Stiff Blood Vessels Linked to Enzyme That Fosters Cell ‘Chatter’

In a study in mice, Johns Hopkins Medicine researchers have found that the smooth muscle cells lining the walls of blood vessels can lose their elasticity and lead to vascular stiffening, a condition that can precede heart disease and stroke. The finding, say the researchers, may provide a new focus for developing drugs that target the molecular roots of such stiffness.

The muscle cells in healthy blood vessels are elastic and can stretch like rubber bands, allowing high volumes of blood to pump through, explains Lakshmi Santhanam, Ph.D., associate professor of anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine. When the blood vessel tissues lose their elasticity, the vessels stiffen, forcing the heart to work harder to pump blood throughout the body. While diet, exercise and medication can improve overall heart health, there are no drugs on the market to treat underlying stiffening in blood vessels.

Most research into blood vessel stiffening has focused on the material surrounding the living cells — called the extracellular matrix — as the most important contributor to this condition. However, in their paper published July 29, 2021, in the journal Cell Death  Discovery, Santhanam and her team lay out evidence that smooth muscle cells independently contribute to vascular stiffening.

To study this connection, the researchers first had to cut the line of communication between cells and the surrounding matrix. They used a gene editing tool called CRISPR to breed mice lacking the gene that produces tissue transglutaminase (TG2), an enzyme enabling this crosstalk to take place.

“The crosstalk between cells and their surrounding matrix impacts how they behave and respond to changes in one another,” says Santhanam.

Compared with mice that had normal TG2 production, the researchers found that in mice with no TG2 — where the crosstalk between the matrix and vascular smooth muscle cells was uncoupled — the development of vascular stiffening was reduced by nearly 70% at age 15 months. This is old age for a mouse and, generally, the time when blood vessels stiffen. The researchers say this indicates smooth muscle cells independently contribute to vascular stiffening, and that crosstalk influences vascular aging.

Santhanam and her team suspect that severe vascular stiffening, like that seen in humans of old age, could be caused by out-of-control feedback between smooth muscle cells and their surrounding matrix.

The researchers believe continued research on TG2 may lead to drugs that can impact the vessel-tissue crosstalk and its associated impact on vascular stiffening.

Santhanam is available for interviews.


COVID-19 NEWS: For Many, Long COVID Looks a Lot Like Chronic Fatigue

A team of researchers, including two from Johns Hopkins Medicine, have published a review article highlighting similarities between certain lingering symptoms following COVID-19 illness — a condition called “long COVID” — and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a debilitating, complex disorder previously known as chronic fatigue syndrome.

The researchers say the symptoms shared by the two conditions may involve a biological response that goes haywire when the body encounters certain infections or other environmental hazards.

“The body’s response to infection and injury is complex and covers all body systems,” says lead author Bindu Paul, Ph.D., assistant professor of pharmacology and molecular sciences at the Johns Hopkins University School of Medicine. “When that response is in disarray — even just one aspect of it — it can cause feelings of being tired, brain fog, pain and other symptoms.”

In their review, published Aug. 16, 2021, in the Proceedings of the National Academy of Sciences, Paul and her co-authors highlight the evidence seen in both acute COVID and ME/CFS of various underlying biological disorders. In particular, the researchers suggest a central role for the way cells behave when too many oxygen molecules pile up in a cell — a process called oxidative stress or redox imbalance. The team describes how redox imbalance may be connected to the inflammation and disorders of metabolism that are found in the two diseases.

Paul has previously studied the role of oxidative stress in conditions such as Huntington’s disease, Alzheimer’s disease and Parkinson’s disease.

As of August 2021, approximately 36 million Americans have been diagnosed with COVID-19. “We do not yet know how many of these patients will experience long COVID, but it’s estimated that at least 7% experience extended symptoms,” says co-author Anthony Komaroff, M.D., the Steven P. Simcox, Patrick A. Clifford and James H. Higby Distinguished Professor of Medicine at Harvard Medical School.

The expert team urges that some of the recent National Institutes of Health funding assigned to study the long-term health effects of COVID-19 be used to investigate both long COVID and ME/CFS. Those studies, they believe, could shed light on other diseases characterized by oxidative stress, inflammation and metabolic disorders.

