Theory: Heart Disease is Caused by a Couple of Genetic Defects, but there is a Work-Around

Summary:  Primates mutated and lost the ability to make vitamin C about 40 million years ago.  When humans went north they ate less vitamin C rich food, and when they made long sea voyages they often died from either infection or internal bleeding.  Matthias Rath, M.D., found that Lipoprotein(a) was another mutation which, again, only appears in primates, often plugged the gap by binding with lysine at the site of a broken blood vessel.  Lp(a) plus fibrogen, calcium, LDL, created a kind of blood vessel bandage, and Rath and Pauling wrote a paper suggesting that Lp(a) is a surrogate for vitamin C.  They recommend 2 to 3 grams of vitamin C per day to keep blood vessels healthy, together with 2 grams of lysine which will, again, help with blood vessel integrity, but free lysine will also bind with Lp(a) and deactivate it.

Heart disease appears to be caused by two genetic mutations.  The first one caused a problem that the second mutation resolved, but its solution causes standard heart disease, and so limits life spans.  So, it is not an ideal solution.

With that in mind, about 40 million years ago, some mammals, mostly primates, which would include the distant forebearers of humans, lost the ability to make Vitamin C.  Most animals in the world make vitamin C in the liver.  This is the first mutation.

What happened was a mutation deactivated the l-gulono-lactone oxidase gene (also known as GLO) with the consequence that the last step in making of vitamin C from glucose was blocked.

This does not not immediately cause heart disease in primates, and that was because these animals were living nearer to the equator where there was plenty of food rich in vitamin C.  But it did permit this defect to continue in the animal population.

Even today animals living in these same regions get pretty good amounts of vitamin C rich food. Gorillas eat 1400 mg to 5100 mg per day depending on the size of the animal, spider monkeys eat three times the rate of intake of a gorilla, and bats eat 8 to 10 times the rate of a gorilla. 

This is quite a lot of vitamin C.  These animals don’t experience much heart disease, nor do animals that make their own vitamin C, which is all animals, as I have said, except primates and a few others.

So, the question becomes how did humans come to get heart disease from not making vitamin C?

The short answer is that these animals moved north, where foods rich in vitamin C were in short supply. 

A fuller explanation is that it turns out that vitamin C is essential in the making of collagen - an ion of ascorbate (vitamin C) is sacrificed in every molecule.  Collagen is the binding protein that allows the body to make organs, bones, brains.  Basically, without collagen we would be single-cell amoeba.  But importantly, among the things that collagen makes are blood vessels. 

Think of the poor sailors sent out across the Atlantic Ocean a few hundred years ago.  The body does not store vitamin C, so slowly they begin to suffer from vitamin C-collagen deprivation, called scurvy.  Sailors noticed their gums were bleeding, their skin develops black and blue spots because they injure easily.  Soon enough their teeth are actually falling out, and finally, after two or three months, their blood vessels fall apart and at least half of the sailors who died from scurvy died from internal bleeding (the other half die from infection).

Canadian Physician Discovers Plaques

In 1953, a Canadian physician G.C. Willis found that plaques form over vitamin C depleted blood vessels.  He used x-rays to survey the tissue and found plaques were not found throughout the body but primarily around the heart which experiences the most turbulence.  Turbulence, which could jostle vessels that might be weak from lack of vitamin C and collagen.

It was theorized by Linus Pauling and Matthias Rath that after genes for vitamin C were interrupted, the primate body recruited the LDL molecule and with the addition of apolipoprotein(a) string becomes a sticky molecule which can prevent blood vessel leakage, and that new molecule is called lipoprotein(a).  This is genetic mutation number two.

Lipoprotein(a) = Lp(a) = Lipoprotein A, all the same thing

Lipoprotein(a) plus LDL cholesterol plus fibrin and fibrinogen create a kind of blood vessel bandage or scab.  Doctors call this wonderful chemical bandage plaque, and they think it is awful, but consider this:  that bandage may well have kept sailors alive for an extra month or two before the lack of vitamin C would leave so many gaps in blood vessels that the lipoprotein(a) couldn’t fix them all, so they died from internal bleeding or infection, but some would have made it to the New World.

