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The answer to the blood pressure mystery could lie in our genes
Hypertension affects one billion people and is considered the number one cause of death worldwide. Mass testing of genetic variants can now shed light on its cause.
High blood pressure is often called the silent killer. Globally, more people die each year from cardiovascular disease than from any other disease.
High blood pressure – or hypertension – increases the risk of heart disease, kidney failure, and stroke. The healthcare system estimates that only half of those who have hypertension are aware that they have it.
And among those who are aware and receive treatment, only half have their blood pressure under control.
“Blood pressure research is a huge field,” Rune Mo says. He is a cardiologist and associate professor at NTNU.
Hypertension has been extensively researched
Thousands of scientific articles on hypertension are published every year.
It is well known that hypertension ‘runs’ in families. However, researchers have not been able to point to one specific cause of the disorder.
Only in 10 to 15 per cent of cases are the underlying causes known.
“Blood pressure is the mechanical pressure that the blood exerts on the blood vessels, which is necessary for the blood to flow through the vascular system. Blood vessels are elastic. They can expand and contract so that the pressure isn’t too high or too low,” Mo explains.
Despite complex and advanced regulatory mechanisms, in some individuals, blood pressure will permanently remain so high that it causes damage to blood vessels and organs.
Like a thermostat turned up too high
The reason that the direct cause of high blood pressure has not yet been determined might well be because so many different mechanisms in our body influence it.
Our autonomic nervous system is the key to regulating blood pressure and other unconscious tasks that are not under our control.
The autonomic nervous system enables the body to cope with various challenges, like keeping the body’s basic functions in balance and regulating our body temperature, breathing, digestion – and blood pressure.
Imagine a person who is caught off guard by a storm in the mountains and ends up sitting in the snow, freezing. The person’s sensory cells register that the body’s core temperature is dropping.
The cells send a nerve impulse to the hypothalamus, one of the centres in the brain. Here, the body’s temperature is compared to the biological thermostat, which is set to 37 degrees Celsius.
Then, the hypothalamus takes action to raise the body temperature. It might send nerve impulses to the vascular system under the skin with a message to contract, and for the muscles to start trembling.
Regulating blood pressure follows the same pattern. We have nerve cells in our heart and blood vessels that monitor blood pressure by registering the stretch in the heart and artery walls. These nerve signals are sent up to a separate centre in the brain.
If the signals report that the blood pressure is lower than the pre-set value, the centre will tell the blood vessels to constrict, and the heart to increase its frequency and stroke volume. This raises the blood pressure.
“If you have a family history of high blood pressure, it’s as if this thermostat is turned way up,” Mo says.
Salt is the crux of high blood pressure
Nerve signals from the blood vessels are only one of the triggers that cause the veins to contract.
“If blood pressure drops or the kidneys have a reduced blood supply, the kidneys will secrete the enzyme renin. Renin causes the arteries to constrict via a hormonal cascade, which increases the resistance in the blood vessels so the blood pressure rises,” Mo says.
Our blood pressure is also affected by blood volume.
“A person who becomes dehydrated or loses blood causes the volume of blood to decrease and the blood pressure drops. In severe cases, healthcare personnel will administer saline fluid or blood intravenously to prevent the blood pressure from becoming too low. Intravenous drugs that constrict the blood vessels can also be used,” he says.
Too much salt in the blood can cause the blood pressure to become too high, and reducing the salt content in food has long been a recommendation against high blood pressure.
Salt binds water and increases blood volume. Salt can also contribute to constricting the blood vessels, thereby increasing blood pressure.
Chinese writings dating back to 3500 BCE even make mention of salt affecting blood pressure. “Too much salt makes the pulse hard,” they wrote.
“Many people with high blood pressure are salt-sensitive, but not all. Some are vulnerable to effects of high salt intake, others less so,” Mo says.
Salt is stored in the skin
The exact reason why salt increases blood pressure is still not known. About half of all people are salt-sensitive, meaning they experience changes in blood pressure when their salt intake varies.
This suggests that part of the solution to the blood pressure puzzle lies in how the body handles salt, Professor Helge Wiig at the University of Bergen notes.
“Large population studies have shown a connection between salt intake and blood pressure. If you have a hereditary condition where you respond to changes in salt intake, it can increase your blood pressure by as much as 10 per cent. But we’re talking about a complex connection,” Wiig says.
Sex hormones could be involved as well. In women, you often see an increase in blood pressure after menopause.
Wiig and his colleagues in Bergen have chosen to study the skin’s role in regulating blood pressure. Recent research indicates that this organ may play a previously unknown role.
“The kidneys are the major organs involved in regulating the body’s salt balance, but we and other researchers have findings indicating that salt can be stored in the skin. It seems the skin acts as a kind of buffer,” Wiig says.
Skin acts as a barrier to fluid loss
Salt consists of the two substances sodium and chloride. Animal experiments now show that the sodium ions are taken up by cells in the skin, in exchange for potassium ions. The so-called osmotic pressure in the cells thus does not change, and the local fluid balance is maintained. The blood pressure rises in response.
“What we’ve found is that we have an intracellular storage of salt, another way of saying that sodium is stored in the cells. This happens not only in the skin but also in the muscles,” Wiig says.
