectly with the thrombogenic hypothesis.

As mentioned, LDL and Lp(a) are virtually identical. And the LDL receptor is not able to differentiate between them, so an increased expression of LDL receptors will result not just in a decrease in LDL in the bloodstream, but also in a decrease in Lp(a). That is why the PCSK9 inhibitor evolocumab has been found to decrease Lp(a) by around 30%. It’s likely also why there is any correlation at all between LDL and heart disease – the LDL receptor is responsible for removing both LDL and Lp(a). But it’s the Lp(a) that’s contributing to heart disease, not the LDL. It’s a classic case of correlation being mistaken for causation.

So, that’s just a few thoughts on how I think PCSK9 inhibitors work, and why this doesn’t imply support for the LDL hypothesis. For a more in-depth discussion of the thrombogenic hypothesis and the evidence in favour of it, as well as a deep-dive in to why the LDL hypothesis is utter nonsense, I strongly recommend Malcolm Kendrick’s new book “The clot thickens”.

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30 thoughts on “What causes heart disease?”

  1. As always, a well researched and thought provoking article. I would love to know how to best reduce Lp(a) given its critical role in cardiovascular disease.

      1. I understand it is important to ensure thyroid hormones are good before starting statins. Especially T3 which is so rarely tested. The thyroid connection is mentioned on the NHS website …

      2. Dr Malcolm Kendrick’s first book “The Great Cholesterol Con”, should you read it, will convince you that statins are useless and potentially harmful.

        From my experience, the bigger problem arises when you tell your doctor you don’t want to take a statin.
        It will even get worse if you tell him/her that you have read a credible book on the subject.
        And even worse if you buy the book for your doctor.
        It takes determination to confront your doctor. But it has to be done.

  2. thanks,
    have purchased the kindle version as I am on repatha every two weeks, and history of past MI.

  3. Another interesting read Dr. Rushworth!

    Based on what you wrote, it seems that damage to the arterial wall is “normal”, and there is a process to repair the damage. As you stated, the process is for endothelial progenitor cells to “cover” the blood clot (could this be referred to as a scab?) to produce a new layer of endothelium and wait for the clot to be absorbed. If damage occurs, we want the clot to be covered with a new layer of endothelium, and we also want the clot to be absorbed as fast as possible.

    It seems then, that the rate at which the clot is absorbed is critical. And a contributor to the slow rate of absorption is Lp(a), possibly a significant reason.

    I have three questions. 1.) Is it possible that the LDL lowering statins are actually helping by lowering Lp(a)? This would make the statins useful in some way? 2.) Is a more stable clot desirable? It seems to me that this may be possible if you mean the stability will keep the clot in place and not allow it to circulate and cause a stroke. 3.) Do you mean that PCSK9 inhibitors should be used instead of the classic statins?

    I suppose I need to get Kendrick’s book.

    1. 1) Funnily enough, statins don’t decrease Lp(a), they increase it. It’s worth remembering that unlike PCSK9 inhibitors, statins are ”dirty” drugs in the sense that they have lots of different effects, so it’s likely that although they lower Lp(a) through their effect on the LDL receptor this is more than made up for by some other effect that causes an increase in Lp(a). The reduction in heart disease found with statins likely has to do with something else entirely, such as their anti-inflammatory or anti-coagulant effects.
      2) yes, although what’s best is for the clot to go away completely, a stable clot is definitely better than an unstable clot.
      3) If they were as cheap as statins, then I think they would be preferrable, due to a better side effect profile. At present they are many times more expensive.

      1. I’ve been on statins for some 30 years with no side effects. The reason was familial very high cholesterol.
        So, is it the case that statins reduce heart attack risks for other reasons but lead to higher Lp(a) which is beneficial in stabilising clots.
        That would seem to be a win win scenario for statins.
        Meanwhile I have a review every 5 years when any arterial calcification is checked and so far I have always scored zero. Currently aged 72.

  4. My mum has suffered a heart attack recently and has narrowing and hardening of arteries – I’d love to know how to protect my heart into old age, as heart problems run in our family it seems.

    1. Start by educating yourself in the science of human metabolism. Sounds very dauting for a non-scientist but there are lots of good books available that would help in your journey. You could start with reading books such as Good Calories Bad Calories by Gary Taubes, The Big Fat Surprise by Nina Teicholz, Dr. Jason Fung’s books, Dr. Ken Berry’s, read all the posts on Dr. Kendrick’s blog page, listen to the podcasts on LowcarbMD.com, and watch the numerous youtube videos available on the internet by these and many other medical professionals. Pay specific attention to the role of insulin and insulin resistance. If what you are watching or reading doesn’t address Insulin and insulin resistance, it is junk. There are very many good sources for information of high quality on the internet. You just have to start reading.

  5. Do anti-coagulants have some bearing on this process? (I am taking them for atrial flutter.) Since their purpose is to reduce blood clots, do they have a role in reducing atherosclerosis?

