New Hints on Preeclampsia Mechanism Revealed

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The system that regulates blood cholesterol goes into overdrive in women who are experiencing preeclampsia, according to results of a recent study.

Published in the Journal of Lipid Research, the study provides the latest clue into what may cause preeclampsia, a condition in which women experience elevated blood pressure and protein in the urine during pregnancy (Mistry HD, et al. J Lipid Research 2017; 58:1186–1195). It also adds to emerging evidence linking cardiovascular disease risk to malfunctioning in the body’s cholesterol flushing system.

Placenta problems?

Better understanding of this complex condition is critically important because it occurs in about 3%–5% of pregnancies in the United States, according to the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). It also accounts for about half of maternal deaths in the developed world, according to NICHD. Women who experience preeclampsia and survive have an elevated risk of cardiovascular disease and kidney disease. Their children also face a higher risk of heart disease later in life.

“We’re still trying to work out what happens during preeclampsia and what causes it,” said Hiten Mistry, PhD, a senior research fellow in the Division of Child Health, Obstetrics & Gynecology at the University of Nottingham’s School of Medicine. “If we understand the mechanism, we can do something to prevent it.”

Already, scientists know that the placenta plays an important role in preeclampsia. For example, a previous study by Mistry and his colleagues revealed signs of atherosclerosis in blood vessels in the placentas of women who had preeclampsia (Hentschke MR, et al. J Lipid Research 2013; 54:2658–2664).

This is the same kind of narrowing and hardening caused by a buildup of cholesterol seen in the arteries of people with heart disease. Atherosclerosis constricts blood flow and in people with heart disease may lead to heart attack, stroke, or death. In the placenta, this narrowing might compromise the flow of nutrients from the mother to the developing fetus and the flow of waste from the fetus to the mother. Such a constriction might explain why some babies born to mothers who had preeclampsia are smaller than expected.

“We know the placenta is involved,” Mistry said.

Cholesterol implicated

Appropriate levels of cholesterol are necessary for both healthy adults and developing fetuses. It is used to build new cells for growth and repair, to protect nerves, and to make important hormones. But too much so-called bad cholesterol or low-density lipoprotein (LDL) cholesterol has been linked to heart disease and preeclampsia (Spracklen CN, et al. Am J Epidemiol 2014; 180:346–358).

Sufficient levels of a type of cholesterol called high-density lipoprotein (HDL) on the other hand have been found to be important for good heart health.

Low levels of HDL are associated with insulin resistance and other factors that may contribute to heart disease, so it has been hard to tease out HDL’s role, noted Anand Rohatgi, MD, an associate professor and preventive cardiologist at the University of Texas Southwestern Medical Center in Dallas. One reason HDL may be helpful is that it helps the body remove LDL cholesterol and transport it to the liver where it can be eliminated. The first step in that process is called efflux.

Rohatgi and his colleagues found that people who are better at removing LDL cholesterol this way have a lower risk of having a heart attack, stroke, or other serious heart disease–related event (Rohatgi A, et al. N Engl J Med 2014; 371:2383–2393).

That study led Mistry to wonder whether this cholesterol flushing system also might play a role in preeclampsia.

Pregnant mothers need to supply their fetuses with cholesterol for development and they need it to aid their recovery after delivery, Mistry explained.

“It’s getting the balance right,” he said.

He and his colleagues suspected pregnant women with preeclampsia wouldn’t clear cholesterol as efficiently as pregnant women without the condition. So they compared cholesterol efflux in pregnant women with and without preeclampsia. But they found that efflux is turned up in women with preeclampsia and in their fetuses. This may help the women try to mitigate the potentially harmful effects of elevated cholesterol.

“This study showed this is a compensatory mechanism for damage limitation,” Mistry said.

The findings add some much needed information about efflux during pregnancy, said Rohatgi, but more studies are needed to understand whether efflux is a cause of preeclampsia or merely an indicator.

“I think this is provocative,” Rohatgi said. “Because it is case controlled you get a link to efflux at the time of preeclampsia, but you don’t know if it is causing preeclampsia.”

