Your cells die every day. Don’t worry, your body is protecting itself. In a process known as apoptosis or programmed cell death, cells that are no longer needed commit suicide. Some cells are only required for a short time, they maybe infected by a virus or develop harmful cancerous mutations. Cell death is also an essential part of development from an embryo. For example mouse paws begin as spade-like structures and only form the individual digits as the cells in between die . During apoptosis the cells fragment into smaller apoptotic bodies, and their cell surface is flipped open to display lipid molecules called phosphatidylserines, which act as an “eat me” signal to recruit cells called macrophages to engulf them, before their contents spill out and damage the surrounding tissue. This is a process known as efferocytosis.
However cell death is not always so orderly. Some cells suffer premature death known as necrosis, where they burst open for various reasons such as infection, physical trauma or extreme temperatures. However as the cell’s contents are released into the open, an inflammatory response is triggered, so the macrophages sent to engulf these cells release substances that can damage the surrounding tissue, resulting in a build-up of dead cells.
It is this damaging chain of events that often occurs in atherosclerosis; the build-up of fatty plaques which can block arteries or trigger blood clots leading to heart attacks, strokes or tissue death, known as ischaemia. As fatty lipid molecules (primarily LDL or ‘bad’ cholesterol) build up in arteries, they act like damage signals. Macrophages recognise these damage signals as if it is phosphatidylserine, and engulf the lipids to become what is known as a foam cell; a cell full of lipid. A healthy macrophage can repackage the LDL into larger HDL cholesterol, which is released back into the bloodstream to be excreted by the liver. The foam cell can also leave the atherosclerotic plaque to be disposed of via lymphatic vessels, thus shrinking the plaque.
However, foam cells can be overwhelmed by engulfing excess cholesterol, increasing harmful inflammatory signals, stress and apoptosis. But all is not lost here. If other macrophages clear the dying foam cells, less harm will be done. The problem is the increased inflammation renders efferocytosis defective, resulting in a process called secondary necrosis. Here apoptotic bodies swell and burst open, as they haven’t been cleared in time. As a result, a large amount of cell debris builds up inside the atherosclerotic plaque, creating what is referred to as a necrotic core. The core is pro-thrombotic when it is exposed to clotting factors in the bloodstream.
A recent study showed that a compound found in red meat called L-carnitine could be responsible for increasing the risk of vascular disease by altering the bacteria found in our guts . Lets look at this study in further detail.
L-carnitine and choline (found in excess amounts in eggs, dairy products) is broken down by our gut microbes into a compound called TMA, which is then converted by liver enzymes into TMAO - associated with cardiovascular disease and atherosclerosis. TMAO is detected in the blood of omnivores but not vegans, following the intake of L-carnitine capsules for three days. It seems a species of bacteria belonging to the genus Prevotella is the main bacterial population that metabolises carnitine into TMAO.
And interesting point is that the presence of TMAO has no effect on the expression of the receptor for LDL (low density lipoproteins or bad cholesterol) or cholesterol production genes. So how can TMAO increase atherosclerosis? In the liver it prevents the breakdown of cholesterol into bile acids. It appears that TMAO also reduces a process called reverse cholesterol transport – the expulsion of excess cholesterol by gut cells, and macrophages in atherosclerotic plaques. TMAO does this by lowering the presence of cholesterol transporters in the gut. Thus if excess cholesterol cannot be eliminated from the circulation by gut cells, or the artery wall by macrophages, the development of atherosclerosis and the risk of cardiovascular disease increases.
So now we know how red meat on its own can increase cardiovascular disease. Over the years it has been documented how the food industry handles red meat to enhance its visual appeal and marketability such as the use of red food colouring and soaking meat in salt water to enrich its flavour. We cannot establish on what scale such tampering has affected the health of the general population. But one thing is for certain, don’t eat meat that looks red.
 Koeth, R. a, Wang, Z., Levison, B. S., Buffa, J. a, Org, E., Sheehy, B. T., … Hazen, S. L. (2013). Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine, 19, 576–85. doi:10.1038/nm.3145
You’ve heard all the usual health advice to keep your heart healthy or reduce your risk of cancer, but sometimes you are tempted by that mouth-watering piece of cake in the patisserie window or want to miss that workout for the day to catch your favourite TV show. And to be honest there is no harm in occasionally being a little lazy and treating yourself. But maybe you would find it easier to be healthy if you understand why taking such health precautions are good for you. In my previous post, you learned what causes heart attacks and strokes. Now here is how you can prevent them happening to you.
