̽��ֱ�� of Cambridge - blood pressure

Skin found to play a role in controlling blood pressure

cjb250 — Wed, 25 Oct 2017 22:30:22 +0000

In a study published in the open access journal eLife, the researchers show that skin – our largest organ, typically covering two square metres in humans – helps regulate blood pressure and heart rate in response to changes in the amount of oxygen available in the environment.

High blood pressure is associated with cardiovascular disease, such as heart attack and stroke. For the vast majority of cases of high blood pressure, there is no known cause. ̽��ֱ��condition is often associated with reduced flow of blood through small blood vessels in the skin and other parts of the body, a symptom which can get progressively worse if the hypertension is not treated.

Previous research has shown that when a tissue is starved of oxygen – as can happen in areas of high altitude, or in response to pollution, smoking or obesity, for example – blood flow to that tissue will increase. In such situations, this increase in blood flow is controlled in part by the ‘HIF’ family of proteins.

To investigate what role the skin plays in the flow of blood through small vessels, a team of researchers from Cambridge and Sweden exposed mice to low-oxygen conditions. These mice had been genetically modified so that they are unable to produce certain HIF proteins in the skin.

“Nine of ten cases of high blood pressure appear to occur spontaneously, with no known cause,” says Professor Randall Johnson from the Department of Physiology, Development and Neuroscience at the ̽��ֱ�� of Cambridge. “Most research in this areas tends to look at the role played by organs such as the brain, heart and kidneys, and so we know very little about what role other tissue and organs play.

“Our study was set up to understand the feedback loop between skin and the cardiovascular system. By working with mice, we were able to manipulate key genes involved in this loop.”

̽��ֱ��researchers found that in mice lacking one of two proteins in the skin (HIF-1α or HIF-2α), the response to low levels of oxygen changed compared to normal mice and that this affected their heart rate, blood pressure, skin temperature and general levels of activity. Mice lacking specific proteins controlled by the HIFs also responded in a similar way.

In addition, the researchers showed that even the response of normal, healthy mice to oxygen starvation was more complex than previously thought. In the first ten minutes, blood pressure and heart rate rise, and this is followed by a period of up to 36 hours where blood pressure and heart rate decrease below normal levels. By around 48 hours after exposure to low levels of oxygen, blood pressure and heart rate levels had returned to normal.

Loss of the HIF proteins or other proteins involved in the response to oxygen starvation in the skin, was found to dramatically change when this process starts and how long it takes.

“These findings suggest that our skin’s response to low levels of oxygen may have substantial effects on the how the heart pumps blood around the body,” adds first author Dr Andrew Cowburn, also from Cambridge. “Low oxygen levels – whether temporary or sustained – are common and can be related to our natural environment or to factors such as smoking and obesity. We hope that our study will help us better understand how the body’s response to such conditions may increase our risk of – or even cause – hypertension.”

Professor Johnson adds: “Given that skin is the largest organ in our body, it perhaps shouldn’t be too surprising that it plays a role in regulation such a fundamental mechanism as blood pressure. But this suggests to us that we may need to take a look at other organs and tissues in the body and see how they, too, are implicated.”

̽��ֱ��study was funded by Wellcome.

Reference
Cowburn, AS et al. Cardiovascular adaptation to hypoxia and the role of peripheral resistance. eLife; 19 Oct 2017; DOI: 10.7554/eLife.28755

Skin plays a surprising role in helping regulate blood pressure and heart rate, according to scientists at the ̽��ֱ�� of Cambridge and the Karolinska Institute, Sweden. While this discovery was made in mice, the researchers believe it is likely to be true also in humans.

Nine of ten cases of high blood pressure appear to occur spontaneously, with no known cause

Randall Johnson

Matt Reinbold

Skin texture

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Major global study reveals new hypertension and blood pressure genes

sc604 — Mon, 12 Sep 2016 15:00:00 +0000

̽��ֱ��discoveries include DNA changes in three genes that have much larger effects on blood pressure in the population than previously seen, providing new insights into the physiology of hypertension and suggesting new targets for treatment.

High blood pressure or hypertension is a major risk factor for cardiovascular disease and premature death. It is estimated to be responsible for a larger proportion of global disease burden and premature mortality than any other disease risk factor. However, there is limited knowledge on the genetics of blood pressure.

̽��ֱ��teams investigated the genotypes of around 347,000 people and their health records to find links between their genetic make-up and cardiovascular health. ̽��ֱ��participants included healthy individuals and those with diabetes, coronary artery disease and hypertension, from across Europe, (including the UK, Denmark, Sweden, Norway, Finland and Estonia), the USA, Pakistan and Bangladesh. ̽��ֱ��study brought together around 200 investigators from across 15 countries.

Study author Professor Patricia Munroe from QMUL said: “We already know from earlier studies that high blood pressure is a major risk factor for cardiovascular disease. Finding more genetic regions associated with the condition allows us to map and understand new biological pathways through which the disease develops, and also highlight potential new therapeutic targets. This could even reveal drugs that are already out there but may now potentially be used to treat hypertension.”