ME/CFS is a complex condition affecting 1 million to 2.5 million people in the United States. It is characterized by a cluster of symptoms, including severe and debilitating fatigue, disrupted and unrefreshing sleep, difficulty thinking (commonly called “brain fog”), abnormalities of the autonomic nervous system and post-exertional malaise — a flare-up of multiple symptoms following physical or cognitive exertion.

In addition to Paul and Komaroff, the researchers who contributed to the review article are Marian Lemle, M.B.A., of the Solve ME/CFS Initiative (which provided partial funding for Paul’s research) and Solomon Snyder, M.D., D.Phil., D.Sc., professor of neuroscience at the Johns Hopkins University School of Medicine.

The team hopes that this scientific review will spur and help focus research on the molecular basis of both long COVID and ME/CFS.

Paul is available for interviews.


To Reduce Preeclampsia Risk, Study Says Take Action Before and Between Pregnancies

Preeclampsia — a complication that occurs in about 1 in every 25 pregnancies in the United States — is characterized by high blood pressure and signs of damage to an organ system, most often the liver or kidneys. It usually begins after 20 weeks of pregnancy in women whose blood pressure had previously been normal. In a new study, a multidisciplinary team of Johns Hopkins Medicine researchers has found that the periods before pregnancy and in between pregnancies are key times to address preeclampsia risk factors like obesity, diabetes and hypertension.

The team, led by S. Michelle Ogunwole, M.D., a fellow in the Division of General Internal Medicine, and Wendy Bennett, M.D., M.P.H, associate professor of medicine, both at the Johns Hopkins University School of Medicine, published their findings Aug. 16, 2021, in the Journal of the American Heart Association.

“Preconception health care is really important as it’s a window of opportunity to think about your future health,” says Ogunwole. “We encourage patients to work on chronic disease issues before their pregnancies and between their pregnancies.”

Ogunwole says a woman who develops preeclampsia during her first pregnancy is more at risk of the condition repeating during a second or any successive pregnancies.

“As an internist concerned about maternal outcomes, I am interested in what health care providers can do to help women reduce their risk of preeclampsia, including being a big proponent of preconception counseling,” says Ogunwole.

In their study, Ogunwole and her colleagues statistically compared two sets of women who were participating in the Boston Birth Cohort, an ongoing collaboration between the Johns Hopkins Bloomberg School of Public Health and Boston University led by the former’s Xiaobin Wang, M.D., Sc.D., M.P.H., Zanvyl Krieger Professor in Children's Health.

Since 1998, the cohort has looked at a broad array of early life factors and their effects on pregnancy, infancy and child health outcomes.

The researchers wanted to understand the differences between women who developed preeclampsia and those who did not, and how a first case of the condition affects subsequent pregnancies. The team, says Ogunwole, studied 618 women to gain “rich maternal health data among racially and ethnically diverse pregnant women.”

“We wanted to make sure that we’re asking questions in a population that looks like the populations we serve,” she says. “I’m interested in the life course of women and pregnancy complications that can shape the trajectory of their future health.”

Ogunwole’s team found that obesity, diabetes, high blood pressure, gestational diabetes and preterm birth were common factors in women who had preeclampsia during both first and second pregnancies, or developed the condition during gestation with a second or later child.

“We know that improving weight will improve other conditions, so we advise that women create healthier lifestyles before and between pregnancies,” says Ogunwole. “Whether you have another pregnancy again or not, you can still improve your overall health.”

Ogunwole says future research will hopefully include larger studies to confirm the findings of the current research. She also plans to study the structural barriers that may keep women from engaging in healthy lifestyles and develop strategies to improve long-term health outcomes for women.

Ogunwole is available for interviews.


COVID-19 NEWS: Vaccines Effective Even Without Post-Shot Symptoms or Prior Infection

Vaccination with the two messenger RNA (mRNA) vaccines for SARS-CoV-2, the virus that causes COVID-19, yields a robust antibody response, even if a person did not develop significant symptoms following vaccination or did not have a prior SARS-CoV-2 infection. That’s the key finding from a recent study of nearly 1,000 health care workers in the Johns Hopkins Health System who received two doses of either the vaccine manufactured by Pfizer/BioNTech or the one produced by Moderna.