Doctors recommend medications called statins to prevent the manufacture of LDL cholesterol, which may only have been found at the scene of the crime, and was not the principal player.  Nevertheless, it may prevent larger plaques, and there is a good rationale to believe this.  Because lipoprotein(a) is sticky, it includes LDL, calcium, fibrin, fibrinogen, and these bandages or scabs can become enormous and block off blood flow.  Worse, they can break off and cause an immediate stoppage of blood flow, and this we call a myocardial infarction or heart attack.  So anything which can reduce the size of these plaques would be useful, and reducing LDL could possibly help.  This is the statin theory (which is not connected to the theory I am writing about).  However, at least one cardiologist, Robert DuBroff, M.D., who has published on this area, thinks the LDL theory needs to be revamped at a minimum  (see link below) because he apparently found only 2 studies out of 29 showed any overall mortality benefit.  LDL lowering drugs are not working as theorized.

So, evolution’s solution to prevent babies dying early in life from vitamin C and collagen deprivation (scurvy), is this lipoprotein(a) bandage.  But it is a genetic solution which came in the form of a double-edged sword.  It saved the lives of many offspring who would otherwise die of vitamin C deprivation, but also seems to put an upper limit on primate life by creating these plaques, which at some point doctors correctly consider life-threatening, especially in older folks, but plaques can be forming all of your life from a shortage of vitamin C.

An Article Piques Linus Pauling's Interest

According to Linus Pauling, it was an article in Scientific American by Texas researchers, Brown and Goldstein, who won a Nobel for figuring out how LDL binds to the rest of this blood vessel bandage-plaque that intrigued him.  It was the first sentence in their article that was the clincher, “the primary cause of cardiovascular disease…is a lesion in the wall of a blood vessel.”  The trouble coming from efforts to fix it.  Pauling asked: “Why should there be a lesion in the wall of a blood vessel?”  And he thought he knew the answer to that: “People do not get enough vitamin C.”

Vitamin C Builds Strong Blood Vessels

Pauling thought that the presence of vitamin C would result in more collagen, and more collagen would mean more blood vessel material and stronger blood vessels, and this should ultimately remove the need for statins if vitamin C were started early enough in life.

This was kind of off-the-shelf thinking for Linus Pauling, who was a very great chemist of the past century.  He did his serious thinking when he was younger, using quantum mechanics, which he had studied with Niels Bohr and Erwin Schrodinger, to explain how chemical bonds work, especially on inorganic molecules.  He wrote a book about this for which he was awarded the Nobel Prize.  He might have won several such awards for chemistry.  Eventually, he moved on to organic chemistry, and he worked on the chemical structure of hemoglobin, that work led to a paper that said in sickle cell anemia the shape of the molecule changed, and made it difficult for blood to pass through the vessels.  That paper was the first to describe a molecular disease.  And anyone who has read James Watson’s book about finding out the structure of DNA, The Double Helix, knows the only person that Watson and Crick ever truly worried about getting there first was Linus Pauling.  But Pauling never saw Rosalind Franklin’s crystallography which showed clearly that DNA had a helical structure, so he dreamed up a three-strand solution on inadequate data, and that turned out to be incorrect.  Interestingly, Watson wanted to study with Pauling, but he was rejected by Caltech, where Pauling taught.

I call this off-the-shelf thinking for Pauling because he had already written a book called Vitamin C and the Common Cold.  Unfortunately, Pauling never had a good working theory for explaining why vitamin C would quell the common cold, though if half of the sailors who died crossing oceans died from infection, he might forgiven for thinking that it had a role.  It does not appear that vitamin C has a dramatic effect against the common cold, at least at oral levels, and the medical community have been quick to point out his short-comings, and seemed to hold him in contempt, perhaps annoyed at his positive assertions, crazy in his dotage, and this continues to this day.

But I’d say he had all the knowledge on hand to solve the problem of leaky blood vessels, because he knew about vitamin C, and he knew blood vessels were made from collagen, and he understood that chemistry very well.  He called the strands of collagen the principal structural macromolecule in animals (as cellulose is in plants). 

