Posts Tagged ‘hypertension’


The antihypertension drugs called ARBs disrupt the pathway that leads to blood vessel constriction by preventing angiotensin II from binding to the AT1 receptor. This now-available angiotensin is then processed by ACE2 (not shown) into the form that leads to blood vessel dilation. ACE inhibitors work by blocking the production of angiotensin II.


A coronavirus spike protein (red) binds to an ACE2 receptor (blue).

For the past few weeks, research journals have been publishing reports on the connection between medications that reduce high blood pressure and COVID-19. The concern is that the medications might increase the abundance of the receptor that SARS-CoV-2—the virus that causes COVID-19—uses to enter cells. Boosting levels of these ACE2 receptors on lung and heart cells could give the virus more cellular entry points to target and potentially make symptoms of the disease more severe.

It’s a hypothesis that is important to test, notes Carlos Ferrario, a professor of general surgery at Wake Forest School of Medicine who specializes in research on antihypertensive drugs.

So far, the data supporting the connection between blood pressure medications—specifically, angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)—and COVID-19 are scant. Yet media coverage of the connection has led patients prescribed the drugs to call their doctors asking if they should stop taking them. In response, several medical associations—including the American College of Cardiology, the American Heart Association, the Heart Failure Society of America, and the European Society of Cardiology—have issued guidelines saying patients should not stop taking the antihypertensive drugs because there’s no evidence to support the claim that they cause more-severe SARS-CoV-2 infections.

In support of that recommendation, Ankit Patel, a clinical and research fellow focusing on the kidneys at Brigham and Women’s Hospital in Boston, and his Brigham colleague Ashish Verma dug into the literature to address the confusion and reported March 24 in JAMA that there’s no definitive evidence to suggest ACE inhibitors and ARBs increase the severity of COVID-19. Another team of doctors, writing in the March 30 issue of the New England Journal of Medicine, came to the same conclusion.

Instead of making COVID-19 symptoms worse, some antihypertensive drugs may actually reduce the severity of infections, and could therefore be used to treat the disease, both sets of doctors say. A closer look at the underlying mechanisms of the medications has also buoyed another idea for how to treat COVID-19—give patients the enzyme ACE2 as a decoy to direct SARS-CoV-2 away from their cells. A biotech company developing such an approach using recombinant ACE2 received regulatory approval today (April 2) to start clinical trials on COVID-19 patients.

“It’s a very interesting idea,” David Kass, a cardiologist at Johns Hopkins School of Medicine tells The Scientist. “Obviously, if the virus binds to this form of ACE2 that’s floating around in the bloodstream and not attached to a cell, it won’t be able to multiply and damage the cells.”

How ACE2 acts in the body

The ACE2 decoy idea can be traced back to early work on the receptor by Josef Penninger, a molecular immunologist at the University of British Columbia. Roughly 20 years ago, he was working as a researcher at the Ontario Cancer Institute when he cloned ACE2 and started probing what it does.

A senior investigator in the lab thought the work was a waste of time, Penninger recalls, telling him that scientists already knew everything they needed to know about the renin–angiotensin system, which regulates blood pressure and fluid and electrolyte balance. The senior researcher added that ACE2, which is associated with the system, was so boring Penninger should stop working on it before he ruined his career. At the time, it was a painful comment to hear, but it made Penninger even more determined to understand ACE2’s biological function. “It’s funny now,” he says.

Over time, he and others started to unravel how ACE2 operates within the renin–angiotensin system. The system starts with a hormone secreted by the kidneys called renin that cleaves the peptide hormone angiotensinogen into angiotensin I. That cleavage product is then converted into a version of angiotensin II by ACE, the angiotensin-converting enzyme. That version binds to the angiotensin II type 1 (AT1) receptor, on the surface of blood vessels, lung, and heart cells among other cells in the body. Where those molecules meet, blood vessels constrict and blood pressure rises, which can contribute to acute respiratory distress syndrome.

This is where ACE2 comes in. The enzyme cleaves an amino acid off angiotensin II to create angiotensin 1-7, which dilates blood vessels, reduces inflammation, and inactivates angiotensin II before it gets to a cell’s AT1 receptor.

“Whenever there is a hormone that has a certain interaction in the body, there’s often another hormone to counteract it,” Patel says. ACE2 counterbalances ACE, and “the body tries to maintain those two in balance to keep things in check.”