The researchers also believe that the skin, acting as a barrier against fluid loss, might have an impact on blood pressure.
“As you age, the skin no longer performs this barrier function as well, and you can lose more water through the skin than when you were younger. This is one of the reasons why older people can easily become dehydrated," Wiig says.
The body protects itself from losing water through the skin by constricting blood vessels. When blood vessels contract, blood pressure increases, the researcher explains.
The answer to high blood pressure may lie in our genes
Along with high salt intake, a number of other risk factors are known to affect blood pressure. Obesity, smoking, excessive alcohol intake, and lack of physical activity are high on the list.
So how can we determine if a person's risk of high blood pressure and cardiovascular diseases is a result of years of high salt intake, smoking, being a couch potato, or if it's simply due to genetics?
“We talk about having a genetic susceptibility. But genetics in relation to blood pressure is complex, because so many different systems and interactions between the systems play in. Researching genetics and hypertension is almost like going for a walk in the woods. You see something here and something there, but you don’t quite know what it all means,” Mo says.
However, an increasing number of researchers believe that the answer to the blood pressure puzzle lies, at least partially, in our genes. We react differently to, for example, salt, depending on the genes we carry.
“High blood pressure is at least partly genetically determined,” Knut Erik Berge says. He is a specialist in medical genetics at Oslo University Hospital.
Studies have shown that hereditary factors contribute to between 30 and 40 per cent of blood pressure variation in the population. However, only in a small number of cases can a specific gene be pinpointed as the root cause of the problem.
“We have a genetic group in the population that has what can be called a monogenic form of hypertension, but that’s very rare. In the vast majority of cases, the increase in risk is a matter of having a combination of genes in conjunction with lifestyle factors,” Berge says.
More than 1,500 genetic variants
Knowledge about monogenic forms - cases where only one specific set of genes is involved - can still shed light on the mystery of blood pressure.
“If you have a mutation in a particular gene, and this causes high blood pressure, then understanding the genetic mechanism can also provide knowledge about what causes hypertension in general,” Berge says.
An example is Liddle syndrome, which is caused by a mutation in a single gene that codes for a protein in the kidneys. The protein is part of a mechanism that causes the kidneys to increase the amount of salt in the blood, leading to severe high blood pressure in carriers of this gene, often from a young age.
Today, inhibition of this protein is a known mechanism for treating hypertension, even if the patient does not have Liddle syndrome.
“About 30 different monogenic causes of high blood pressure are currently known. In several of these conditions, people who are affected also have measurable disturbances in the salt composition of the blood,” Berge says.
Through genome-wide association studies (GWAS), where gene variants in hundreds of thousands of people are compared in relation to the risk of a specific disease, over 1,500 genetic variants associated with altered blood pressure levels have been found so far.
“Having a combination of several of these ‘unfortunate’ variants could explain why some people have higher blood pressure than others. It’s still too early to be able to apply this in a clinical context, but these findings could point to connections that are currently unknown. They increase our understanding, and in the long run, the hope is that this will lead to more precise treatment,” Berge says.
The kidneys are in control
“High blood pressure is the domain of nephrologists,” Stein Hallan says.
We find senior consultant Hallan at the Division of Nephrology at St. Olav’s Hospital. He is also a professor in the renal medicine research group at NTNU.
“The reason for that is that the kidneys are so important for managing blood pressure over time. Many things can raise blood pressure, but healthy kidneys are usually able to regulate the body so that the pressure remains normal," Hallan says.
He adds that if you have something wrong with your kidneys, your blood pressure will also be problematic. And high blood pressure, in turn, damages the kidneys, so it's a reciprocal relationship.
Hallan and NTNU are involved in several national projects where data from HUNT – the Health Survey in Trøndelag – is used to investigate kidney damage and genetic changes in the kidneys related to high blood pressure.
“Almost all causes of hypertension are linked to the kidneys and the kidneys’ handling of salt,” he says.
According to Hallan, there is progress in blood pressure research, although they are still looking for the underlying causes.
“In most patients we don’t know the exact cause of the high blood pressure, but in some we can find a cause that can be treated. We find that some patients with hypertension produce too much of the hormone aldosterone," he says. “This is a hormone that has to do with how salt is handled. The problem lies in the adrenal glands, where a benign tumour causes increased hormone production. Before we thought this condition was very rare, but now we’re finding more and more patients who have it,."
The goal is personalised treatment
Today, high blood pressure is treated with lifestyle changes and a combination of medications known to have blood pressure-lowering effects. Doctors also rely on national and international recommendations regarding medications that not only lower blood pressure but also have a proven effect on morbity and mortality.
At Oslo University Hospital, Berge believes that the goal should be to use genetic risk variants to identify individuals who are at high risk of developing high blood presure.
“These individuals could then be tracked so that preventive drug treatment could start before organ damage occurs, and measures could be taken to reduce adverse lifestyle factors to an even greater extent,” he says.
Berge adds that looking even further into the future, the hope is that they can provide personalised treatment specifically targeting the cause of an individual's high blood pressure.
"Genetic analyses will also play an important role then,” Berge concludes.
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