Understanding the link between preeclampsia and heart disease later in life

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Preeclampsia is a serious complication of pregnancy that affects 5 to 10 percent of all pregnancies — over 8 million a year worldwide — and claims the lives of 76,000 mothers and half a million babies each year.

The condition causes hypertension and abnormal protein in the urine, and has few effective preventive or therapeutic strategies. The clinical abnormalities usually resolve completely after delivery, but recent research shows that women who have had preeclampsia have higher rates of heart disease later in life, for reasons that are poorly understood.

That’s where Mark HlatkyVirginia Winn, and their Stanford Medicine research team come in. They were recently awarded a 4-year, $6 million NIH grant from the National Heart, Lung and Blood Institute to study the links between preeclampsia and the subsequent risk of atherosclerotic cardiovascular disease (ASCVD) as women grow older.

“The goal of this study is to improve cardiovascular health in women, by learning how pregnancy affects heart disease later in life,” said Hlatky, a Stanford Health Policy fellow. “We hope that shedding new light on these links can lead to better prevention and treatment.”

The interdisciplinary study called EPOCH — Effect of Preeclampsia On Cardiovascular Health — could eventually help millions of women and their clinicians worldwide.

“Since about 85 percent of women become pregnant at some point during their lives, and heart disease is the leading cause of death in women, determining how pregnancy complications might increase the risk of heart disease later in life could be very important,” said Hlatky, a professor of health research and policy and of cardiovascular medicine. “If there is a specific biomarker ‘signature’ of heart disease risk in women who have had preeclampsia, it would open up new possibilities for risk assessment and better treatment to prevent heart attacks and strokes.”

Hlatky and his co-principal investigator, Stanford high-risk obstetrician Winn, note that a history of preeclampsia doubles the woman’s risk of future heart disease and stroke, and triples her risk of hypertension. And these adverse consequences occur at younger ages than in women who never developed the condition during pregnancy.

"The dramatic physiologic changes that happen during pregnancy are indeed remarkable," said Winn, the Arline and Pete Harman faculty scholar in the Department of Obstetrics and Gynecology. "This study highlights how complications that occur in pregnancy impact women's health beyond pregnancy." 

The pathogenic links between preeclampsia early in life and ASCVD late in life have been difficult to investigate because the process develops over decades, the authors said. And few clinicians are aware of the link between the condition and late ASCVD risk and there are no validated biomarkers for this process.

Preliminary data that contributed to the application of the project was a direct result of Winn’s endowed Arline and Pete Harman Faculty Scholar award and funding from the Stanford Maternal and Child Health Research Institute and the Stanford Cardiovascular Institute.

The 4-year grant will support a multi-disciplinary research team in taking a life-course approach. The EPOCH study will enroll three cohorts of women at distinct points in the natural history of the disorder: during pregnancy in their reproductive years; during the long, asymptomatic period in mid-life; and the ultimate development of ASCVD in later life.

“It’s very difficult to study the effects of early life events on the development of diseases late in life, since they are separated by 40 years or more,” Hlatky said. “We don’t have reliable health records in the United States from 40 or more years ago, so it’s a challenge for American researchers.” This is why, he said, the EPOCH study includes researchers from Denmark, which has a national health system, complete medical data of their citizens since the 1970’s, and a national biobank that will allow study of later life events.

The first cohort of women will include some of those who are already part of the Stanford March of Dimes Prematurity Research Center. The center, led by David Stevenson began recruiting women in 2011 to study pregnancy from the first trimester through delivery. The study has collected a wide array of “omics” measures at multiple time points: metabolomics, proteomics, cell-free RNA, the microbiome and immune cells for analysis, as well as collection of amniotic fluid, cord blood, and the placenta. The pregnancy cohort will enroll additional women who are cared for at Lucile Packard Children’s Hospital for treatment of preeclampsia, about 100 in all, plus a matched group with uncomplicated pregnancies.

This is where it gets pretty technical — but also pretty cool

The researchers will collect high-dimensional “omic” biomarker data to assess the pathophysiology of preeclampsia and its relationship to cardiovascular function and disease. They’ll assess cell signaling pathways using single-cell immune profiling (CyTOF) methods in the lab of Brice Gaudilliere, an assistant professor of anesthesia.

They will then analyze the cell-free RNA profiles using methods developed by co-investigator Stephen Quake, a professor of bioengineering and applied physics, and co-president of the Chan Zuckerberg Biohub. They will assess metabolomics using novel methods also developed at Stanford by co-investigator Michael Snyder,  professor and chair of genetics.

Stanford data scientists, including co-investigators, Robert Tibshirani and Nima Aghaeepour, have been at the forefront of developing and applying novel statistical and bioinformatic approaches, which the team will use to analyze the torrents of data that can now be collected by modern “omics” technologies from individual clinical research subjects.

“The EPOCH study is truly interdisciplinary — we are bringing together faculty from eight different departments to study a major problem in women’s health.”

The second, mid-life cohort will be recruited from women who had a pregnancy complicated by preeclampsia. Marcia Stefanick, professor of medicine in the Stanford Prevention Research Center, will use the Stanford Medicine Research Data Repository (STARR), which contains electronic records from more than 1.6 million patients since 1995, to identify eligible women. Stefanick and the EPOCH team will recruit 200 pre-menopausal women who had either a pregnancy complicated by preeclampsia or an uncomplicated pregnancy.

The third, late-life cohort of women will be identified in the Danish National Biobank by Stanford visiting professor Mads Melbye. Samples will be retrieved from women who had preeclampsia early in life and ASCD later in life, as well as a set of matched control subjects, and analyzed in Stanford laboratories.

“We’re not quite sure whether the physiologic challenges of pregnancy that result in preeclampsia simply reveal underlying cardiovascular risk, or causes change that leads to the increased risk in later life,” Winn said. “The EPOCH study will identify unique aspects of preeclampsia that links it to later ASCVD, opening potential novel approaches to improve women’s health.”

The EPOCH study brings together investigators from eight departments. Additional faculty include Gary Shaw and Seda Tierney (Pediatrics), Martin Angst (Anesthesia), Nicholas Leeper (Surgery) and Heather Boyd (Danish Biobank).