Cardiovascular diseases and related events like heart attacks and strokes are the leading causes of death in humans today, causing more than 17 million deaths every year. Remarkably though, most other animals barely ever get heart attacks! Understanding why could help us to elucidate the biological underpinnings of this deadly disease in humans, and use these insights to design new medicines and preventative strategies. Let’s begin with a short introduction.
Heart Attacks: How do they Happen?
Most heart attacks and strokes are complications of atherosclerosis – narrowing and hardening of the arteries which supply oxygen and nutrients to the heart or brain. This chronic event develops over many years, during which a cholesterol-rich plaque accumulates at sites of damage in the artery wall, causing the vessel lumen to become narrow. Over time this plaque can grow and become covered in a hard fibrous cap, which can then rupture to release a clot into the artery. Eventually this can cause a blockage, which as you might imagine, can interrupt the flow of blood to the tissues and organs that that artery supplies. So if your coronary arteries supplying the heart become blocked , there won’t be enough oxygen and nutrients flowing to the heart which it needs to function normally. This can result in a heart attack – in medical terms, it’s called a myocardial infarction. The same thing can happen in a vessel supplying the brain, which instead can lead to a stroke.
In truth, the exact sequence of events which produce an atherosclerotic plaque is not completely understood, and what I am offering you is a wildly simplified version of reality. Atherosclerosis is a chronic inflammatory process, during which gangs of hungry immune cells called macrophages infiltrate the artery walls and become engorged with an oxidised form of LDL cholesterol (commonly known as “the bad cholesterol”). These lipid-laden immune cells are now called “Foam Cells” – a hallmark of early “fatty streaks” which proceed atherosclerosis and its complications.
So now that we have an idea of how it happens, we want to know why – or more importantly, in the case of most animals, why not?
What is it about animals that has allows them to dodge this epidemic while we humans suffer? Perhaps its because they’re not sitting around working office jobs, watching Netflix, reading blogs and feasting on greasy hamburgers and fries.
I would probably tell you, if I believed in God, that this is his way of punishing us for all the torture we’ve been putting the poor animals through, and that if we all just went vegan, perhaps he’d leave our poor hearts and arteries alone. Having had that thought now I can’t erase it, because aside from the whole God delusion, it actual would make a lot of sense… But scientists don’t think so – they’ve come up with some other intriguing explanations. It turns out that animals have got some clever tricks up their sleeves!
Is it all about Cholesterol?
We know that many of the factors which increase heart disease risk in humans are related directly or indirectly to our diets – too much fat in the blood, obesity, diabetes and high blood pressure, can all be triggered by an unbalanced diet – in particular one high in cholesterol, processed foods and saturated animal fats, and low in vitamin-rich vegetables, fruits and wholegrains (1). Cholesterol is often pinned as the primary culprit, and while high cholesterol certainly is a major risk factor for heart disease, it is not solely to blame. In fact many animals, like bears, who have much higher levels of cholesterol than even the unhealthiest of humans, still manage to evade the cardiovascular curse (2). It’s clear then that cholesterol is only part of a larger picture, and sure enough, the drugs we’ve created to lower cholesterol like statins are only somewhat effective at reducing the burden of heart disease.
The Vitamin C Factory
“So, what have animals got that we haven’t?” you ask.
L-gulono-gamma-lactone oxidase! That’s what!
Haven’t you heard?
L-gulono-gamma-lactone oxidase is an enzyme that allows animals can make their own Vitamin C. On the other hand, we humans lack this enzyme, and instead rely on our diets to provide us with this essential vitamin. Viatmin C has been linked to cardiovascular health, and is often lacking in a typical Western diet. This offer some clarity as to why heart attacks are so rare amongst the animal kingdom. Some scientists have specultated that this deficiency in our Vitamin C factories might underly our increased susceptibility.
Vitamin C isn’t a particularly difficult one to come by – you will find it in high amounts in many common fruits and vegetables, especially kiwis, citrus fruits and cruciferous vegetables, which is again great news for us broccoli enthusiasts! But many of the foods which have scourged today’s western society, like meats, dairy and processed carbohydrates, contain very low levels – the slice of pickle and lettuce in your Big Mac won’t get you very far. Relying on these foods without adequate fruit and vegetable intake can result in deficiency. Serious deficiency is rare today in developed countries but can still occur in people with limited food variety. Why does this matter?