1) Ditch the lard
As mentioned in my previous post, fats are essential to start the atherosclerotic process. If there is too much ‘bad cholesterol’ (otherwise known as low density lipoproteins or LDL) and another type of fat call triglycerides, in your blood from all those hamburgers or a full English breakfast (red meat is particularly high in fat), they will deposit in curved or branching arteries triggering the immune response where macrophages initially consume the fats, clear them from the artery and break them down into cholesterol, which become a vital part of the cell membrane. However the amount of LDL eventually overwhelms macrophages, so they die and deposit in the artery wall contributing to the build up of the atherosclerotic plaque. And why in particular is LDL so dangerous? The clue is in the name, the particles are of a low density and thus are small enough to fit through the spaces between endothelial cells and deposit inside the artery wall, while also being more easily consumed by macrophages. The dying macrophages also contribute to the problem, as their cell membranes become part of the growing plaque increasing the level of cholesterol inside. And it’s not just the fat inside your arteries that creates problems. As more fat is consumed, the body primarily deposits the excess fat around the abdomen resulting in an increase in number and size of fat cells, called adipocytes, which are full of triglycerides and cholesterol. And crucially these adipocytes release chemicals, which increase the aggressive immune activity of macrophages, making them more likely to build up and cause damage in the artery wall.
2) Keep working out
The recommended amount is equivalent to half an hour everyday, my suggestion is to do as much as you can! Research suggests that physical activity; particularly aerobic exercise (such as running, cycling, swimming) can lead to better control of the production of inflammatory signals, which would normally mobilise the immune cells, such as macrophages, responsible for exacerbating atherosclerosis. In fact exercise stimulates the production of anti-inflammatory signals, which dampen down the potentially damaging inflammation, reduce adipocytes, help macrophages to expel cholesterol, reduce growth of the plaque, and in already advanced plaques it can increase the thickness of the fibrous cap (by promoting the growth of smooth muscle cells) therefore it is less likely to rupture and create a blood clot. So it is never too late to start exercising, even as you get older it could save your life!
3) Eat your five-a-day or even more!
Studies show that the more fruit and vegetables you eat, the lower your risk of suffering a heart attack or stroke, particularly with green leafy vegetables and fruits such as apples. Research is ongoing to establish exactly why fruit and vegetables are so beneficial. Early studies suggest a protein called sulforaphane – found in green vegetables such as broccoli – can suppress the activation of endothelial cells, thus it could reduce atherosclerosis by preventing the chain of events that start the disease process.
Earlier I mentioned the dangers of LDL or ‘bad cholesterol’. But there is also ‘good cholesterol’ otherwise called high density lipoproteins or HDL. And as you’ve probably guessed from the name, HDL is not dangerous to the artery wall like LDL because the particles are of a high density and are unable to squeeze in between the endothelial cells and deposit in the artery wall. In addition, HDL serves many benefits. HDL can reduce the inflammatory actions and the entry of macrophages into plaques while increasing their exit from atherosclerotic plaques, thus reducing the size of plaques even if they are already large in size. HDL also promotes the breakdown of cholesterol and its excretion by macrophages, thus reducing the fat content of plaques. So how can you increase your HDL levels? Foods that are known to increase HDL levels in the blood are: fish, high fibre foods (such as oats, fruit, vegetables, grains), nuts, legumes, yogurt, fruit juice, dark chocolate, garlic, and red wine (or dark grape juice if you don’t drink alcohol). And if you have been prescribed statins, keep taking them as they reduce LDL levels while increasing HDL in your blood, and have many anti-inflammatory benefits.
4) Don’t add salt to taste
A high intake of salt increases blood pressure, and the higher your blood pressure the higher your risk of suffering a heart attack or stroke. A higher salt concentration in your blood promotes the diffusion of fluid; primarily water, into the circulation increasing blood volume and thus increasing pressure and potentially damaging the blood vessel wall, particularly the endothelial cells. When pulses of blood are pumped around the body, the arteries need to expand and relax with each pulse of blood that moves through. But if the endothelial cells are damaged, they cannot send signals to stimulate the expansion of the vessel wall further increasing the pressure created by flowing blood and imposing stress on the cells. All of these events increase inflammation creating the conditions for atherosclerosis to begin and further increase blood pressure.
5) Don’t give in to your sweet tooth
There is no doubt about the association between high sugar intake and cardiovascular disease, but we still don’t really know why this is the case. Studies performed so far suggest that high blood glucose levels can increase inflammation, promote the entry of macrophages into the artery wall and possibly interfere with the expulsion of cholesterol by macrophages. It also appears that LDL is increased in diabetics, thus sugar and cholesterol may work together to promote atherosclerosis. While more studies are needed to firm up these conclusions, the link between diabetes and cardiovascular disease is very clear so don’t tickle you sweet tooth too often!
6) Limit the booze
Early studies demonstrate that light drinking (up to the recommended 2-3 units of alcohol a day) reduces atherosclerosis, and the risk of strokes and heart attacks, but consuming higher amounts of alcohol on a regular basis increases atherosclerosis significantly. But a recent small-scale study published by New Scientist  showed that when regular social drinkers gave up alcohol for a month, they experienced a large drop in liver fat, blood glucose and cholesterol, and improved their sleep quality and concentration, although more scientific evidence is needed to back up these results. So you can still enjoy that tipple, but only in moderation.