Doctors prescribe ACE inhibitors to people with high blood pressure and other heart problems to prevent ACE from converting angiotensin I into the form of angiotensin II that constricts blood vessels, leading to lower blood pressure. ARBs prevent angiotensin II from binding to AT1 receptors so ACE2 metabolizes it, also lowering blood pressure.

“We actually know a lot about ACE2 and its biology,” Penninger says. “We should follow the data.”

An ACE2 boost might distract the coronavirus

Penninger published his work on ACE2 biology in 2002, just before the outbreak of SARS in 2003. After the virus infected humans and started to spread, a team from Boston published the first clues to how SARS-CoV targets ACE2 to gain entry into human cells. There were other receptors proposed as entry points at that time, but the mention of ACE2 caught Penninger’s attention.

He started a study in mice, and in 2005 published the first definitive evidence that SARS-CoV uses ACE2 to infect its host’s cells. In the same study, Penninger and his colleagues showed that the virus reduces ACE2 abundance, which results in ramped-up angiotensin II levels, in turn causing acute lung failure. The work revealed what made SARS-CoV so deadly, he says.

Based on the data, Penninger’s team argued that administering a recombinant ACE2 protein could trick the virus into binding with it, rather than actual ACE2 receptors. This could then protect endogenous receptors and allow them to continue to function in counterbalancing ACE, and, ideally, protect the lung and heart from damage during a viral infection.

Penninger has been working on developing a recombinant ACE2 protein therapy for 15 years. He first tested it in mice after they’d inhaled acid; treatment with ACE2 prevented the animals from developing acute lung injury. Other studies showed the recombinant proteins could be used to treat heart failure, and eventually the research led to clinical trials to test ACE2’s safety in humans.

So far, early clinical trials of the drug have shown it does not have any harmful side effects in healthy humans or in patients with lung failure. (Penninger was not involved in conducting the clinical trial).

The next step is to see if the recombinant enzyme can intervene in a SARS-CoV-2 infection. In a study published today in Cell, Penninger’s group shows the drug can reduce the viral load of SARS-CoV-2 in experimental models by a factor of 1,000 to 5,000. Today, Apeiron Biologics, the biotech company Penninger founded in 2005, was also awarded regulatory approval to start clinical trials to test the drug in patients with severe COVID-19 symptoms, which, he says, could happen as early as the end of next week.

Ramping up ACE2 using ARBs instead

Penninger’s early work on SARS-CoV is part of what prompted the discussion among physicians about the safety of ACE inhibitors and ARBs, which regulate levels of angiotensin II directly or via its cell receptor. Another study related to the antihypertensive drugs that got the doctors’ attention was one done by Ferrario more than a decade ago. Administering ACE inhibitors or ARBs to rats led to increased ACE2 activity in the animals’ hearts, exactly where scientists and physicians wouldn’t want more ACE2 receptors for SARS-CoV-2 to target. Or at least, that’s what one might think.

But Penninger’s preliminary work from 2005 implies that increasing ACE2 levels through antihypertensive drugs might treat symptoms of SARS-CoV-2 infection, with ARBs showing more promise than ACE inhibitors.

ACE inhibitors lower levels of angiotensin II, and when they do, there’s less substrate for ACE2 to metabolize, which could leave the enzyme idle and therefore open to attack by SARS-CoV-2. That’s part of the argument some researchers were making about ACE inhibitors contributing to COVID-19 infection. However, there are no data to show that happens, Penninger says. Still, he argues, the way ACE inhibitors work in the body, freeing up ACE2 on cells for viral targeting rules them out as potential COVID-19 treatments.

Using ARBs to combat the virus is a more promising approach. As Penninger’s team showed, SARS-CoV reduced the abundance of ACE2, causing hypertension and lung failure in mice. If ARBs boost ACE2 expression, that might counteract the effects of the infection. The hypothesis is preliminary at this point, says David Gurwitz, a geneticist with a background in pharmacology at Tel Aviv University. He described the idea, which seems paradoxical, March 4 in a review article published in Drug Development Research. The main difference between ACE inhibitors and ARBs is that the former just frees up existing ACE2 receptors, while the latter leads to an increase in the number of receptors, allowing more angiotensin II to be converted to angiotensin 1-7. That would dilate blood vessels and reduce inflammation, countering any hypertensive state caused by a viral infection.