Pauling and Rath's paper was entitled, "Hypothesis: Lipoprotein(a) is a Surrogate for Ascorbate."  I'm uncomfortable with the word "surrogate."  Vitamin C is a cofactor in enzymatic reactions and an antioxidant.  It is essential in the manufacture of collagen.  Lipoprotein(a) is a protein coded by DNA.  Nevertheless, there appears to be a direct correspondence between vitamin C and lipoprotein(a), which was their point.  Vitamin C and amino acids lysine and proline are the building blocks of collagen.  Lipoprotein(a) is a collagen repair protein.  It is likely the latter would never have come into being if the coding for vitamin C had not stopped 40 million years ago.  Lipoprotein(a) works to protect blood vessel integrity in a vastly different way from the way vitamin C and collagen work.  It is the difference between fixing an old rusty chain link fence with a new chain link fence, and taking a wire and pliers and fixing the old fence.  You may tie together the fence, but it may look quite ugly depending on the state of the fence and the gaps in the chain links.

Pauling's vitamin C solution seemed to work anecdotally for some people who learned about his heart theory, but at least one scientific colleague complained to him he would get pain from angina when exercising too much, and that provoked Pauling to add one of the building blocks of collagen to the equation.  He suggested l-lysine.  And later further added proline, two amino acids which are part of the protein collagen.  And this helped the scientist who asked for the advice.

Free lysine deactivates Lipoprotein(a)

It turns out you get a twofer with lysine, which seems every bit as important as vitamin C in this scheme.  On the one hand, the amino acid lysine becomes part of the collagen molecule, and since blood vessels are made from collagen, it can help restore blood vessels to full strength.  But when collagen breaks up in a blood vessel (say from turbulence), lipoprotein(a) apparently binds to the blood vessel wall at the site of a lysine molecule.  Linus Pauling felt that if there was sufficient free lysine in the blood, that it would bind to the lipoprotein(a) and thus deactivate it.  Pauling and his associate Dr. Matthias Rath hypothesized that the lysine-lipoprotein(a) bond might be used to clear plaque from blood vessels.  This is the theory.

The Beauty in a Good Theory

There is an interesting fact which seems to support this whole vitamin C – collagen – lipoprotein(a) scenario.  It turns out that the only animals which make this sticky protein, lipoprotein(a), are a pretty good match for those animals which no longer manufacture vitamin C.  Mainly, the primates.

The research arm of the pharmaceutical industry pursued the idea of reducing LDL cholesterol in the bloodstream with statins, which Google says helps in 5%-10% of cases.  Logically, you would expect it to reduce the size of plaques, which would help, and the statins do knock down the numbers on LDL, but apparently that is not the problem.  One wonders if they should not have attempted to lower lipoprotein(a), though, let’s think about this: if you are chronically short of vitamin C, you will need the lipoprotein(a) solution to bind leaks in the blood vessels and prevent internal bleeding.  But the obvious flaw in the statin solution is that although it may slow plaque formation, it does not end it or prevent it, and cannot make stronger blood vessels, only collagen can do that.

I also considered this chemistry.  Apparently a molecule of Lp(a) is made from an LDL molecule, to which an APO molecule is added.  So, you would think that if a statin reduced LDL, it would also reduce Lp(a).  Apparently, not.

I asked Google if this were true, and it cited this:  

While statins are well-established for lowering LDL-C levels, statins do not seem to lower Lp(a) levels similarly. In fact, several studies show conflicting results: some show that statins may increase Lp(a) levels, while others show a decrease of Lp(a) levels.Nov 25, 2021

I went to another source, ChatGPT, and asked the same question:

Lipoprotein(a) [Lp(a)] is indeed composed of a low-density lipoprotein (LDL) particle linked to apolipoprotein(a) [APO(a)]. Statins primarily work by inhibiting the enzyme HMG-CoA reductase, which is involved in the synthesis of cholesterol in the liver. They are very effective in lowering LDL cholesterol levels.