Any questions? Please comment below
Ten years ago when my father was hospitalised after suffering a heart attack, the nurses gave him a video to watch about heart attacks. The video detailed the symptoms and treatment given, and when addressing the cause of heart attacks, the narrator stated that it is not really known, all is known is that a blood clot arises blocking the artery’s blood flow from reaching the heart, thus starving the heart muscle of vital nutrients and oxygen for survival and ultimately damaging the heart. While the latter is true, the events prior to blood clot formation have been well known for years, in fact centuries! A more accurate statement would have been that it is not fully understood how the various symptoms of a heart attack, such as vomiting and excessive sweating, occur. Nonetheless as an A-level student, this deepened my curiosity into the cause of heart attacks ultimately leading me to undertake a PhD on atherosclerosis – which I will define later in this post.
If you watched the second episode of the recent “Watermen: A Dirty Business” series on BBC Two, you will have seen how drains are often blocked because hundreds of litres of cooking fat is poured down household sinks every week. Over time the fat builds up inside the pipework, particularly at joints and bends, eventually blocking the pipes and causing the rather unpleasant consequence of sewage spewing out onto the roads! The process of fat blocking our sewage pipes is reminiscent of what happens in our own arteries.
So what is the disease inside our arteries that can have such deadly consequences? Firstly it is important to clear up a couple of terms which can cause confusion, even to me! Arteriosclerosis refers to the hardening and thickening of the arterial walls. The middle layer of the artery wall (the tunica media) primarily consists of smooth muscle cells, which contract and relax, like our muscles, to create an elastic effect so that each time the heart pumps, the artery wall expands and constricts to allow pulses of blood to flow through. Hardening of the artery wall means this elasticity is lost and blood pressure increases in the artery. The subsequent narrowing of the artery reduces the ability of blood to flow to the intended tissues.
Hardening can occur for several reasons; calcium deposits can build up in the tunica media. Or a process called intimal hyperplasia can occur (please don’t worry too much about the jargon!) where smooth muscle cells multiply excessively and move towards the inner layer of the artery wall. ‘Intimal’ refers to the innermost layer of the artery – the intima, and ‘hyperplasia’ refers to the excess reproduction or multiplication of cells. Additionally the smooth muscle cells produce proteins such as collagen and elastic fibres further hardening and clogging up the artery.
But the main type of arteriosclerosis causing major problems in the human population, and primarily responsible for heart attacks and strokes, is atherosclerosis. It is a disease that takes decades to develop and inflict its potent consequences on us but by the time we know it’s happening, it is often too late. So what exactly is atherosclerosis? As you read the next part, watch this video which may help you visualise the disease (video created by 3FX medical animation inc.):
Just like the fatty sewage pipes, atherosclerosis begins at bends and branches of arteries. Blood pressure can be high in these regions, and the blood tends to slow down or swirl around causing the cells lining the inside of the artery (called endothelial cells) to become ‘activated’ setting off a chain of events. Firstly ‘lipids’ including cholesterol – particularly low density lipoproteins, more commonly known as ‘bad cholesterol’ - deposit in the artery wall in between the endothelial cells; hence why you should stay away from those pesky fast food outlets! But atherosclerosis is not simply a fatty plaque that blocks your artery. As these lipids slowly build up in the artery, our immune system is called to action by the active endothelial cells and sends in cells called macrophages to consume, break down and dispose of these lipids, and initially they are successful. But over time the amount of lipid building up can become excessive and overwhelm the macrophages, so these cells consume surplus lipid and become immobile, just like if you eat too much chocolate cake and feel so sick you can’t move! The macrophages eventually die and add to the material building up in the artery wall. There are many other types of immune cell that become involved and contribute to the problem but macrophages are the main protagonist (and incidentally the main cell of interest in my research!)
The artery tries to tackle this problem by expanding outwards to increase the diameter of the artery, and by moving smooth muscle cells from the wall to the surface of what is now a developing atherosclerotic plaque. The smooth muscle cells create a ‘cap’ at the surface separating blood flow from the plaque as exposure of dead cells to flowing blood can trigger the formation of a blood clot. Eventually the artery cannot expand any further and so the growing plaque begins to constrict blood flow. The growing plaque can be enough to obstruct blood flow. Narrowing of the artery also causes the flowing blood to exert force on the cap and weaken it eventually causing it to burst open or rupture. A blood clot will then form on the surface, which may or may not block blood flow in the artery. If blood flow is blocked in the coronary arteries supplying blood to heart muscle, a heart attack occurs and some of the heart muscle can die. Alternatively blocking blood flow to part of the brain, either by a blood clot or part of a plaque dislodging and blocking the small blood vessels in the brain, leads to a stroke.
So atherosclerosis is an extremely complex process with many different factors involved, hence why it is so difficult to treat. Research is vital to fully understand this disease and improve existing treatments. Much like cancer, which is so difficult to treat because cancer in each patient can be caused by a different mutation in a different gene, thus we cannot use a ‘one size fits all’ drug.
Now that you know what atherosclerosis is, I will explore how you can reduce your risk of suffering from a heart attack or stroke in my next post.
Dr. Anusha Seneviratne
My research is funded by the British Heart Foundation. To donate click sponsor me below.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.