The Johns Hopkins Medicine study is described in a research letter published August 16 in JAMA Internal Medicine.

The two mRNA vaccines evaluated in the study introduce the body’s immune system to S1, a protein subunit that’s a component of the spikes found on the surface of SARS-CoV-2. The spikes enable the virus to latch onto healthy cells and infect them. Immunoglobulin G (IgG) antibodies, elicited by S1 from the vaccines stimulating the immune system, neutralize the virus particles, preventing infection by SARS-CoV-2, or at least, reducing the severity of the disease.

“It wasn’t known if a lack of symptoms following vaccination or prior SARS-CoV-2 infection would indicate a less-than-adequate antibody response in people who received either the Pfizer/BioNTech or Moderna vaccines, so we studied an available group of staff from our hospital to see if there were any connections,” says study senior author Aaron Milstone, M.D., M.H.S., associate hospital epidemiologist at The Johns Hopkins Hospital.

The researchers recruited 954 Johns Hopkins Medicine health care workers who had received both doses of either the Pfizer/BioNTech or Moderna vaccines, including some who had a known prior SARS-CoV-2 infection. Infection was defined as having a positive SARS-CoV-2 polymerase chain reaction test result prior to 14 days after a second vaccine dose or a high IgG antibody count against S1 prior to vaccination. Participants self-reported symptoms following vaccination as none, mild (injection site pain, mild fatigue or headache) or clinically significant (fatigue, fever or chills).

Clinically significant symptoms were reported by 52 (5%) of the participants after the first vaccine dose and by 407 (43%) after the second shot. After adjusting for prior SARS-CoV-2 infection, age and sex, the odds of clinically significant symptoms following either dose were higher among those who received the Moderna vaccine. Prior SARS-CoV-2 infection was associated with increased odds of clinically significant symptoms following one dose but not two.

Regardless of symptoms, nearly all participants (953 of 954, or 99.9%) developed spike IgG antibodies 14 or more days following the administration of the second dose. The one person who did not have IgG antibodies was taking an immunosuppressant medication.

Factors that were independently associated with higher median IgG levels (after adjusting for time following the second vaccine dose) were reporting of clinically significant symptoms, age younger than 60, being female, receipt of the Moderna vaccine and prior SARS-CoV-2 exposure.

“The findings suggest that either spike mRNA vaccine will work well against SARS-CoV-2, even if a person doesn’t experience symptoms after vaccination or if they had a prior infection by the virus,” says study lead author Amanda Debes, PhD., assistant scientist in international health at the Johns Hopkins Bloomberg School of Public Health. “This should help reduce anxieties that the vaccines will be less effective in either situation.”

Milstone and Debes are available for interviews.


$14 Million Grant to Fund Clinical Trial to Study Effectiveness of Hydrocephalus Treatment

Patients diagnosed with idiopathic normal pressure hydrocephalus (iNPH), a type of brain swelling most commonly seen in older adults — and for which the underlying cause is unknown — are typically treated by surgically installing a shunt (drain) to remove the excess fluid associated with the condition. However, there is controversy in the medical community as to whether or not shunts are an effective form of treatment for patients with iNPH.

Thanks to a $14 million National Institute of Neurological Disorders and Stroke (NINDS) grant, researchers at the Johns Hopkins Cerebral Fluid Center in the Department of Neurosurgery hope to change that. The research is being conducted in partnership with the Adult Hydrocephalus Clinical Research Network (AHCRN) and coordinated by the Hydrocephalus Association, a non-profit organization that raises awareness of and support research on hydrocephalus.

According to the NINDS, hydrocephalus is an abnormal buildup of cerebrospinal fluid (CSF) — the clear liquid that protects and cushions the brain — circulating in the brain’s cavities (ventricles). Hydrocephalus occurs when the normal flow and absorption of CSF is blocked, leaving the excess fluid to widen and swell the ventricles. This puts pressure on the brain and keeps it from properly functioning, leading in turn to neurological damage and, in severe cases, death.

In the Placebo-Controlled Efficacy in iNPH Shunting (PENS) Trial, 100 patients with iNPH will undergo shunt surgery; however, the shunt will be open (on) in one group and remain closed (off) in the other. Only the surgeon will know if the shunt is open or closed. Through evaluations before and after surgery, researchers will determine if typical hydrocephalus-associated symptoms such as walking speed, cognition, mood and bladder control are alleviated in participants during the study period. The data will then be used to assess the effectiveness of treatment. After three months, patients in the closed group will have their shunts opened.

