SFRN Centers Hypertension

Center Director: Elaine Urbina, M.D., M.S., FAHA

At Cincinnati Children’s Hospital, researchers worked in new ways — across institutions and across the country — collaborating on target organ damage in youth with primary hypertension.

The SFRN model was an ideal opportunity to advance the science of high blood pressure research in youth, said Center Director Elaine Urbina, M.D., M.S., FAHA. She is also a leader in the International Pediatric Hypertension Association, which had long been interested in such an opportunity.

“The AHA’s SFRN funding opportunity really gave us the tools we needed to take that next step,” she said. Given the smaller percentage of youth with hypertension (compared to adults), the research required a multi-site approach that was not achievable through traditional funding mechanisms.

“This is the type of study in pediatrics that cannot be done in a single center,” Urbina said. The project’s population researchers studied about 500 youth with high blood pressure and sought to answer the question, “At what blood pressure level does target organ damage begin?” The study looked specifically at the heart, and more specifically at thickening of the heart or imperfect functioning.

Clinical researchers sought to demonstrate that 24-hour ambulatory blood pressure monitoring is feasible on a large scale and will impact treatment decisions for youth regarding hypertension. The clinical team worked closely with the population team, Urbina said.

The basic science team, which was from the University of Cincinnati, investigated epigenetic changes that influence the development of target organ damage in youth with hypertension. Epigenetics is the study of changes in gene function caused by heritable factors that do not involve changes in DNA sequence.

Incorporating basic science into this work — and finding ways to collaborate across the country with this multi-site team — was one of the hallmarks of this Hypertension SFRN, Urbina said.

“We’ve proven that damage to organs in the body can occur in young people with high blood pressure at levels we formerly thought were acceptable,” Urbina said. “So now we have more data to know how to diagnose serious high blood pressure, and how to determine who should get stronger medicines and who could continue on lifestyle modifications.”

The center’s work will continue, particularly with translational studies with the University of Cincinnati. “We’re looking at the long-term,” Urbina said. “How can we keep the collaboration going?”

Center Director: Mingyu Liang, M.B., Ph.D.

At the Medical College of Wisconsin, researchers hypothesized that dietary salt intake, maternal dietary exposures and other lifestyle factors cause genome-wide changes in DNA methylation (one of the mechanisms of epigenetics – which may influence the expression of genes) and that these changes contribute to hypertension or can serve as markers of hypertension and cardiovascular diseases.

Researchers analyzed DNA methylation at near genome-wide scale. The clinical, population and basic science teams worked together with a remarkable synergy to study epigenetic changes in humans and animals to help identify new ways of controlling high blood pressure, said Center Director Mingyu Liang, M.B., Ph.D.

Although the university’s team had discussed working in such a collaborative way previously, the SFRN’s creation solidified the arrangement.

“The three projects in our center really functioned as a single project,” Liang said. “That really was very, very helpful for us to be able to drive the science forward in a way that is relevant to humans and also deep in science.”

The basic science team studied the effect of salt intake on DNA methylation in salt-sensitive rats. They found that salt intake changes DNA methylation in T-cells and the kidney substantially and that these changes contribute to the development of hypertension in saltsensitive rats.

Clinical researchers sought to answer two questions. First, “How will low sodium intake change DNA methylation in T-cells, in humans?” They answered this by studying DNA methylation in a group of 50 people, after giving them a low-salt diet for two weeks. They found significant changes in DNA methylation in T-cells. Second, “can DNA methylation in T-cells explain differences in blood pressure or other characteristics between identical twins”? Researchers studied close to 150 pairs of monozygotic twins, seeking to “take genetics out of the equation” by creating a situation where genetics were nearly identical, Liang said. They found T-cell DNA methylation may explain part of the effect of several lifestyle factors.

The population project used a cohort of approximately 3,000 African Americans first established about 25 years ago. At that time, the original researchers collected samples from study participants. For this project, the team went back to the cohort and analyzed current health. They identified a surprisingly strong association between DNA methylation and blood pressure and a remarkable improvement in predicting if participants would go on to develop cardiovascular health concerns when the researchers included DNA methylation as a predictor.

Current models can predict 10-year risk of cardiovascular disease at about 70%, Liang said. “With the methylation marks that we found in this AHA program, we could improve that to about 80%. It may seem like a small increment, but that’s actually a pretty big increment in terms of clinical application.”

“DNA methylation features are really adding substantial value to the current model,” he said.

It’s his hope that this SFRN’s work will lead to DNA methylation applied at the health care professional level, making it easier for patients to understand their risk for cardiovascular disease.