In clinical analyses designed to ensure that ARBs don’t harm COVID-19 patients, researchers in China have published preliminary data on medRxiv supporting the hypothesis. In the study, the team tracked the health outcomes of 511 patients taking medications for heart conditions who then became infected with SARS-CoV-2. The patients took either ACE inhibitors, ARBs, or other drugs that lowered their blood pressure. The results showed that patients over age 65 taking ARBs were at a lower risk of developing severe lung damage than age-matched patients not taking the medications, but there weren’t enough data to do a similar analysis for ACE inhibitors. The work reveals there was no hazard for ARBs, and there may be benefits, but as always, more data are needed, Kass says.

One way to collect those data on a larger scale, Gurwitz explains, would be to analyze many more COVID-19 patients’ health records to see if they’ve been taking ARBs prior to SARS-CoV-2 infection, then comparing the severity of infection in those patients and how well they recovered with the symptoms of COVID-19 patients not taking the medications.

Gurwitz also recommends researchers compare the percentage of people chronically medicated with different antihypertensive medications in the general population with the percentage of them among hospital admissions for COVID-19. These types of analyses could also be done with many other approved drugs, he notes, not just ARBs.

Already, physicians at University Hospital Zurich have begun a patient registry to do these types of health informatics analyses, and physicians and researchers at Johns Hopkins School of Medicine and other public health schools in the US have been discussing the feasibility of starting these studies.

“Unfortunately for the country, we’re going to have lots of COVID-19 cases,” Kass says. “Groups are now trying to get these epidemiological studies started so we can get answers.”

https://www.the-scientist.com/news-opinion/blood-pressure-meds-point-the-way-to-possible-covid-19-treatment-67371?utm_campaign=TS_DAILY%20NEWSLETTER_2020&utm_source=hs_email&utm_medium=email&utm_content=85706789&_hsenc=p2ANqtz–HTxdAA4l8ORpuJZQE3i–UqSCKXPaN4-_B2bIk8IV5pUfRvwjTqC8GIsP5hN1DJ4aIl7wJ54eQ0sjwTYqx2BbUBCqmA&_hsmi=85706789

There are no instant, miracle cures. But recent studies suggest we have more control over our cognitive health than we might think. It just takes some effort.

When it comes to battling dementia, the unfortunate news is this: Medications have proven ineffective at curing or stopping the disease and its most common form, Alzheimer’s disease. But that isn’t the end of the story. According to a recent wave of scientific studies, we have more control over our cognitive health than is commonly known. We just have to take certain steps—ideally, early and often—to live a healthier lifestyle.

In fact, according to a recent report commissioned by the Lancet, a medical journal, around 35% of dementia cases might be prevented if people do things including exercising and engaging in cognitively stimulating activities. “When people ask me how to prevent dementia, they often want a simple answer, such as vitamins, dietary supplements or the latest hyped idea,” says Eric Larson, a physician at Kaiser Permanente in Seattle and one of a group of scientists who helped prepare the report. “I tell them they can take many common-sense actions that promote health throughout life.”

The Lancet report, distilling the findings of hundreds of studies, identifies several factors that likely contribute to dementia risk, many of which can be within people’s power to control. These include midlife obesity, physical inactivity, high blood pressure, Type 2 diabetes, social isolation and low education levels.

Of course, there are no guarantees. Dementia is a complicated disease that has multiple causes and risk factors, some of which remain unknown. Nevertheless, there is increasing evidence that people—even those who inherit genes that put them at greater risk of developing Alzheimer’s in later life—can improve their chances by adopting lifestyle changes.

“It’s not just about running three times a week,” says Sarah Lenz Lock, executive director of AARP’s Global Council on Brain Health. “Instead, it’s about a package of behaviors, including aerobic exercise, strength training, a healthy diet, sleep and cognitive training.”

Because most neurodegenerative diseases take years, if not decades, to develop, researchers say the best time to focus on brain health is long before symptoms occur—ideally by midlife if not before. Still, they emphasize that it is never too late to start.

What follows is a look at what scientific studies tell us about possible ways to reduce dementia risk.

1. Blood-pressure control

The potential role that cardiovascular health—including blood pressure—plays in dementia has been one of the tantalizing highlights of recent research based on the Framingham Heart Study, which has followed thousands of residents of Framingham, Mass., and their relatives since 1948.

