A murder mystery often begins with what seems like an open and shut case – a woman alone in the room, gun in hand body on the floor. She’s guilty, bang to rights. This is how the so-called ‘Cholesterol Hypothesis’ has always been presented. Cholesterol is found in the plaque that blocks arteries. So – less cholesterol, less plaque, less heart disease. QED.
However, as Dr. Malcolm Kendrick pokes into the details, the apparently watertight case begins to unravel. Maybe there is a more plausible explanation. Uncovering it has led our detective hero to declare cholesterol innocent.
This is, of course, a serious challenge to the cholesterol-lowering statin industry and all those who work in it. A U-turn would be seriously embarrassing for healthcare professionals as statins are the world’s best-selling drug, routinely recommended to everyone in the UK from 55- 60 years old for the rest of their lives.
So what does cause heart disease?
Dr. Kendrick, an independent-minded GP from Macclesfield in Cheshire, is one of the most persistent and best-informed critics of the statin story – you know, the one where lowering cholesterol saves lives. For decades, Dr. Kendrick has been pointing out that the splendid cloak of evidence-based medicine worn by statins and the cholesterol hypothesis is a patched and threadbare thing, not fit for purpose.
While Dr. Kendrick has gathered an impressive following of patients and doctors who share his concerns, many would be hard pushed to summarise his response to the key question: if the villain is not raised cholesterol, what does cause heart disease?
It’s not really surprising since, over the last few years, Dr. Kendrick has been exploring this whodunnit in a series of fascinating and deeply knowledgeable on-going blog posts – which now number 65…
Dr. Kendrick’s investigation provides the basis for a biochemical detective story that starts at the crime scene – a corpse with a wodge of stuff blocking one or more arteries. How did it get there and why? What follows is my heavily condensed retelling of the story of Dr. Kendrick’s painstaking investigation, as told originally in an interview with blogger and health activist Ivor Cummings, recently posted on his website.
Causes come in two varieties
Dr. Kendrick reveals that his attempt to crack the clot mystery started in medical school. ’When I was at Aberdeen University in 1982, one of my teachers remarked gnomically that “LDL cannot cross the endothelium”. I had no idea what she was talking about; I’d never heard of the endothelium, although I vaguely knew what LDL was. I felt like I’d been told a secret, which in a way I had.’
Just to clarify: LDL (Low-Density Lipoprotein) is the transporter made of fat that carries cholesterol around the body. Statins lower LDL cholesterol levels by reducing cholesterol production in the liver.
Dr. Kendrick begins by setting out the basic principle of his investigation. There’s no soundbite answer to the question ‘what is the cause?’ because it’s clear to him that heart disease is a process, like developing rheumatism, rather than an infectious disease like tuberculosis, which really is an open and shut case. In that case, there is a single cause – the tuberculosis bacterium. No bacterium, no tuberculosis.
But, in medical detective stories like this, finding the cause is half the battle. There are usually two criteria for causation: 1) ‘necessary’ – no condition without it; and 2) ‘sufficient’ – if you have it you will get the condition. With tuberculosis, the bacterium supplies both. You have to have the bacterium to get the disease so it’s ‘necessary’, and just having the bacterium is ‘sufficient’.
Many of the factors described as ‘causing’ heart disease, however, are neither necessary nor sufficient, such as smoking or air pollution, although stopping either or both will reduce your risk. Raised cholesterol is also not necessary or sufficient – in fact, some big Japanese studies have found that older people with higher cholesterol actually live longer.
Damage to the arteries is where it all begins
Kendrick realized to get a fix on what was actually happening in a heart attack he would have to identify one or more conditions that were sufficient to cause it without any other risk factors being involved. In fact, he found two, albeit pretty obscure conditions.
One is sickle cell disease, in which blood cells become sickle-shaped with pointy ends, making them sharp and abrasive. ‘It’s like putting sandpaper into your blood,’ says Kendrick. The other is Kawasaki disease, which involves severe but temporary inflammation of the arteries. Although it runs its course within a few weeks, the blocked arteries sometimes swell and burst.
