SFRN Centers: Go Red for Women

Center Directors: Marie-Pierre St.-Onge, Ph.D.;
Lori Mosca, M.D., Ph.D., M.P.H

Sleep — or the lack thereof — was the focus of research at Columbia University Irving Medical Center, which recruited pre- and post-menopausal women to study how restricted vs. adequate sleep patterns can affect cardiovascular health.

“There’s very little information about the negative influence of poor sleep in older adults and women transitioning across menopause,” said Center Directors, Marie-Pierre St.-Onge, Ph.D., and Lori Mosca, M.D., Ph.D., M.P.H.

“We had done studies that showed that restricting sleep — very severely restricting sleep — increased food intake and could lead to obesity, which increases the risk of hypertension and cardiovascular disease,” St.-Onge said. “We thought, perhaps, there’s specifically in women, a link between poor, short sleep duration and cardiovascular disease.”

The study recruited 20 post-menopausal and 20 pre-menopausal women, excluding participants with underlying conditions such as depression or other factors that could influence sleep degradation. Once participants were selected, they were first studied during adequate sleep periods and then instructed to reduce their sleep nightly by an hour and a half for a six-week period. Monitoring included blood work, sleep diaries, tracking wristwatches and, at the end, ambulatory blood pressure monitors.

“What we did was restrict sleep but to a smaller extent than we had done in the past — but for a longer period of time, which reflects more closely what short sleepers actually do in the general population,” St-Onge said.

Blood results and other data are still being analyzed, but findings so far can already teach lessons for the general population and health care professionals, St.-Onge said.

Not only were blood pressure readings better when women received adequate sleep; stable schedules, including regular bedtime and rising times, also seemed to improve circadian rhythms and other markers.

“It’s important for the population and health practitioners to know that sleep quality is something that should be asked about in health encounters. Just as you would ask about diet, just as you would take blood pressure and weight, just as you would ask about a person’s mood, you should be asking about their sleep,” St.-Onge said.

Center Director: Pamela Ouyang, M.B.B.S., M.D.

Heart failure affects an estimated 6 million Americans each year. Nearly half of cases requiring hospitalizations are caused by heart failure with preserved ejection fraction, also known as HFpEF. This occurs when the left ventricle can contract or pump normally but is unable to relax between heartbeats, which can lead to higher pressure within the muscle. Johns Hopkins used AHA funding to focus on HFpEF and why the condition is more common in older women, particularly African Americans.

Despite the prevalence of HFpEF, there are no specific effective treatments. Johns Hopkins conducted studies to identify whether sex hormones are a significant factor in the problem and sought to identify potential solutions, tests and therapies.

Much of the study focused on cyclic GMP (cGMP), a signaling molecule, or “second messenger,” vital to organ function, that produces its effect through the enzyme protein kinase G (PKG).

“We were interested in the sex differences but also that the underlying mechanisms leading to HFpEF may be very heterogenous and maybe there are subgroups within that population, and, ultimately, therapy may need to be focused in different subgroups, as opposed to one-size-fits all — and maybe that’s why studies to-date have not shown particular therapies that have helped the overall population,” said Center Director Pamela Ouyang, M.B.B.S, M.D.

Patients were recruited from a heart failure pool for the clinical studies, and data was also analyzed from cohorts of participants that had already been studied for decades. The basic, clinical and population studies included biopsies, blood work, exercise tests and MRIs to look at muscle and fat distribution. A separate study in mice looked at the function of estrogen and ovaries when it came to heart pathway modulation.

Some findings have already been enlightening and, at times, surprising.

“What our team found was that many of the patients with HFpEF had a condition called amyloid,” said Wendy Post, M.D., M.S. “abnormal protein deposits in the wall of the heart — and that makes the heart stiff, makes the pressure go up and can cause HFpEF. So, with these biopsies, we saw a relatively high prevalence of amyloid in HFpEF. I think that’s leading to a greater awareness of the fact that, when we see older patients who are more likely to have amyloid who also have HFpEF and thick heart wall muscles, we should also do a complete work-up for amyloid, which is now treatable.”

When it came to heart wall thickness relative to cGMP, studies concluded the opposite of what researchers had expected, Post said.

They had assumed lower levels of cGMP would be associated with thicker muscle — often a precursor or indicator of HFpEF. But it turned out that higher levels were a better predictor because the body was producing more as a “compensatory mechanism.”

“So, it appears that higher cGMP in the blood is a marker of future risk,” she said.

Center Director: Carl Hubel, Ph.D.

The correlation between pregnancy complications and the risk of future cardiovascular disease is still largely a mystery and often overlooked by primary physicians, said Center Director Carl Hubel, Ph.D.

“We and others have been very intrigued, from the epidemiologic perspective, by the associations between pregnancy complications and risk of future cardiovascular disease, which includes hypertension, stroke and coronary heart disease,” Hubel said.

Not all women who’ve had pregnancy complications will go on to have heart disease. Hubel wants to probe the mechanisms underlying these conditions for better clues to identify which women are at risk.

“So, we can better tease out which women really should be followed closely and monitored on the basis of their pregnancy history, and if we can get a better handle on mechanisms, we may be able to actually do things to intervene to change the trajectory that some of these women appear to be on,” Hubel said.

Magee researchers studied women during pregnancy and a year after, particularly assessing microvasculature and placenta using everything from blood tests and imaging to electron microscopes. Another aspect of the population project studied women 8-10 years after giving birth to determine what might be hidden risk factors, conducting heart measurements that included 2-D echocardiograms and focusing on small vessel impairment.

