Observatory and Fast Facts

July 20, 2022

Pregnant women with polycystic ovary syndrome at risk of heart complications during delivery

A common hormone disorder among women of reproductive age has been linked to an increased risk of adverse cardiovascular events and pregnancy outcomes at the time of birth, according to a new study led by Johns Hopkins Medicine researchers.

The study was published in the Journal of the American Heart Association.

Polycystic ovary syndrome (PCOS) affects an estimated 5%–13% of women in the general population. It causes irregular periods, excess levels of male hormones (androgens) and, at times, infertility. Building on previous research that shows PCOS is linked to future cardiovascular disease risks later in life, the new findings reveal that it can also significantly increase heart problems among pregnant women during delivery. These problems include preeclampsia (dangerous levels of high blood pressure with organ damage), peripartum cardiomyopathy (a weak or enlarged heart), heart failure, abnormal heart rhythms and venous thromboembolism (blood clots), compared with women without PCOS.

“Oftentimes, women with PCOS are understandably concerned about the immediate effects, like an irregular menstrual cycle, excess body hair, weight gain and acne. However, the long-term cardiovascular complications are also a serious problem,” said Erin Michos, MD, Associate Professor of Medicine at the Johns Hopkins University School of Medicine and corresponding author of the study. Michos said the new study should encourage women with PCOS to live a heart-healthy lifestyle before, during, and after pregnancy to reduce the risk of adverse outcomes.

For the study, researchers analyzed data gathered on more than 17 million U.S. births between 2002 and 2019 drawn from the National Inpatient Sample. Among those with hospitalized deliveries, 195,675 had PCOS. The prevalence of PCOS — and obesity among those with the hormone disorder — increased significantly during the study period. The number of women with PCOS went from a reported 569 per 100,000 deliveries in 2002 to 15,349 per 100,000 deliveries in 2019. During that same time period, obesity also skyrocketed from 5.7% to 28.2% among women with PCOS.

After adjusting for age, race, other disorders not related to PCOS, insurance coverage and income, PCOS remained an independent predictor of heart complications during delivery compared with women who did not have the hormone disorder. Complications included preeclampsia, with a 56% increased comparative risk; heart failure, with a 76% increased risk; abnormal heart rhythms, with a two-fold higher risk; weakened heart, with a 79% higher risk; and an 82% higher risk of developing blood clots.

Women with PCOS were overall older (31 versus 28) and had a higher prevalence of diabetes, obesity, and high cholesterol. The study also found black women with PCOS were at greater risk for preeclampsia and other adverse outcomes.

“Currently, the overall goal is to reduce the rising mortality rate among pregnant women in the U.S., with a mission of identifying risk factors. Our study shows that PCOS is indeed a risk factor for acute cardiac complications at the time of delivery and should be taken seriously,” says Salman Zahid, MD, a resident physician in the Rochester General Hospital Internal Medicine Residency program in Rochester, New York, and lead author of the study. “We want to stress the importance of optimizing the cardiovascular health of women with PCOS with prevention efforts, especially black women and lower socioeconomic groups because we believe that those are the most vulnerable populations and will benefit most from intervention.”

Identification of 1,000+ genes linked to severe COVID-19

Researchers from Stanford Medicine and the University of Sheffield in the U.K. have identified more than 1,000 genes linked to the development of severe COVID-19 cases that required breathing support or were fatal, according to a news release.

The team was also able to identify specific types of cells in which those genes act up. It’s one of few studies to link coronavirus-associated genes to specific biological functions.

The researchers used a machine learning tool named RefMap, which can find patterns in vast amounts of data, to help identify the genetic basis for complex and poorly understood diseases.

“We mapped the genetic architecture of coronavirus infections and found that these 1,000 genes account for 77% of the drivers of severe COVID-19,” explained Michael Snyder, PhD, Professor and chair of genetics.

A paper describing the research was published in Cell Systems.

Snyder, the Stanford W. Ascherman, MD, FACS, Professor in Genetics, and Professor of medicine Philip Tsao, PhD, are co-senior authors. Genetics instructor Sai Zhang, PhD, and neuroscientist Jonathan Cooper-Knock, PhD, a Stanford visiting scholar and lecturer at the University of Sheffield, share lead authorship.

The researchers used two large data sets to unpack the genetics behind severe COVID-19. The first data set contained genomic information from healthy human lung tissue. The data helped identify gene expression in 19 different types of lung cells, including epithelial cells that line the respiratory tract and are the first defense against infection. (Gene expression is the process by which certain genes are switched on to make RNA and proteins.)