The research found a 44% decline in the dementia rate among people age 60 or older for the period 2004 to 2008, compared with 1977 to 1983. Diagnoses fell to two for every 100 study participants from 3.6 in the earlier period. Over the same roughly 30 years, the average age at which dementia was diagnosed rose to 85 from 80.

Co-author Claudia Satizabal, an assistant professor at UT Health San Antonio, says the research suggests that improvements in cardiovascular health and education levels help explain the trend. Improvements in dementia rates have occurred only in participants “who had at least a high-school diploma,” the study says. And as dementia rates have fallen, the study also says, so have the rates of “stroke and other cardiovascular diseases,” thanks in part to a greater use of blood-pressure medication.

Unlike studies in which participants are randomly assigned to different treatment groups and then monitored for results, the Framingham study and others that analyze population data cannot definitively prove a cause-and-effect relationship. Dr. Satizabal says that while the significant decline in dementia rates since 1977 suggests that management of stroke and heart issues could have contributed, that “is something that needs more research.”

A recent study that randomly assigned participants to different treatment goals offers further evidence for the idea that high blood pressure is a treatable risk factor that leads to dementia.

In 2010, researchers at Wake Forest School of Medicine began enrolling almost 9,400 people age 50 and older with high blood pressure in one of two groups. With the aid of medication, one group reduced its systolic blood pressure—which measures pressure in the arteries when the heart contracts—to less than 120. The other group aimed for less than 140.

The group with lower blood pressures experienced such significantly lower rates of death, strokes and heart attacks that in 2015 the researchers stopped the trial ahead of schedule. The scientists concluded it would be unethical to continue because most people should be targeting the lower blood pressure, says the study’s co-author Jeff Williamson, a Wake Forest medical school professor.

In 2017 and 2018, the researchers performed a final round of cognitive tests on participants and discovered that the lower-blood-pressure group had 19% fewer diagnoses of mild cognitive impairment, often a precursor to dementia, and 15% fewer cases of any type of dementia, mild or otherwise.

Using MRIs, the researchers scanned 673 participants’ brains and, upon follow-up, found less damaging changes in the lower-blood-pressure group.

“This is the first trial that has demonstrated an effective strategy for prevention of cognitive impairment,” says Kristine Yaffe, professor of psychiatry, neurology and epidemiology at the University of California, San Francisco. “That’s pretty big news,” says Dr. Yaffe, who wasn’t involved in the study.

2. Exercise

Several studies that have followed large numbers of people for years suggest that physically active individuals are less likely than inactive peers are to develop dementia, according to a recent World Health Organization report.

Exercise increases the flow of blood to the brain, improves the health of blood vessels and raises the level of HDL cholesterol, which together help protect against cardiovascular disease and dementia, says Laura Baker, a professor at Wake Forest School of Medicine. Exercise can also lead to the formation of new brain synapses and protect brain cells from dying.

Prof. Baker’s studies suggest that aerobic exercise can help improve cognitive function in people with mild memory, organizational and attention deficits, which are often the first symptoms of cognitive impairment.

One recent study conducted by Prof. Baker and several co-authors enrolled 65 sedentary adults ages 55 to 89 with mild memory problems. For six months, half completed four 60-minute aerobic-exercise sessions at the gym each week. Under a trainer’s supervision, they exercised mainly on treadmills at 70% to 80% of maximum heart rate. The other half did stretching exercises at 35% of maximum heart rate.

At the beginning and end of the study, researchers collected participants’ blood and spinal fluid and obtained MRI scans of their brains. Over the six months, the aerobic-exercise group had a statistically significant reduction in the level in their spinal fluid of tau protein, which accumulates in the brains of people with Alzheimer’s. They also had increased blood flow to areas of the brain that are important for attention and concentration, and their scores on cognitive tests improved. The stretching group, in contrast, showed no improvement on cognitive tests or tau levels.

3. Cognitive training

Many population studies suggest that education increases cognitive reserve, a term for the brain’s ability to compensate for neurological damage. The Framingham study, for example, found that participants with at least a high-school diploma benefited the most from declining dementia rates, compared with participants with less education.

In another population study, researchers at Columbia University analyzed data from 593 people age 60 or older, 106 of whom developed dementia. People with clerical, unskilled or semiskilled jobs had greater risk of getting the disease than managers and professionals.