Vitamin C is a multifunctional nutrient and offers many health benefits:
- It is required for biosynthesis and metabolism of important proteins, such as collagen, which plays a vital role in wound healing (3)
- It enhances immune responses to help fight off colds, flus and other infections (4)
- It is required for the synthesis of neurotransmitters – the chemicals that send messages between cells in your brain. It has been found to improve cognitive function and protect against age-related mental decline and Alzheimer’s disease (5)
- It can help to lower blood pressure (6) and can keep our blood vessels operating healthily by improving the function of endothelial cells lining vessel walls (7).
Vitamin C is also a powerful antioxidant. Specifically, it is known to inhibit oxidation of LDL cholesterol, which we know is a pivotal event in the formation of “Foam Cells” which leads to atherosclerotic plaques. It is no wonder then that a low Vitamin C intake, coupled with elevated cholesterol, can increase your risk of heart disease. The natural ability of many animals to synthesise this vitamin endogenously may well confer some benefit to their hearts’ health.
Linus Pauling & Lessons from Evolution
Some researchers have hypothesised that modern man’s unfortunate susceptibility to cardiovascular disease may be tracked back to a distinct evolutionary event – a genetic switch which occurred 40 million years ago. At this point in history, the emerging human genome lost its instructions for synthesising Vitamin C, and gained expression of Lipoprotein A, which negatively impacts cardiovascular health (8). So animals which make their own Vitamin C do not express Lipoprotein A, while the opposite is true of us primates and a small number of other animals like the guinea pig and European hedgehog.
Vitamin C and Lipoprotein A serve similar functions in the body during wound healing responses and in the damaged artery wall, and both also function as antioxidants to prevent oxidation of lipids. This similarity in function suggests that Lipoprotein A may serve as a surrogate for Vitamin C in certain species following this evolutionary split. So now when we find ourselves deficient in vitamin C, the body’s response is to synthesise the functionally similar Lipoprotein A in an attempt to repair damage to the artery walls.
Interestingly, the inverse correlation of these two substances in cardiovascular diseases can also be observed in cancer, diabetes and other diseases. And guess what! Not only do most animals not get heart attacks, but they are also much less prone to developing cancer and diabetes! Although aetiologically diverse, these diseases do have certain commonalities – all these diseases involve a change in the integrity or stability of the tissue – particularly the extracellular matrix. This protein-rich network of macromolecules is found between and around adjacent cells and is important in providing these cells with structural and biochemical support, and so allowing our tissues to function properly. Biosynthesis of collagen – an important protein component of this matrix – is dependent on the activity of Vitamin C.
The collagenous matrix provides strength and stability to the artery walls, which need to withstand continual stress throughout the lifetime, flattening and stretching with every heart beat. Conceivably, vitamin deficiency can cause weakening and damage to the artery wall. The body responds by producing excess cholesterol in the liver and depositing it in the injured artery. Chronic deficiency can permit the build-up of oxidised LDLs in the artery wall, which over time can produce an atherosclerotic plaque and trigger a heart attack later down the line.
If I haven’t convinced you to eat your fruits and greens, perhaps Linus Pauling will. He was a lead author of the research I have just discussed – an unwavering Vitamin C enthusiast and the only person to have won two Nobel prizes – the first in Chemistry in 1954; the second, the Nobel Peace Prize in 1962. Here is a quote of his that makes me smile:
“Facts are the air of scientists. Without them you can never fly.”
Linus Pauling would want you to believe that you can magically cure almost anything by supplementing excessive doses of this vitamin, but much of the earlier research backing his bold claims has since been criticised. Pauling sadly died of prostate cancer in 1994, though he vehemently asserted that supplementing Vitamin C had delayed the onset of the disease, and that the majority of cancers could be prevented and cured by vitamin C alone!
When it comes to reducing our own risk of heart disease, more recent studies suggest little benefit of Vitamin C supplementation (9). Epidemiological data is conflicting – some studies suggesting a meaningful benefit and others suggesting none. Most clinical intervention trials – where thousands of individuals are given the supplement once a day for many years, and compared to a control group not consuming the supplementary dose – have failed to find any benefit of Vitamin C for primary or secondary prevention of cardiovascular disease (9).
Eat Fruit not Pills
The authors of a 2008 meta-analysis, which included more than 370,000 people and a total of 7415 incidents of coronary heart dissease, concluded that increased dietary intake of antioxidant vitamins, but not supplementary intake has encouraging prospects for disease prevention (10).