Most genetic blood pressure discoveries until now have been of common genetic variants that have small effects on blood pressure. ̽��ֱ��study, published in Nature Genetics, has found variants in three genes that appear to be rare in the population, but have up to twice the effect on blood pressure.

“ ̽��ֱ��sheer scale of our study has enabled us to identify genetic variants carried by less than one in a hundred people that affect blood pressure regulation,” said study author, Dr Joanna Howson from Cambridge’s Department of Public Health and Primary Care. “While we have known for a long time that blood pressure is a risk factor for coronary heart disease and stroke, our study has shown that there are common genetic risk factors underlying these conditions.”

RBM47 is a gene that encodes for a protein responsible for modifying RNA. RRAS is involved in cell cycle processes and has already been implicated in a syndrome related to ‘Noonan syndrome’ which is characterised by heart abnormalities. COL21A1 is involved in collagen formation in many tissues, including the heart and aorta. COL21A1 and RRAS warrant particular interest since both are involved in blood vessel remodelling, with relevance to hypertension.

̽��ֱ��team also found a mutation in a key molecule ENPEP that affects blood pressure. This gene codes for an enzyme that is a key molecule involved in regulating blood pressure through the dilation and constriction of blood vessels, and is currently a therapeutic target.

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation which part-funded the research, said: “Large scale genetic studies continue to expand the number of genes that may contribute to the development of heart disease, or risk factors such as high blood pressure. But so far most of the genes discovered in these studies individually have only very small effects on risk – though they may still provide valuable clues for new drug targets.

“This study has increased the number of genes implicated in control of blood pressure to almost 100 and, in the process, has also identified three genes that have larger effects on blood pressure than previously found.”

̽��ֱ��study was also funded by the National Institute for Health Research (NIHR), National Institute of Health (NIH), Wellcome Trust and the Medical Research Council.

Reference:
Surendran et al. ‘Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension’. Nature Genetics 2016. DOI: 10.1038/ng.3654

Thirty-one new gene regions linked with blood pressure have been identified in one of the largest genetic studies of blood pressure to date, involving over 347,000 people, and jointly led by Queen Mary ̽��ֱ�� of London (QMUL) and the ̽��ֱ�� of Cambridge.

While we have known for a long time that blood pressure is a risk factor for coronary heart disease and stroke, our study has shown that there are common genetic risk factors underlying these conditions.

Joanna Howson

Yale Rosen

Pulmonary hypertension-associated vasculitis

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Old drug performs new tricks

Anonymous — Mon, 21 Sep 2015 08:24:54 +0000

Spironolactone, one of a range of drugs given according to doctors' preference to patients with resistant hypertension (high blood pressure that doesn't respond to a standard drug treatment), is in fact "outstandingly superior" to the alternatives, researchers have found. They recommend it should now be the first choice for such patients, and say that – for most – this well-known but under-valued drug will bring their condition fully under control.

̽��ֱ��discovery could have a profound impact globally, since hypertension, a major contributor to stroke and heart disease, is so common, affecting as many as one in three adults in some countries. It challenges what the authors describe as "a growing perception" that severe hypertension was beyond the control of existing drug treatments, and gives more clues into what causes the condition.

̽��ֱ��latest research, published today in the Lancet to coincide with their presentation to the British Hypertension Society, emerged from the PATHWAY-2 trial, part of the PATHWAY programme of trials in hypertension funded by the British Heart Foundation and led by Professor Morris Brown, professor of clinical pharmacology at Cambridge ̽��ֱ�� and a Fellow of Gonville & Caius College.

̽��ֱ��findings are drawn from what authors Brown and Professor Bryan Williams of ̽��ֱ�� College London describe as an experimental "shoot-out" between three different drugs used by doctors for years to treat patients if the standard initial cocktail of three hypertension drugs do not work.

Spironolactone 'slugged it out' against a betablocker (bisoprolol) and an alpha-blocker (doxazosin) in the trial, which took six years and involved 314 patients in 14 different centres.

̽��ֱ��patients all suffered from resistant high blood pressure that had not responded to the standard treatment for hypertension: a combination of three drugs (an ACE-inhibitor (or angiotensin-receptor blocker), a calcium channel blocker and a thiazide-type diuretic). They continued with this basic combination throughout, but each of the three trial drugs – and a placebo – was added one at a time, in random order, for 12 weeks each.

In what is known as a "double blind" trial, neither the patients nor the researchers knew which patient was taking which drug when. In a pioneering step, the study also used patients' own blood pressure readings taken at home to minimise so-called "white coat syndrome", in which the stress of being in a clinic causes blood pressure to rise artificially.