Center Director: Paul Muntner, Ph.D., M.H.S., FAHA, FASH

University of Alabama at Birmingham researchers focused on what blood pressure looks like during sleep to better understand hypertension’s 24- hour effect on cardiovascular and renal health.

“It’s important that people have their blood pressure measured outside of the doctor’s office,” said Center Director Paul Muntner, Ph.D., M.H.S., FAHA, FASH. “For many people, the blood pressure they experience outside of their doctor’s office, when they go about their everyday activities, has a stronger association with cardiovascular disease risk. That is the key take-away from our research.” The basic science team used animal models to study the mechanisms through which salt could affect 24-hour blood pressure patterns — and also to study whether genes control blood pressure.

Clinical researchers studied how changing people’s diets affected their blood pressure while sleeping, how it affected the severity of sleep apnea and how reducing the amount of salt they ate reduced their blood volume.

The population project looked at the prevalence of hypertension during sleep. Investigators sought to understand what factors led to high blood pressure during sleep, including some differences among racial groups.

The center’s work was unique because it brought together these different groups of scientists and provided an opportunity to conduct translational research, “not just working together on a project, but really on a whole thematic area,” Muntner said. Research from the Center at UAB (as well as with other SFRN participants) contributed to the development of an AHA guideline, released in 2018, that recommends out-of-office blood pressure monitoring.

“The first step to identifying people with hypertension is measuring blood pressure correctly,” Muntner said. “The data from the SFRN provides important information on how to measure blood pressure correctly, as well as the reasons why some people have high blood pressure outside their doctor’s office. It’s important to identify certain populations, for example African Americans, where we can direct our efforts to prevent cardiovascular disease, given that there are health inequities and higher risk in this population.”

UAB’s work is far from finished in this area, as the university has recently established a Hypertension Research Center — a direct result of the SFRN, Muntner said. Researchers are continuing the work through additional AHA grants, as well as funding from the National Institutes of Health.

Center Director: Curt Sigmund, PhD, FAHA

At the University of Iowa, researchers focused on predicting hypertension in pregnancy. They sought a reliable early marker of preeclampsia to help diagnose this often difficult-to-pinpoint condition. The center’s work was led by director Curt Sigmund, Ph.D., FAHA.

“Preeclampsia is really hard to diagnose,” said Mark Santillan, M.D., Ph.D., FACOG, FAHA, one of the center’s principal investigators. “We have a marker for preeclampsia that is elevated as early as the sixth week of gestation, and stays high throughout pregnancy.”

“Our work, which has now been corroborated by other labs, has demonstrated that early pregnancy vasopressin dysregulation is not just predictive of the development of preeclampsia; but it is also a cause of the disease,” he said. “By identifying the early mechanisms of preeclampsia, we have the opportunity to develop novel modalities to more robustly prevent preeclampsia before it starts or gets worse.”

The center’s basic research focused on vasopressininduced preeclampsia in a mouse model. (Vasopressin, a hormone released by the pituitary gland, is important in blood pressure regulation.) Multiple team publications demonstrate that early vasopressin elevation in the model replicates many crucial facets of human preeclampsia. With a model that replicates human preeclampsia well, researchers are investigating multiple therapeutic options to potentially translate to human therapy.

Clinical researchers studied the role of early vascular dysfunction and elevated copeptin in human preeclampsia. Copeptin is a marker for cardiovascular disease. The team has published that early human vascular dysfunction and early neurologic control of blood pressure are associated with the development of preeclampsia. These data further open the possibility of new preventive and therapeutic agents for preeclampsia.

Population scientists studied the predictive capabilities of copeptin as a biomarker for preeclampsia. The team has published that it is predictive of the development of preeclampsia as early as six weeks of gestation. The team’s discovery has led to multiple patents with the hope of bringing this predictive test to the clinic.

The university’s work on these topics continues in multiple avenues, funded by grants from several different sources, including the National Institutes of Health. Results from the Center have been critical in development of several patents in the pipeline related to the diagnosis and therapeutics of preeclampsia, with a focus on vasopressin and vasopressin-related pathways.

Perhaps the greatest benefit from the Center’s work has been increased awareness of preeclampsia, Santillan said.

“Moms who have preeclampsia are at increased risk of developing cardiovascular disease in the future. They could be 20 [years old], get preeclampsia, and then be at increased risk of a heart attack or stroke, just because of that history.

“Preeclampsia is more prevalent than heart attacks, colon cancer and prostate cancer, which all have received more scientific attention resulting in more therapeutic and diagnostic options in comparison to preeclampsia,” he said. “What the AHA has allowed us to do is shine a light on preeclampsia, and to say how important it is — not only to the health of mothers during pregnancy — but to the health of mothers and their children throughout their lives.”