“This study is important because some in the medical community are currently not convinced that shunts are an effective treatment for iNPH,” says Mark Luciano, M.D., Ph.D., professor of neurosurgery at the Johns Hopkins University School of Medicine and director of the Cerebral Fluid Center. “Much of this uncertainty is due to the lack of a high quality randomized controlled trial, so we hope that our study will yield solid evidence about whether shunt surgery significantly helps the sufferers of iNPH.”

Luciano, who is a founding member of the AHCRN, says the trial will be the first to evaluate the true physiological response of shunting. Twenty teams at institutions around the world will contribute data to the study, along with evaluating a variety of methods to better diagnose iNPH.

“The idea of doing a true study on iNPH is something I’ve been working toward for more than 12 years,” Luciano says. “We believe this study will provide a needed firm foundation, not only to study the effectiveness of current treatments in iNPH, but to develop and evaluate new treatments in the future.”

Luciano is available for interviews.


COVID-19 NEWS: Preparing Kids to Go Back to School Amid a Pandemic

Children across the nation are heading back to school, a time of year that can bring a variety of emotions from excitement to anxiety. However, this school year has an extra layer of uncertainty amid the continuing COVID-19 pandemic, so it’s important to take precautions to fight the spread of the disease in the classroom — particularly as the highly contagious delta variant is circulating.

Johns Hopkins Children’s Center (JHCC) experts recommend the following:

  • Children 12 years and older should get a COVID-19 vaccine.
  • Students should wear a mask with at least two layers of tightly woven fabric.
  • Masks should fit well, covering the nose and mouth.

The U.S. Centers for Disease Control and Prevention and the American Academy of Pediatrics recommend masking for all students in grades K–12, even those who are fully vaccinated.

“Getting the COVID-19 vaccine and wearing a face mask are the two most important strategies to decrease the spread of COVID-19 in schools and to keep children safely learning in person,” says JHCC pediatrician Kate Connor, M.D., M.S.P.H., assistant professor of pediatrics at the Johns Hopkins University School of Medicine. “Mask-wearing also can prevent the spread of other viruses that might cause them to miss school.” 

Connor recommends that parents check with their child’s school as to its mandatory COVID-19 safety precautions. However, she strongly encourages parents to send their children to school masked, even if it’s not required.

Along with ensuring children are physically protected against COVID-19, parents may have to deal with some pandemic-related stress and not just the usual back-to-school jitters. JHCC experts suggest calmly talking with children about what to expect when they return and pointing out the precautions that will be in place to keep them safe.

The experts also recommend parents monitor how their children are doing emotionally by asking simple questions such as “How are you feeling about going back to school?”

“Like most big changes in routine, going back to school in person could take some adjustment time for children,” says JHCC child psychologist Andrea Young, Ph.D., assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “So, if the kids seem a little overwhelmed or more reserved than usual, check in with them about their thoughts and feelings.”

Young adds that if parents notice any worsening or persistent irritability, anxiety or sadness, they should consult their child’s pediatrician or a mental health expert.

“It’s also important for parents to be aware of their own anxiety about the return to school, so they don’t transfer it to their children,” she says.

To ease the transition into the school year, Connor and Young recommend gradually shifting children’s bedtimes back 10 minutes earlier each night in the week before school starts. In this way, they will be well rested and able to rise earlier.

Finally, the JHCC experts say parents should check with their child’s pediatrician to ensure routine vaccinations — including those required to attend class — are up to date and annual checkups have been completed before school starts.

“The past 1-1/2 years of the pandemic have brought a wave of emotions for parents and children alike,” Connor says. “Returning to in-person schooling is much needed for the health, education and overall well-being of students, so we have to prepare them as much as possible to have a safe return to the classroom.”

Connor and Young are available for media interviews.

Journal Link: Cell Death Discovery, July-2021 Journal Link: Proceedings of the National Academy of Sciences, Aug-2021 Journal Link: Journal of the American Heart Association, Aug-2021 Journal Link: JAMA Internal Medicine, Aug-2021