    1. That depends on what you mean when you say anti-coagulant. Anti-thrombotics like aspirin and clopidogrel do have an impact – in fact they are prescribed to people after a heart attack as part of the ”package” of drugs that is intended to prevent future events. Anti-coagulants like warfarin and apixaban don’t noticeably impact arterial heart disease risk, although they do decrease risk of venous blod clots and blood clots due to atrial fibrillation. This is because arterial blood clots are activated in a different manner to venous blood clots, and are not as dependent on coagulation factors (which anti-coagulants inhibit).

  6. I’m aware of Prof. Subbotin’s description of an alternate process of atherosclerosis progression (as given some publicity from Ivor Cummins). Now I’m wondering if/how it might assist or pose difficulties for a thrombogenic hypothesis.
    I’m guessing you know of Subbotin’s work, but here is the basic paper:
    Looking forward to reading Malcolm’s book!

  7. Cholesterol is essential to life, is in every cell in our bodies and composes a large part of our brains. If we don’t have enough cholesterol our bodies will make it. The only bad cholesterol is the small dense particles caused by sugar, i.e. carbs, so cut the sugar and refined carbs and you will have healthy buoyant large fluffy cholesterol particles. People with the lowest cholesterol have the highest all cause mortality, and studies have shown that people with dementia and other neurological diseases often have low cholesterol levels.
    Ancel Keys and his cohorts have a lot to answer for with their absolutely wrong lipid hypothesis!

  8. Thanks for the book recommendation. Have you also read “Lies My Doctor Told Me” by Ken Berry and “A Statin Free Life” by Dr Malhotra? I’m looking for a book that essentially captures all the important information on this topic but would you suggest that Dr Kendrick’s book does a more than adequate job providing this?

  9. Changing scientific discourse and hypotheses are all very well, but far too late (as is Malcolm K’s new book) for the untold numbers of us who have literally watched our spouse’s life slowly (sometimes rapidly) destroyed by Statins, whilst simultaneously enduring the nonstop parroted mantra of ‘You must KEEP taking the statins’… from GPs batting-off attempted patient feedback of serious concerns.
    In my experience of this past decade, medicine per se is thoroughly in disrepute. As history will attest, there are now numerous other factors constantly involved with the prescribing of almost any drug, quite apart from professed concern for patients’ health.

    1. You are of course right in you assessment of current medical practice and prescription. However, it was not long ago that doctors were prescribing arsenic and mercury containing drugs for treatments of various illnesses, as I learned from reading this book. Doctors are getting better, but forces exerted by many industrial and pharmacological businesses are acting to suppress knowledge which might hurt their profits. This will not change any time soon.

  10. Thanks for your reply. I took a statin 6 yrs ago post MI, severe myalgias, stopped the Med, but unfortunately the myopathy has stayed—and six different specialists later…. Cannot find a reason. As a retired doc this is so frustrating. So I live mostly in leg weakness and everyday pain. I truly empathize with your comment. We as a group, in my opinion, no longer follow our oath to do no harm. With all respect to my colleagues.
    Larry W Banyash MD, retired

    1. Dr. Banyash,

      Your post touched me and I am sorry for the condition you suffer. I agree that the medical profession seems to be caught-up in following protocols developed by committee. If doctors follow protocols, my guess is that lawsuits will not prevail in court, and that is one reason why doctors behave as they do, a large portion of them. Couple that with disillusionment. I believe that many physicians have become disillusioned with the profession and now treat the profession as a job, go to the office, do the work, go home. Dr. Rushworth has also discussed how doctors are taught in medical schools, which is to accept the theories and issue the prescribed treatments, until the committee decides to change them. Not all physicians are like this. Fortunately, my GP reads. He studies. He attends scientific conferences, not just the prescribed medical ones. He is a learned physician and of course, follows protocols when they make sense. But when there is other data available, he uses that to help his patients.

  11. Dear Dr Rushworth,
    What natural foods or practices provide/mimic PCSK9 inhibitors? I read somewhere that a sizable percentage of centenarians have high Lp(a), so perhaps something is balancing the deleterious effects in that population?
    Your work is much appreciated.

  12. Its refreshing to hear about something other than Covid. I challenged my GP last week on why doctors are still prescribing statins. He agreed that the LDL hypothesis has been largely discredited but he is saying that statins have been found to stabilize the plaque and artery damage and thus prevent further complications of the CVD such as clots and stroke etc.
    Are you aware of any studies (not funded by the statin producers) that support this hypothesis. I am being told that I need to be taking low dose of statins to stabilize my condition. I am having trouble believing this especially as my GP is probably only repeating what has been written by the statin lobby.

  13. Is this medicine effective when a scan has shown calcification in the aorta? Now the cardiologist has given statines, but they bring me cramps and pain in my back. So I stopt taking them. But my aorta is heavily calcified. What to do?

    1. I would add vit K to the vit D that you take. Helps to prevent laying down of calcium in soft tissues and place it in bone where it should go. But cannot say it will remove aortic calcification.
      Larry Banyash MD

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