Once the resulting data had been analysed, it emerged that almost three quarters of patients in the trial saw a major improvement in blood pressure on spironolactone, with almost 60% hitting a particularly stringent measure of blood pressure control. Of the three drugs trialled, spironolactone was the best at lowering blood pressure in 60% of patients, whereas bisoprolol and doxazosin were the best drug in only 17% and 18% respectively.

"Spironolactone annihilated the opposition," said Brown. "Most patients came right down to normal blood pressure while taking it."

He added: "This is an old drug which has been around for a couple of generations that has resurfaced and is almost a wonder drug for this group of patients. In future it will stimulate us to look for these patients at a much earlier stage so we can treat and maybe even cure them before resistant hypertension occurs."

Doctors appear to have been wary of giving patients spironolactone because it raises the level of potassium in the body. But the study revealed the rise to be only marginal and not dangerous.

̽��ֱ��causes of resistant of hypertension are still poorly understood, but one theory is that the condition could be the result of sodium retention: too much salt in the body.

Spironolactone is a diuretic and helps the body get rid of salt. In the trial, it worked even better than average on patients whom tests showed had high salt levels. Brown said the findings appeared to confirm that, in most patients with resistant hypertension, excessive salt was the problem, probably caused by too much of the adrenal hormone aldosterone.

Instead of seeing the treatment-resistant form of high blood pressure as simply the result of having the condition for a long time or of poor treatment, it should be regarded as a different sub-group of hypertension which would need different investigations and treatments, Brown said.

Patients with the most dangerous type of high blood pressure will be able to receive far more effective treatment after Cambridge-led research reveals the powers of a "wonder drug" that has lain under the noses of doctors for 50 years.

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Blood pressure breakthrough holds real hope

bjb42 — Thu, 07 Oct 2010 00:00:00 +0000

After 20 years of research, scientists from the ̽��ֱ�� of Cambridge have now cracked the first step in the main process that controls blood pressure. Their findings, published today in the journal Nature, are likely to have significant implications for the treatment of pre-eclampsia as well as high blood pressure (also known as hypertension).

Blood pressure is controlled by hormones called angiotensins, which cause the blood vessels to constrict. These hormones are released by the protein angiotensinogen. Until now, it was not understood how this occurred.

Dr Aiwu Zhou, a British Heart Foundation (BHF) Fellow at the ̽��ֱ�� of Cambridge, who made the breakthrough, said: "Although we primarily focused on pre-eclampsia, the research also opens new leads for future research into the causes of hypertension in general."

To make the discovery, the researchers solved the structure of angiotensinogen with the help of an extremely intense X-ray beam produced by Diamond Light Source, the UK synchrotron. Their results revealed that the protein is oxidised and changes shape

to permit ready access to angiotensinogen by an enzyme, renin. Renin cuts off the tail of the protein to release the hormone angiotensin, which then raises blood pressure.

Taking their lab results into the clinic at the ̽��ֱ�� of Nottingham, the research team showed that the amount of oxidised, and hence more active, angiotensinogen was increased in women with pre-eclampsia.

Professor Robin Carrell at the ̽��ֱ�� of Cambridge, who led the 20-year research project, explained: "During pregnancy oxidative changes can occur in the placenta. These changes, the very ones we have found stimulates the release of the hormone angiotensin and lead to increased blood pressure, can arise as the circulation in the placenta readjusts the oxygen requirements of the growing foetus with the delivery of oxygen to the placenta from the mother."

Drugs currently used to treat high blood pressure - such as ACE inhibitors - focus on the later stages of the mechanism that controls blood pressure. Today's findings, which give insight into the previously mysterious early stages of the regulation process, provide scientists with new opportunities to research novel treatments for hypertension.

Professor Peter Weissberg, Medical Director of the BHF, which largely funded the study, said: "Every year in the UK pre-eclampsia is responsible for the deaths of around six women and several hundred babies. This research is of the highest quality and offers real hope for developing strategies to prevent or treat this dangerous condition by targeting the process that these scientists have identified. And of course, although the researchers only looked at pre-eclampsia in this study, similar strategies may be useful for those people with high blood pressure that is not effectively controlled by current medicines."

High blood pressure frequently affects pregnancy. However, in 2-7 per cent of pregnancies this develops into pre-eclampsia, which threatens the health and survival of both the mother and child. In Britain, it affects about one in 20 women during pregnancy, and every year 50,000 women and 500,000 infants die globally as a result of pre-eclampsia. There is no treatment for pre-eclampsia and often the mother is either induced early or undergoes a Caesarean.

̽��ֱ��research was largely funded by the British Heart Foundation, with additional funding provided by the Medical Research Council, the Wellcome Trust and the Isaac Newton Trust.

Photo credit: House of Sims

Scientists have discovered a mechanism which raises blood pressure in pre-eclampsia, a potentially deadly condition which occurs during pregnancy.

This research is of the highest quality and offers real hope for developing strategies to prevent or treat this dangerous condition by targeting the process that these scientists have identified."

Professor Peter Weissberg, Medical Director of the BHF

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blood pressure

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