In a separate study, some of the same researchers followed 1,772 people age 65 or older, 207 of whom developed dementia. After adjusting the results for age, ethnic group, education and occupation, the authors found that people who engaged in more than six activities a month—including hobbies, reading, visiting friends, walking, volunteering and attending religious services—had a 38% lower rate of developing dementia than people who did fewer activities.

In yet another study, researchers at institutions including Rush University Medical Center’s Rush Institute for Healthy Aging examined the brains of 130 deceased people who had undergone cognitive evaluations when alive. Among individuals in whom similar levels of Alzheimer’s-related brain changes were seen in the postmortem examinations, the researchers found that those who had more education generally had shown higher cognitive function.

Yaakov Stern, a professor at Columbia University College of Physicians and Surgeons who has written about these studies and the impact of education on dementia, recommends maintaining “educational and mentally stimulating activities throughout life.” This fosters growth of new neurons and may slow the rate at which certain regions of the brain shrink with age. It also promotes cognitive reserve, he says.

4. Diet

Efforts to study the impact of diet on dementia are relatively new, but there are some indications that certain diets may be beneficial in lowering the risk of dementia.

Several population studies, for instance, suggest that people with a Mediterranean diet, which is high in fish, fruits, nuts and vegetables, have lower rates of dementia, according to the World Health Organization.

But a variation on that diet may offer even more protection against the development of Alzheimer’s disease, according to a study released in 2015.

In this study, researchers including Dr. Martha Clare Morris, director of the Rush Institute for Healthy Aging, analyzed data from 923 people ages 58 to 98 who kept detailed food diaries about what they ate from 2004 to 2013.

In total, 158 subjects developed dementia. But among individuals who remained cognitively healthy, a high proportion had consumed a diet heavy in leafy green and other vegetables, nuts, berries, beans, whole grains, fish, poultry, olive oil and wine (in moderation). Their diets were limited in red meat, butter, cheese, sweets and fried and fast foods.

This diet, which researchers named the Mind diet, shares many elements of a Mediterranean diet. But the Mind diet prescribes more foods—including berries and leafy green vegetables—that are associated with lower rates of neurological diseases.

The researchers scored each of the 923 participants on how closely their detailed eating habits followed three diets: Mind, Mediterranean, and Dash diet, designed to reduce high blood pressure. For each diet, researchers ranked the participants based on their scores, subdividing them by the degree to which they followed each diet—closely, partly or little.

This led to several discoveries: First, there were about 50% fewer Alzheimer’s diagnoses among participants who most closely followed either the Mind diet or the Mediterranean diet, compared with those who followed either diet only a little. For the Dash diet, there was a 39% reduction for those who were most faithful to its rules.

Meanwhile, even those who only partly followed the Mind diet saw a 35% reduction in Alzheimer’s diagnoses, while no reduction was seen for those who only partly followed either the Mediterranean or Dash diet.

In contrast to the Mediterranean and Dash diets, “even modest adherence to the Mind diet may have substantial benefits for prevention of Alzheimer’s disease,” says Kristin Gustashaw, a dietitian at Rush.

5. Sleep

No one knows for sure why we sleep. One theory is that sleep helps us remember important information by performing a critical housekeeping function on brain synapses, including eliminating some connections and strengthening others.

Another theory is that sleep washes “toxic substances out of our brains that shouldn’t be there,” including beta amyloid and tau proteins that are implicated in Alzheimer’s, says Ruth Benca, a professor of medicine at the University of California, Irvine.

In a 2015 study, Prof. Benca and others examined 98 participants without dementia ages 50 to 73. Many were at genetic risk for the disease. Brain scans revealed that those reporting more sleep problems had higher levels of amyloid deposits in areas of the brain typically affected by Alzheimer’s.

“Poor sleep may be a risk factor for Alzheimer’s,” says Prof. Benca, who is conducting a study to see whether treating sleep problems may help prevent dementia.

She says sleep—or a lack of it—may help explain why about two-thirds of Alzheimer’s patients are women. Some researchers theorize that during menopause women can become vulnerable to the disease, in part due to increased prevalence of insomnia.

6. Combination

There is a growing consensus that when it comes to preserving brain health, the more healthy habits you adopt, the better.

According to a forthcoming study of 2,765 older adults by researchers at Rush, nonsmokers who stuck to the Mind diet, got regular exercise, engaged in cognitively stimulating activities and drank alcohol in moderation had 60% fewer cases of dementia over six years than people with just one such habit.