Other data came from the COVID-19 Host Genetics Initiative, one of the largest genome-wide studies of critically ill coronavirus patients. The researchers looked for genetic clues in the data — DNA mutations, called single nucleotide polymorphisms — that might indicate if someone is at a higher risk for severe COVID-19. They tracked whether some mutations occurred more or less often in COVID-19 patients with severe disease.

Mutations that continued to appear, or were notably absent, in the patients who developed severe COVID-19 suggested those variations might be behind the infection’s severity.

To verify whether the suspicious mutations might in fact increase odds for severe COVID-19 infection, the researchers performed a genome-wide search in lung tissue for the mutations from patients critically ill with COVID-19 and from healthy people.

“We did this for the 19 lung cell types,” Zhang said. Although it was clear which mutations were most likely to convey risk for severe disease, the researchers still didn’t know which genes were affected by the mutations. So the team worked backward, using molecular clues to decipher the region of the genome in which the mutation occurred and, finally, narrow the region down to specific genes. “Then we had our final gene list associated with COVID-19 severity.”

“When you’re studying the genetic basis of disease, you’re trying to pinpoint regions in the genome that are responsible,” Snyder explained. The researchers also wanted to know which types of cells harbored faulty gene expression. Through their machine learning tool, they determined that severe COVID-19 is largely associated with a weakened response from two well-known immune cells — natural killer (NK) cells and T cells. “NK cells and a subtype called CD56bright are the most important,” Cooper-Knock said. “T cells rank second.”

NK cells, which you’re born with and are the body’s first line of defense against infection, are known for their ability to destroy viruses and cancer cells. NK cells also help produce a range of immune system proteins called cytokines, Cooper-Knock said.

“CD56bright cells are like the general directing the war. They mobilize other immune cells, telling them where to go and what to do. We found that in people with severe coronavirus infection, critical genes in NK cells are expressed less, so there’s a less robust immune response. The cells aren’t doing what they’re supposed to do,” Cooper-Knock explained.

Snyder likened COVID-19 risk genes to harmful variants of the BRCA genes that predispose some people to breast and ovarian cancer.

“Our findings lay the foundation for a genetic test that can predict who is born with an increased risk for severe COVID-19,” he said. “Imagine there are 1,000 changes in DNA linked to severe COVID-19. If you have 585 of these changes, that might make you pretty susceptible, and you’d want to take all the necessary precautions.”

“The drugs bind to receptors on the NK cells and trigger them to have a more robust response,” he said. Trials of NK cell infusions for severe COVID-19 are underway. 

Elderly COVID-19 patients at greater risk

When COVID-19 began surging around the world in early 2020 and physicians were confronting a deadly disease they knew little about, scientists at the University of Minnesota’s Institute on the Biology of Aging and Metabolism (iBAM) swung into action to help, according to a news release.

“Early in the pandemic it became very clear that certain people were at greatest risk—the elderly, people with diabetes, and people with obesity,” says Laura Niedernhofer, Professor of Biochemistry in the Medical School and Director of iBAM. “And one common thread between those groups? They all have increased levels of senescent cells.”

Senescent cells are aging cells that have stopped dividing but haven’t died. According to Niedernhofer, the burden of senescent cells in our body doubles with every decade of life.

“Senescent cells drive inflammation, and that inflammation then puts you at greater risk for disease and aging,” explains iBAM Associate Director Paul Robbins, also a Professor of Biochemistry in the Medical School. “If you have a perfectly healthy, robust immune system, your body clears these cells for you. But as we age, our immune response wanes and stops clearing these cells effectively.”

What if there were a drug that could help clear senescent cells and slow the onset of not just the aging process, but of the many diseases associated with aging, such as heart disease, cancer, type 2 diabetes, and Alzheimer’s disease?

That question led Niedernhofer and Robbins, working with colleagues at the Mayo Clinic, to become the first scientists to describe a new class of drugs called senolytics in 2015. More recently, they’ve shown that fisetin, a natural antioxidant found in various fruits and vegetables (apples, strawberries, onions, and cucumbers, for example), successfully clears senescent cells.

“We do have preliminary data [indicating] that fisetin clears senescent cells in humans,” says Niedernhofer, “and there are now many clinical trials underway to study it further.”

When COVID-19 struck, iBAM scientists quickly geared up to see whether the senolytics they were developing to promote healthier aging could also be used to treat the viral infection caused by SARS-CoV-2.

“The excitement around senolytics as a COVID-19 treatment has been growing,” says Camell, “since the group’s results were published in the prestigious journal Science.” Clinical studies are under way in Minnesota to evaluate the success of treating COVID-19 patients with senolytics.