In fact, the role of efflux in cardiovascular disease more generally is still being worked out. Some phase 2 trials are currently underway to test whether treatments that boost efflux would improve patient’s cardiovascular disease outcomes.

“What has been established pretty well is that as a cardiovascular risk prediction marker efflux does work,” Rohatgi said. “We still don’t know what drives efflux—what makes it go up or down.”

Emphasis on prevention

The findings may have important implications for protecting the long-term cardiovascular and renal health of mothers who experience preeclampsia, as well as the health of their children.

Women who have elevated cardiovascular risk are at higher risk of preeclampsia. After preeclampsia, a woman’s cardiovascular risk is elevated substantially, noted study co-author Markus Mohaupt, MD, a nephrologist and head of internal medicine at Lindenhofgruppe, a foundation based in Bern, Switzerland, that supports research. Understanding these relationships may aid prevention and possibly treatment efforts.

“Is it a disorder that preexists the development of preeclampsia or a disorder that develops after [that contributes to the elevated cardiovascular risk]?” asked Mohaupt, who is also a professor at the University of Bern. “It could be either or both.”

In addition to having an elevated risk of heart disease over the long term, women who experience preeclampsia are also more likely to undergo a renal biopsy, develop chronic kidney disease, and require treatment for kidney disease, Mohaupt said.

To help prevent such poor outcomes, Mohaupt recommended that clinicians monitor lipid levels in women with a history of preeclampsia, especially after menopause.

Rohatgi agreed that long-term monitoring for signs of cardiovascular disease is warranted. He also emphasized the importance of good prenatal care and managing conditions like high blood pressure or gestational diabetes that increase the risk of preeclampsia. “The low hanging fruit is simple prenatal care,” he said.

Children whose mothers had preeclampsia are also at elevated risk for cardiovascular disease.

“The literature is scarce, but what is available tells us a story where the offspring may share the adverse cardiovascular risk factors with their mothers,” said Ingvild Alsnes, MD, a PhD candidate at the Department of Public Health and General Practice at the Norwegian University of Science and Technology in Trondheim, Norway.

Alsnes and her colleagues recently compared the cardiovascular risk of siblings whose mothers had preeclampsia (Alsnes IV, et al. Hypertension 2017; 69:591–598). It turns out that the siblings have similarly elevated risks of cardiovascular disease regardless of whether their mother had preeclampsia during their own gestation.

“It might suggest that it is not the exposure [to preeclampsia] per se that gives an adverse cardiovascular risk profile, but perhaps genetics or lifestyle,” she suggested.

Unanswered questions

Many unanswered questions remain about preeclampsia itself. Alsnes said it would be important to better understand if the cardiovascular risk profiles of women who had severe or mild preeclampsia are different.

“Perhaps they should not be subgroups, but different entities altogether,” she said. “We also need to know whether cardiovascular disease is preventable in this patient group, and how or if they should be followed up or treated.”

The heart risk may differ among women who have had preeclampsia—some may not have an increased risk—so it will be important to identify markers that distinguish those with an elevated heart risk, Rohatgi said.

“Efflux as a marker might help determine which ones are at risk,” he noted.

Markers of elevated cardiovascular risk in women in general are needed, Rohatgi said. Most current heart risk calculators are geared toward men.

“There is a lot of room for improvement in picking out women who are at higher risk,” Rohatgi said.

Early warning sign?

Mistry and his colleagues plan to monitor cholesterol efflux in women earlier in pregnancy to look at whether efflux is elevated before the condition is diagnosed. If so, it might be an early warning sign. They would also like to examine efflux prior to pregnancy in women with chronic hypertension or signs of kidney dysfunction who are at risk of preeclampsia. Rohatgi agreed that these types of studies will be helpful, as will studies that track the long-term cardiovascular outcomes of women who have had preeclampsia.

In the meantime, Mistry emphasized the importance of routine lipid monitoring during pregnancy. He also expressed optimism that elevated cholesterol efflux during pregnancy might one day prove to be a useful tool for monitoring women’s cardiovascular health.

“In the future, it could be a predictor of heart disease later in life,” he said. “If we know a woman is at higher risk, we can intervene early and prevent it.”