However, the effect of statins on Lp(a) levels is not as straightforward as their effect on LDL cholesterol. While statins can significantly reduce LDL cholesterol levels, their impact on Lp(a) levels tends to be more variable and modest. Some studies suggest that statins may modestly lower Lp(a) levels in certain individuals, while others show no significant effect.

What these answers show is that scientists do not have a clear understanding of how these things work at a fundamental level.

There is experimental evidence for the use of vitamin C in heart disease. I invite you to review a summary of the evidence yourself.  Enter this in your search engine: “Vitamin C heart disease a review based on findings” and the first entry should be the summary of research.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5000725/

Summarizing, two studies showed there was an inverse relation between the amount of vitamin C taken and heart disease.  That is, the more vitamin C consumed, the less heart disease.  One study showed only vitamin C supplements reduced heart disease risk, two studies didn’t show any connection to heart disease risk, and one indicated an increased risk of heart disease.

More studies are needed to establish its usefulness of this solution, if it is useful, studies with differing amounts of vitamin C.  Vitamin C with lysine, without lysine, with proline, without proline, with both lysine and proline.  And different age groups, and other nutrients, may affect results.

Pauling recommends at least 2 or 3 grams of vitamin C per day.  But he himself took 10 grams per day, and reported that at that level he only passed 1.5 grams of vitamin C in his urine, which means his body was using 8.5 grams.  He also recommended two or three grams of lysine, and also proline, components of collagen.

Toxicity.  If too much vitamin C is taken through the intestines, gas and diarrhea will result.  And vitamin C can interfere with anesthesia, so probably best to take after a procedure.  There may be other risks, but if most animals make vitamin C in their liver, and humans almost make it (we are missing the final step) then you might expect those risks are probably limited.  Lysine and proline are two of the twenty amino acids which make all proteins, so they are found in the body at all times.  But toxicity is an important issue, and just about everything can be toxic at some point, even water.

There may be a role for a statin until vitamin C has been taken for a period of time, and has repaired the lesions, tears, and breaks in blood vessel walls. 

A Possible Good Subject for CRISPER

Finally, since so much of the machinery is already in place to make vitamin C from glucose, this may be a good subject for the use of CRISPR.  It is apparently only missing the final step.  After all, this is a gene that is in almost all of the animal kingdom, and was at one point part of human ancestral DNA, so it seems a natural choice for the use of that tool.  Perhaps some harmless virus can be used to inject it into the body, and ultimately, into the human genome.  

Also, I thought CRISPR might be a useful tool to remove the genes which make lipoprotein(a).  But there is quite a bit of controversy about the body's use of lipoprotein(a), it may be useful against cancer, for example, so maybe we don't want to stop its manufacture altogether.  

Apparently Big Pharma thinks lipoprotein(a) is worth a look  

Amgen and Arrowhead Pharmaceuticals, Eli Lilly, Silence Therapeutics, and Novartis, all think Lp(a) is important in heart disease, and they are working on schemes to silence the gene that makes lipoprotein(a).  Amgen is planning to interfere with the mechanism at the point where RNA makes the protein.  I would hope for pretty extensive testing because Lp(a) has been around for millions of years, and the body will use what it has on hand to solve multiple issues.  It would make the best sense to take the Amgen medication, Olpasiran, with vitamin C because, as with the statins, this medication will not make strong, rugged blood vessels, and without vitamin C, and without the backup system of lipoprotein(a), there could be blood vessel leakage, and chronic vitamin C deficiency could result in internal bleeding.  

It is possible these techniques may be so effective as to reduce Lp(a) to unsafe levels.  Nevertheless, CRISPR might be a possibility.  It may turn out that those who make too much Lp(a) have too many copies of the gene in their DNA.  Maybe extra copies can be snipped out, who knows?

But until that day when vitamin C is in the DNA for humans, it appears a good work-around for these genetic mutations that appear to cause heart disease is to take vitamin C, and the amino acids lysine and proline.  Though vitamin C plus Amgen’s solution may also work, although it may not clear existing plaques, which the Pauling-Rath Vitamin C plus lysine and proline appear to do.