Rather than turning to supplementary megadoses, we may be better off focusing on getting enough Vitamin C in our diet to avoid deficiency. Vitamin C is a water soluble vitamin, which means that any excess we take in beyond our body’s requirements will quickly be excreted in the urine rather than being stored in our tissues. Our cells become saturated with about 100-200mg, so if we’re already taking that much in our diet, a supplement won’t make any difference. Most epidemiological studies don’t take this into account and neglect to record Vitamin C levels in participants at baseline.
Supplementation may offer cardiovascular benefits in people with inadequate dietary levels – but won’t reap all the added benefits of consuming the whole fruits and vegetables, which of course are packed with many other antioxidants, vitamins, minerals and fibre.
For healthy adults, the recommended daily allowance (RDA) for vitamin C is about 60mg (recommendations differ from country to country). A lot of us get much more than that through a healthy diet. A single kiwi or one large orange will provide just about this! Some vegetables like broccoli contains even more, although most is lost from the vegetable during cooking.
Do Humans just Live too Long?
Some have suggested that animals don’t get heart attacks because they simply don’t live as long as we do. It usually takes many years for the fats in our arteries to build up into a fully formed atherosclerotic plaque. Heart attacks usually afflict us in middle and old age, though they can occur in younger individuals. However, this theory doesn’t explain why guinea pigs, who live only 8-10 years (and who like us, can’t make their own Vitamin C), develop arterial damage within just a few weeks when Vitamin C sources are removed from their diet.
Robert Sapolsky- A Case for Stress
The Vitamin C hypothesis isn’t the only one out there. Some believe the difference all comes down to stress. A 2017 study published in The Lancet found that heightened activity in the amygdala – a region in the brain involved in stress – is associated with an increased risk of heart disease and stroke (11).
In response to a stressful event – like Climate Emergency and the Earth’s impending doom – your body starts to release higher levels of adrenaline – commonly referred to as the “stress hormone”. This causes your breathing and heart rate to temporarily speed up and your blood pressure to increase. Your body is clever – it’s not trying to give you a heart attack – this is its way of preparing for the “fight or flight” response to save you from a perceived threat or harmful event. If you were being attacked by a bear for example, your body would need to undergo certain physiological changes to provide a temporary increase in strength and reaction speed – increasing heart rate and blood flow to muscles in your legs. But the increase in blood pressure, which adrenaline triggers, places an excess strain on the vessel walls, making them more prone to damage. Such damage then triggers a series of complex inflammatory reactions which drives the slow process of atherosclerosis. It’s hard to be human.
As well as directly impacting heart disease risk by elevating blood pressure, stress can also have indirect effects on heart health. Humans like to “manage” their stress by turning to harmful habits like smoking, excessive alcohol consumption and overeating unhealthy foods which can all increase heart disease risk. Animals experience stress too, but they don’t react to it the way we do. In recent decades, we humans, faced with increasing societal pressures and complex emotional lives, are experiencing psychosocial stress more commonly that ever before.
Robert Sapolsky, Professor of Biological Sciences and Neurology, has spent decades investigating the effects of stress on health and disease. He explains that, like other animals, our body’s have adapted well to dealing with acute physical stressors, but when the same responses are triggered in the long-term for purely psychosocial reasons, stress can wreak havoc on our physical health. Most animals don’t experience these kinds of long-term stresses – the kind brought on by social pressures, work deadlines, exams and relationship problems. Not only can chronic stress elevate blood pressure and increase our cardiovascular disease risk, but can also increase the risk of developing diabetes, gastrointestinal and neurological disorders and infections (12).
Chronic stress can also affect our gut microbes. There’s a lot of crosstalk going on between the brain and the gut. The gut even contains its own nervous system – the Enteric Nervous System or “Second Brain” which contains some 100 million neurons. Changes in the bacterial populations hanging out in our guts, which can be triggered by chronic stress, poor diet, or medications, have been linked to several human diseases including heart disease (13) .
Heart disease is an exceptionally complex and multifactorial condition. It is unlikely to be explained by any single simple theory or trigger, nor curable by any single silver bullet nutrient or wonder drug. Nevertheless it is intriguing to speculate – Why don’t animals get heart disease? Why has evolution been so cruel? Alas, this mysterious phenomenon remains a subject of debate. What’s your take?