A study published in July found that people at greater genetic risk for Alzheimer’s appear to benefit just as much from eating well, exercising and drinking moderately as those who followed the same habits but weren’t at elevated genetic risk for the disease.

The study, by researchers including Kenneth Langa, associate director of the Institute of Gerontology at the University of Michigan, examined data from 196,383 Britons age 60 and older. Over about a decade, there were 38% fewer dementia diagnoses among individuals who had healthy habits and a gene, APOE4, that puts people at higher risk for Alzheimer’s, than there were among people who had the gene and poor habits. The gene increases the risk for Alzheimer’s by two to 12 times, depending on how many copies a person has.

Among participants with low genetic risk for Alzheimer’s, healthy habits were associated with a 40% reduction in the incidence of the disease. The results suggest a correlation between lifestyle, genetic risk and dementia, the study says.

Many point to a recent clinical trial in Finland of 1,260 adults ages 60 to 77 as proof that a multipronged approach can work.

The researchers, from institutions including the Karolinska Institute in Sweden and the National Institute for Health and Welfare in Helsinki, randomly assigned half of the participants, all deemed at high risk for dementia, to regular sessions with nutritionists, exercise trainers and instructors in computerized brain-training programs. The participants attended social events and were closely monitored for conditions including high blood pressure, excess abdominal weight and high blood sugar.

“They got support from each other to make lifestyle changes,” says co-author Miia Kivipelto, a professor at the Karolinska Institute in Sweden.

The other half received only general health advice.

After two years, both groups showed improvements in cognitive performance. But the overall scores of the intensive-treatment group improved by 25% more than the scores for the other group. The intensive-treatment group scored between 40% and 150% better on tests of executive function, mental speed and complex memory tasks, suggesting that a multifaceted approach can “improve or maintain cognitive functioning in at-risk elderly people,” the study says.

“We are studying whether exercise and lifestyle can be medicine to protect brain health as we get older,” says Prof. Baker, who is overseeing a U.S. study modeled on the Finnish trial.

https://apple.news/AzlC5CLNvQJWJrsP-qrJFIw

inhaled-version-of-blood-pressure-drug-shows-promise-in-treating-anxiety-pain-309437

An inhaled form of a high blood pressure medication has potential to treat certain types of anxiety as well as pain, according to a new study by the Centre for Addiction and Mental Health (CAMH).

Anxiety disorders are usually treated with different types of medications, such as antidepressants, and psychotherapy. Amiloride is a medication offering a new approach, as a short-acting nasal spray that could be used to prevent an anxiety attack.

“Inhaled amiloride may prove to have benefits for panic disorder, which is typically characterized by spells of shortness of breath and fear, when people feel anxiety levels rising,” says lead author Dr. Marco Battaglia, Associate Chief of Child and Youth Psychiatry and Clinician Scientist in the Campbell Family Mental Health Research Institute at CAMH.

The study was based on understanding the key physiological changes in brain functioning that are linked to anxiety and pain sensitivity. The researchers then tested a molecule, amiloride, which targets this functioning.

Amiloride was inhaled so that it could immediately access the brain. The study showed that it reduced the physical respiratory signs of anxiety and pain in a preclinical model of illness. This therapeutic effect didn’t occur when amiloride was administered in the body, as it didn’t cross the blood-brain barrier and did not reach the brain.

Results were published in the Journal of Psychopharmacology.

The role of early life adversity
The study is based on years of research into how a person’s early life experiences affect their genes, says Dr. Battaglia. Childhood adversity, such as loss or separation from parents, increases the risk of anxiety disorders and pain, among other health issues.

At a molecular level, these negative life experiences are linked to changes in some genes of the ASIC (acid-sensing-ion-channels) family. While the DNA itself doesn’t change, the way it functions is affected.

DNA is converted into working proteins through a process called gene expression. As a result of childhood adversity, some ASIC genes showed increased expression and epigenomic changes. (“Epigenomic” refers to changes in gene regulation that can inherited by children). Overlapping genetic changes were also seen in blood taken from twins who responded to specific tests designed to provoke panic.

These genetic changes are linked to physical symptoms. Breathing can be affected, due to over-sensitivity to higher carbon dioxide levels in the air. In such situations, a person might hyperventilate and experience growing anxiety. Preclinical and human data are strikingly similar in this regard. “As a treatment, amiloride turned out to be very effective preclinically,” says Dr. Battaglia.