In addition, to the possible side effects of such a new drug, you might miss out on other important effects of proper vitamin C levels, such as knee and hip health, which see:

There may be a bonus from regular intake of vitamin C

You can say that age might be the cause the huge number of knee and hip replacements, almost of epidemic proportions, but there might be a cause for these, and it might not be "age" per se.  Remembering that most all of the elements of either a knee or hip replacement involve collagen - bones, cartilage, tendons, ligaments, muscles - it seems possible that a lifetime of vitamin C deprivation, and therefore, collagen deprivation, could be the cause these ailments, and not age.  More like a lifetime of neglect.

The RDA (Recommended Daily Allowance) may prevent obvious signs of vitamin C deprivation, bleeding of teeth, teeth falling out, death, but it may be insufficient to prevent a knee replacement, or classic plaque-related heart disease.  I could not find any study designed to see if vitamin C might prevent such ailments; however, it is creeping into the literature and it is often that doctors recommend vitamin C be taken after a hip or knee replacement to aid recovery.

Also, it occurs to me that if Vitamin C + Lysine can clear up blood vessels, wouldn't that mean better blood flow to the brain?  This could mean possibly two things.  More oxygen to the brain, but it may also be useful in removing unwanted metabolites. 

I am not a doctor or a Ph.D. researcher, I am an English major, but on the upside that means I can read and think, and so can you.  But admittedly, this is complicated stuff.  There are twenty-eight types of collagen, so unless you know what type of collagen to take, I don’t think I would attempt to buy collagen as a short-cut, though it may help.  You would have to know what kind you are buying and what kind you need.  Maybe you are best off just taking the building blocks - amino acids lysine, proline, and vitamin C, and so on.  And remember, free lysine (as opposed to lysine buried in collagen) may prevent lipoprotein(a) from binding with blood vessels. 

I only looked into this because I had a reaction to the statins, and wanted to know if there was a work-around for the statin.  I saw on the internet that Linus Pauling had a theory about heart disease, and gave it some attention even though he came on to this in old age, and even though his theory about vitamin C and the common cold was a bust (at least at oral levels), I paid attention because he was the most important chemist of the twentieth century, the chemist other chemists went to.  My function here is a journalist's job, to alert the public by bird-dogging a few leads for you, alert you to other possibilities. 

There are 224,000 cardiologists in the United States.  Linus Pauling came up with this theory over 30 years ago, which shows just how long it can take to get basic information like this into general use - because we are not there yet.  Doctors are still testing for LDL, when it appears that lipoprotein(a) may be the molecule that does the most harm.  Though to be fair, as a cardiologist said to me, they knew it was a problem 30 years ago, but there was no good reason to test for it.  If they find it high, there’s nothing in their toolkit for it.  Thirty years seems like it should be a long enough time to test these ideas of Pauling and Rath, but apparently not.  After all, there is no money in it for Big Pharma if the solution is just a cheap vitamin and a cheap amino acid.  This theory may not be easy to understand, but it is also not quantum mechanics.  In any case, I feel confident that few cardiologists have made their patients aware of this knowledge, and that may be because they were also let down by their medical educators, so apparently there is a need for this kind of public service message.  Read and think for yourself, consult your doctors, inform your doctors, agitate for medical research, support this video by sharing or sending contributions, and above all, come to your own conclusions, it’s your body.

Useful videos and websites:

Linus Pauling Discusses Vitamin C and Heart Disease at Stanford

https://www.youtube.com/watch?v=2bymKIPaTws&t=2454s

This might be what it's like to see a great scientist give a talk like a Schrödinger or a Max Planck.  He gives the talk with no notes, he knows this material by heart.  Though he does hesitate as he calls on his memory, and his voice vibrates annoyingly.  I don't believe he gets any facts wrong even though 90 at the time of the talk.