There were leads he could work with. Could it be that for a heart attack to happen there has to be some sort of damage to the arterial wall? The best-known condition that does this is high blood pressure. ‘This puts biomechanical stress on arteries,’ he says, ‘especially in areas of localized turbulence such as junctions, where atherosclerosis (plaques) is more likely to develop.’
The next key question was: ‘What exactly happens when the walls of the artery are put under stress or damaged?’ The answer to this would form the backbone of his hypothesis – an alternative to pinning the blame on cholesterol.
From his intensive investigations, Dr. Kendrick concluded that damage to the inner lining of the artery wall, known as the endothelium, is necessary for a heart attack.
It’s in this protective layer, which is inside every artery, where much of the action that ultimately helps or hinders heart disease takes place, he believes. But few doctors consider what’s happening in the endothelium when diagnosing heart disease – and few patients would ask.
How can the endothelium be protected?
Establishing this theory promises a new direction for heart protection where researchers investigate the factors that help to protect the endothelium and those that damage it.
Significantly, none of the substances or events that damage the endothelium involves LDL cholesterol. Cigarettes, for instance, damage it via the microparticles they contain but the body can recover by releasing a type of cell, called the ‘endothelial progenitor cell’, which repairs the damage. Raised levels of the amino acid homocysteine – linked with both heart disease and Alzheimer’s – are also harmful. So too are the raised levels of glucose and insulin that come with diabetes.
Age is certainly a risk factor simply because all processes like repair or renewal slow down. We can’t yet physically turn back the clock, but you can do things to reduce the harm from the disorders that come with it, such as controlling diabetes via a low carb diet. Saturated fat, however, like cholesterol, doesn’t affect the endothelium, according to Dr. Kendrick.
Having identified the importance of the endothelium, Dr. Kendrick began interrogating the literature to discover more and found something vital to its protection – the glycocalyx. This is the super-slippery coating that makes it hard to hold a live fish and also coats the endothelium.
A thick endothelium has several beneficial effects including expanding blood vessels, which is good for reducing blood pressure and reducing clotting (but not too much) as well as increasing the production of the endothelial progenitor cells for repair. Interestingly, another heart-harming effect of diabetes is that it can reduce the thickness of your glycocalyx covering.
The magic of nitric oxide – a must-have for heart protection
Possibly the most important heart-protective effect of the glycocalyx is that it releases an enzyme that produces nitric oxide, which is responsible for many of these beneficial effects.
The triggers for nitric oxide release include exercise and sunlight also, interestingly, Viagra. Being unable to get an erection can be a sign you are not producing enough nitric oxide. Curious fact: statins also slightly raise nitric oxide.
Drugs that lower nitric oxide includes the widely prescribed PPI inhibitors, which have names ending ‘-sole’, such as Omeprazole.
The EndoT theory
Kendrick’s hypothesis, which might be termed the ‘EndoT theory’, proposes a much wider range of factors that are capable of raising or lowering your risk of heart disease. It could also explain why factors such as lead and air pollution cause heart disease as both damages the endothelium. Conversely, the cholesterol hypothesis can’t explain this.
EndoT can also explain the mystery of why a class of blood pressure pills called ACE inhibitors are more effective at cutting heart disease than other drugs with the same action. No surprise; they increase nitric oxide production.
Here’s the new takeaway message:
By now the medical detective has constructed a new and convincing theory of heart disease that has major implications for treatment. The slow build-up of the condition starts with damage to the artery lining. A new class of attackers and defenders, some familiar others less so, have emerged.
The challenge now facing the medical Sherlock is explaining away the familiar components of the cholesterol hypothesis. A keen supporter might argue that simply listing factors that increase the risk is all very well but it doesn’t do away with the main issue: the plaques filled with fat (lipids) and cholesterol that block arteries.