The next step in his research is to test whether it eases anxiety symptoms. Dr. Battaglia is now launching a pilot clinical trial, supported through a seed grant from CAMH’s new Discovery Fund. Collaborators at the University of Utah are testing the drug’s safety.

Amiloride has been used as an oral treatment for decades for hypertension, and as an inhaled spray in a few experimental studies of cystic fibrosis, he notes. The researchers are therefore further ahead than if they had to develop and test an entirely new medication.

https://www.technologynetworks.com/neuroscience/news/inhaled-version-of-blood-pressure-drug-shows-promise-in-treating-anxiety-pain-309437

By Sarah C. P. Williams

There’s a reason people say “Calm down or you’re going to have a heart attack.” Chronic stress—such as that brought on by job, money, or relationship troubles—is suspected to increase the risk of a heart attack. Now, researchers studying harried medical residents and harassed rodents have offered an explanation for how, at a physiological level, long-term stress can endanger the cardiovascular system. It revolves around immune cells that circulate in the blood, they propose.

The new finding is “surprising,” says physician and atherosclerosis researcher Alan Tall of Columbia University, who was not involved in the new study. “The idea has been out there that chronic psychosocial stress is associated with increased cardiovascular disease in humans, but what’s been lacking is a mechanism,” he notes.

Epidemiological studies have shown that people who face many stressors—from those who survive natural disasters to those who work long hours—are more likely to develop atherosclerosis, the accumulation of fatty plaques inside blood vessels. In addition to fats and cholesterols, the plaques contain monocytes and neutrophils, immune cells that cause inflammation in the walls of blood vessels. And when the plaques break loose from the walls where they’re lodged, they can cause more extreme blockages elsewhere—leading to a stroke or heart attack.

Studying the effect of stressful intensive care unit (ICU) shifts on medical residents, biologist Matthias Nahrendorf of Harvard Medical School in Boston recently found that blood samples taken when the doctors were most stressed out had the highest levels of neutrophils and monocytes. To probe whether these white blood cells, or leukocytes, are the missing link between stress and atherosclerosis, he and his colleagues turned to experiments on mice.

Nahrendorf’s team exposed mice for up to 6 weeks to stressful situations, including tilting their cages, rapidly alternating light with darkness, or regularly switching the mice between isolation and crowded quarters. Compared with control mice, the stressed mice—like stressed doctors—had increased levels of neutrophils and monocytes in their blood.

The researchers then homed in on an explanation for the higher levels of immune cells. They already knew that chronic stress increases blood concentrations of the hormone noradrenaline; noradrenaline, Nahrendorf discovered, binds to a cell surface receptor protein called β3 on stem cells in the bone marrow. In turn, the chemical environment of the bone marrow changes and there’s an increase in the activity of the white blood cells produced by the stem cells.

“It makes sense that stress wakes up these immune cells because an enlarged production of leukocytes prepares you for danger, such as in a fight, where you might be injured,” Nahrendorf says. “But chronic stress is a different story—there’s no wound to heal and no infection.”

In mice living with chronic stress, Nahrendorf’s team reported today in Nature Medicine, atherosclerotic plaques more closely resemble plaques known to be most at risk of rupturing and causing a heart attack or stroke. When the scientists blocked the β3 receptor, though, stressed mice not only had fewer of these dangerous plaques, but also had reduced levels of the active immune cells in their plaques, pinpointing β3 as a key link between stress and atheroscelerosis.

The finding could lead to new drugs to help prevent cardiovascular disease, suggests biologist Lynn Hedrick of the La Jolla Institute for Allergy and Immunology in San Diego, California. “I think this gives us a really direct hint that the β3 receptor is important in regulating the stress-induced response by the bone marrow,” Hedrick says. “If we can develop a drug that targets the receptor, this may be very clinically relevant.”

More immediately, the new observations suggest a way that clinicians could screen patients for their risk of atherosclerosis, heart attack, and stroke, Tall says. “Rather than asking four questions about stress levels, we could use their white blood cell counts to monitor psychosocial stress,” he says.

Thanks to Dr. Rajadhyaksha for bringing this to the attention of the It’s Interesting community.

http://news.sciencemag.org/biology/2014/06/how-stress-can-clog-your-arteries