Linus Pauling Discusses Vitamin C and Unified Theory of Heart Disease

Poor quality video.  Static picture for most of it, though the audio continues, and it can be listened to as a podcast.

https://www.youtube.com/watch?v=cYHHKJBRUxw&t=16s

A Review of Linus Pauling's Life

https://www.youtube.com/watch?v=nkI5MCUNuXw&t=1248s

Linus Pauling Reviews His Life

https://www.youtube.com/watch?v=a8maetlPd8Q&t=2360s

Dr. Matthis Rath Discusses Vitamin C and Heart Disease

Matthias Rath traveled to the United States to study with the great chemist, Linus Pauling, even before finishing medical school and becoming a cardiologist.  It seems he stimulated Pauling, who welcomed an opportunity to solve a great problem in human health - heart disease.  Pauling was on much firmer ground with his suggestion of vitamin C, plus lysine and proline in the manufacture of collagen than he was with the common cold.  Rath did important work in identifying lipoprotein(a) as an important culprit in heart disease.  Pauling appears in the video quite happy to regard Rath as his partner in these discoveries.

https://www.youtube.com/watch?v=O0lEmXJD7p4&t=167s

 

Hypothesis: Lipoprotein(a) is a Surrogate for Ascorbate - a paper by Linus Pauling and Matthias Rath

https://www.pnas.org/doi/epdf/10.1073/pnas.87.16.6204

Linus Pauling and Matthias Rath's work is wrapped up in this paper.

Dr. Rath's Vitamin C - Lipoprotein(a) Unified Theory of Cardiovascular Disease

https://www.youtube.com/watch?v=VERKQsI2Kzg

John Cha discusses the work of Matthias Rath's work with lipoprotein(a), vitamin C, and lysine.

Hypoascorbemia induces atherosclerosis and vascular deposition of lipoprotein(a) in transgenic mice

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447075/

Cha, Niedzwiecki, and Rath discuss the results of an experiment with laboratory animals modified not to make vitamin C, but to make Lp(a).  Plaques and heart disease result.

Dr. Gifford-Jones 2nd Opinion on Heart Disease

Ken Walker (Dr. Gifford-Jones) is a graduate of Harvard Medical School, and for decades a medical journalist.  In this video he gives a long talk centering on heart disease.  He survives 20+ years after a serious heart attack and triple bypass at age 74.  Slides include artery clearing with vitamin C and lysine thru optometrist's photos of arteries in the retina of the eye.  At this writing he is now over 100 years.

Experimental Study of Intimal Ground Substance in Atherosclerosis

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1822858/pdf/canmedaj00682-0019.pdf

When Humans Stopped Making Vitamin C

https://academic.oup.com/emph/article/2019/1/221/5556105

The Next Pathway - Lp(a)

https://www.healio.com/news/cardiology/20230213/the-potential-next-pathway-to-target-in-cvd-prevention-common-elevated-lpa?utm_source=selligent&utm_medium=email&utm_campaign=news&M_BT=383589456542

Companies working on Lp(a)

Be careful in your searches about Lp(a)

The new search engines like CHATgpt, which is now used in Bing, will not always deliver useful results.  For example: Yes, one lady doctor reduced her Lp(a) number by 48%.  And yes she published a letter in the prestigious journal, JAMA.  And yes, the lab work was done by the "highly reliable Lawrence Berkeley National Laboratory/Berkeley HeartLab Technology Transfer program."  But this is just one person.  Yes, she followed the Pauling protocol, which she took to be 3 grams each of vitamin C and lysine.  The results are encouraging, but a naïve reader might put more into this than there is.  It's just one person, not a study of 1,000 or 10,000.  You can see from the bold type how a clever search engine might be whooped. 

A Reappraisal of the Lipid Hypothesis by Robert DuBroff, M.D.

https://www.amjmed.com/action/showPdf?pii=S0002-9343%2818%2930404-2

A paper by cardiologist Robert DuBroff, M.D. looking again at the lipid hypothesis.  He found only 2 studies out of 29 showed any mortality benefit from a statin regimen.

Thomas Barnard

tbbarnard@gmail.com

P.O. Box 309, Oak Park, IL 60303-0309

This website is updated as I learn new information.

Update: 03/22/2024