At this point, Kendrick pulls off a classic detective story twist – the demonization of cholesterol is a case of mistaken identity. But before revealing it, let’s have a flashback to show how the mistake arose.
The endothelium springs a leak, maybe due to blood pressure or glucose damage. The clotting mechanism swings into action. The dangerous hole in the artery wall is rapidly closed with platelets and strands of fibrinogen, along with other ingredients from the bloodstream such as bits of the LDL transporters and red blood cells.
But unlike the scab over a wound on your outside, this clot on the endothelium can’t just drop off. Instead, the endothelium absorbs it by signaling to the progenitor cells to set about providing the raw material that allows the endothelium to envelop the clot/plaque. That results in the plaque getting inside the covering of the artery wall.
The case of mistaken identity
This takes us back to the gnomic comment by one of Dr. Kendrick’s teachers about LDL cholesterol not being able to be part of the artery wall. ‘Later I found she had been working on all the stuff I’ve been burrowing into’ – a theory that heart disease is about blood clotting on the artery walls due to damage there. The fact that it’s still pretty much a secret nearly 40 years later should be a major scandal.’
This is where Dr. Kendrick reveals Poirot-style how the case of mistaken identity works. He’s been to forensics where the clot has been put under the spotlight and come back with data that overturns the cholesterol hypothesis.
The clots/plaque that cause atherosclerosis doesn’t contain what everybody assumed.
For decades when researchers analyzed the clots they found both cholesterol and lipoprotein; exactly what you would expect if LDL cholesterol was too high and some of it was swept into a clot as if it was forming.
But forensics, or rather Kendrick’s relentless biochemical research, said otherwise. ‘The type of LDL cholesterol in plaques isn’t the soft waxy stuff people expect it to be,’ he explains. ‘It comes in the form of cholesterol crystals. And such crystals can’t be made from the lipid cholesterol combination that makes up LDL.’
The crystals of cholesterol
These crystals aren’t something your doctor is likely to tell you about as they are fairly obscure but various bodily compounds can turn into crystals. The best known are the crystals of uric acid that cause the pain of gout. So, where do these crystals come from?
‘The only sort of cholesterol that does turn into crystals,’ explains Dr. Kendrick. ‘is pure cholesterol. This is found in red blood cells because it is essential to the structure of the wall of these cells, which are found in plaque clots because they are a key part of the clotting process.’ So the cholesterol in plaque, far from being the cause of a blockage, is just part of normal clot ingredients.
But what about the lipoprotein transporters that have also been identified in clots for many years?
‘Wrong again!’ says our medical Poirot. ‘LDL has a twin called lipoprotein (a) – or Lp(a). It’s exactly the same as the lipoprotein in regular LDL but with the tell-tale protein (a) attached. However, if you are a researcher looking for regular lipoprotein, you’ll think you’ve found that unless you’ve also checked for the (a) protein, which is rarely done.’
So, where has Lp(a) come from and what’s it doing in the clot?
Two decades ago, the late double Nobel Prize winner Professor Linus Pauling identified Lp(a) as a useful member of the endothelium protection squad. During his long research into vitamin C, Professor Pauling found that vitamin C deficiency is another cause of damage to the endothelium. When people are seriously deficient – as in scurvy – the damage can cause them to bleed to death. )
So Lp(a) far from being a villain is something else helping to limit damage to the endothelium.
What to do now?
Since many people are sub-clinically deficient in vitamin C supplementing may be a good idea. And there are two more supplements you might consider: L-carnitine and L-arginine, which are both amino acids needed for the production of nitric oxide.
And in the future…
Hopefully, research can now start to tell us which drugs are likely to be damaging or beneficial and what lifestyle shifts might also be effective.
Jerome Burne is the editor of HealthInsightUK. He is an award-winning journalist who has been specializing in medicine and health for the last 10 years and now works mainly for the Daily Mail. His most recent book “The Hybrid Diet” was written with nutritionist Patrick Holford, published in 2018. Award: 2015: Finalist for ‘Blogger of the Year’ Medical Journalists’ Association.