The basic study focused on mice that developed a hypertensive syndrome during pregnancy — and whether that affected the animals’ future health. It did appear to increase the mice’s susceptibility to cardiovascular problems down the road, Hubel said, with obvious implications for humans. The studies, he said, have led to a “virtual goldmine of data,” much of which has yet to be analyzed and published.

Already though, the team is becoming more aware that there are subsets and subtypes of women who may go on to develop cardiovascular problems following pregnancy.

Microvascular tests of the placenta, heart and even under the tongue could give indications of a patient’s future cardiovascular health, providing insights into previously hidden or overlooked risk factors, according to study findings.

“One of the ways the science really grew beautifully, with our three projects spanning basic to population, was that our five postdoctoral fellows were able to not only experience it, but sort of lead the science,” Hubel said. “So, we feel that we’ve done our part in training the future generation of scientists.”

Center Directors: Harmony Reynolds, M.D.; Judith Hochman, M.D.

More women than men who suffer heart attacks tend to present with arteries that aren’t blocked, raising questions about what led to the cardiovascular event in the first place. NYU’s Heart Attack Research Program set out to investigate the factors behind these differences between the sexes.

“If the arteries are not badly blocked, then we have to work backward and decide: Was this a problem of blood flow to the heart muscle at all? Was it something else entirely?” said Center Director Harmony Reynolds, M.D.

After recruiting patients from 16 sites throughout the U.S. and Canada, NYU researchers employed blood tests, angiograms and platelet studies, as well as sophisticated imaging techniques to get to the bottom of what could be causing the heart attacks, called myocardial infarctions with non-obstructive coronary artery disease, known to the scientific community as MINOCA. This included optical coherence tomography, “which is basically taking a very clear picture from inside the artery to see the artery wall,” Reynolds said.

“We then did cardiac MRI, which can beautifully highlight where damage has occurred, even if that damage is not permanent,” she said. “MRI can show us traces of where injury was just starting to happen.” Using both tests, the investigators were able to find the cause of these previously unexplained heart events in 85% of cases. “Most were true heart attacks and were caused by small cholesterol plaques or blood clots, but some were not heart attack at all, and were actually inflammation of the heart muscle that imitated a heart attack.”

The NYU team showed that platelets, cells that help the blood clot, also provoke plaque buildup. They are looking into whether platelets could explain why some women with smaller plaques have heart attack.

The NYU investigation also delved into how stress and environmental factors, in addition to plaque and platelets, could influence such cardiac events.

“The women were randomly assigned to two different interventions: an educational intervention, or training in stress management techniques. The stress intervention gave the women skills to use so they would be able to interrupt the physical consequences of emotional stress,” Dr. Reynolds said, because “stress is known to be associated with a poor prognosis after a heart attack.”

“Stress may promote heart events over the long term,” she said, adding that stress enhances platelet activity, making blood stickier and more prone to clotting. This may be the mechanism by which stress increases heart attack risk. “We know stress increases risk, but exactly how it does this has not been entirely clear.” The NYU studies found that stress increases platelet activity and makes platelets stick to, and stimulate, inflammatory cells called monocytes. This may represent a new pathway linked to stress-mediated heart disease.

Center Director: Matthew Allison, M.D., M.P.H.

At the University of California, San Diego — with a campus just over an hour north of the Mexican border in a city with a significant Mexican American and Latino population — researchers chose to study sedentary behavior among women of Mexican descent.

“Sedentary behavior, it’s not a new topic, per se, but it’s a relatively new area of research that’s unexplored, especially among women of Mexican descent and other Hispanic/Latino backgrounds,” said Center Director Matthew Allison, M.D., M.P.H.

“It’s important, because prior studies showed, in other populations, that being sedentary is associated with worse outcomes. That is, those who are more sedentary have heart disease and die earlier,” he said. “So, we proposed to study sedentary behavior in women of Mexican descent because this problem has been relatively understudied in this ethnic group and results from other studies have shown that they were more sedentary than their counterparts in the United States.”

Researchers focused on 400 participants with the help of South Bay Latino Research Center and existing community partners.

“In general, individuals of Hispanic/Latino descent have higher rates of obesity and higher rates of diabetes, but their blood pressure, by and large, is similar to non-Hispanic Whites,” Allison said. “Diabetes is definitely a big problem for this group, and they have problems with their lipid profile; both of which can predispose to heart disease.”

Sedentary behavior increases the risk for these conditions. Sitting for long periods of time, day after day, typically increases weight and the chance of developing obesity. It also increases the probability of developing high blood pressure or diabetes, significant risk factors for cardiovascular disease.

Key to the project was the question of just how much of a difference a behavioral intervention could make in reducing sitting time. For example, participants were regularly contacted by phone to encourage movement and even provided with standing desks.

“When it came to sitting time”, Allison said, “our goal was to reduce it by 20%, but we went past that.” The University of California, San Diego researchers, he said, “were all really pleasantly surprised by the magnitude of the change” in women’s lifestyle choices and sedentary patterns.

Monitoring of sitting time utilized a device called the activPal. Also, factors such as weight, cholesterol, blood pressure, and blood components were tracked. Allison said there had also been decreases noted in these biomarkers but data was still being evaluated before publication.

Decreases in those factors, he said, albeit preliminarily and over a relatively short period of time, “were not nearly as large as the sitting behavior.”

He said he hoped the study would help patients and health practitioners learn that people can improve their health, quality of life and longevity by not sitting as much.

“We hope to be able to translate these findings into something that can be used by clinicians for counseling their patients,” he said. “It’s really just standing up; there’s not a lot of thought process to it ... If you do that, that can lead to positive changes in your life and, I think, those things combined constitute a really simple intervention, which has potential.”