Researchers find that accelerated aging biology in the placenta contributes to a rare form of pregnancy-related heart failure

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Peripartum cardiomyopathy is a rare form of heart failure that occurs in women during late pregnancy or early postpartum, and one in which the cause remains largely unknown In a new study, Mass General researchers and colleagues show that elevated levels of proteins related to cellular senescence, or aging, in the blood and the placenta are linked to this form of heart failure Targeting aging-related placental proteins improved heart function in a lab model of peripartum cardiomyopathy, suggesting a potential new approach for therapeutic development BOSTON—A form of heart failure that occurs during late pregnancy or early postpartum, peripartum cardiomyopathy (PPCM) is a major cause of maternal death.

New research led by investigators from Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system, reveals new insights into the mechanisms behind PPCM’s development and points to potential new strategies for therapeutic development. The results are published in Science Translational Medicine.

“Even though heart disease now represents the leading cause of maternal death in the US, our understanding of the biology driving many of these diseases is still very limited,” said co–lead author Jason Roh, MD, MHS, a cardiologist who runs a cardiovascular aging laboratory in the Massachusetts General Hospital Cardiovascular Research Center. “Our study identifies some underlying aging-related biology that contributes to the development of maternal heart failure in pregnancy and provides evidence from both patients and animal models.”

Roh and his colleagues work began with an unexpected finding. While studying the role of senescent (or aged) cells in older adults with heart failure, they were surprised to find that proteins secreted by these aged cells were being detected at even higher levels in the blood of young pregnant women with heart failure.

Based on these initial findings, the researchers conducted experiments to see whether these senescence proteins might be contributing to the development of PPCM as well as preeclampsia, a hypertensive disorder of pregnancy that is a leading risk factor for PPCM and postpartum heart failure.

Their reasoning was based on prior work showing that the placenta, a hybrid maternal-fetal organ unique to pregnancy, manifests markers of increased senescence towards the end of pregnancy.

When the team assessed placentas from women with preeclampsia, they found that they displayed multiple markers of amplified senescence and tissue aging, as well as increased expression of many of the senescence proteins that were detected in the blood of women with preeclampsia or PPCM.

The most highly expressed cellular senescence protein in these placentas was activin A, and higher levels of this protein were linked to either more severe heart dysfunction or heart failure in women with preeclampsia or PPCM.

“While the placenta undergoes a normal physiological process of aging (or senescence) throughout pregnancy, this seems to be further amplified in those who develop heart failure during pregnancy,” said Roh. “We believe this causes it to secrete various factors into the mom's blood that can negatively impact the function of the heart.”

In experiments conducted in mice, the placentas of mice with PPCM showed similarly increased expression of cellular senescence-associated proteins. Treating these mice with fisetin, a drug that can selectively clear highly senescent cells, during mid to late pregnancy partially reduced placental senescence and improved heart function. Treatment with an antibody directed against the receptor for activin A, after pregnancy, had similar effects in these animals.

“Although we are still in the very early stages of understanding how amplified placental senescence can affect the function of the mom's heart, we believe our findings answer some fundamental questions about the biology underlying heart failure in pregnancy,” said Roh. “It is important to note that placental senescence is a normal part of pregnancy. Fully understanding why this process becomes perturbed in pregnancy-related heart disease and rigorously determining how to safely regulate it are critical next steps before translating these findings.”

"We still have lots of work to do, but we hope that this work will help accelerate our understanding of pregnancy-related heart disease and hopefully lead to much needed new diagnostic and therapeutic strategies for women affected by these conditions."

Jason Roh, MD, MHS
Physician Investigator, Division of Cardiology

Authorship:

Jason D. Roh, Claire Castro, Andy Z. Yu, Sarosh Rana, Sajid Shahul, Kathryn J. Gray, Michael C. Honigberg, Melanie Ricke-Hoch, Yoshiko Iwamoto, Ashish S. Yeri, Robert Kitchen, Justin Baldovino Guerra, Ryan Hobson, Vinita Chaudhari , Bliss Chang , Amy Sarma , Carolin Lerchenmüller, Zeina R. Al Sayed, Carmen Diaz Verdugo, Peng Xia, Niv Skarbianskis, Amit Zeisel, Johann Bauersachs, James L. Kirkland, S. Ananth Karumanchi, John Gorcsan 3rd, Masataka Sugahara, Julie Damp, Karen Hanley-Yanez, Patrick T. Ellinor, Zoltan Arany, Dennis M. McNamara, for the IPAC Investigators, Denise Hilfiker-Kleiner, and Anthony Rosenzweig.

Disclosures:

Disclosure forms provided by the authors are available with the full text of this article.

Funding:

Funding for this work was provided by the NIH (K76AG064328 and R01HL1700548 to J.D.R.; R01AG061034 and R35HL155318 to A.R.; K08HL146963, R01HL163234, and R03HL162756 to K.J.G.; K08HL166687 to M.C.H.; R37AG013925 and R33AG061456 to J.L.K.; R01HL126797 and R01HL152446 to Z.A.; R01HL092577, R01HL157635, and R01HL139731 to P.T.E.; R01HL102429 to D.M.M.; T32HL007208 and K01AG0880077 to P.X.; R01HL148191-01A1 to S.S.; and R56HL157579-01 to S.R.); MGH Transformative Scholars Award (to J.D.R.); Fred and Ines Yeatts Fund for Innovative Research (to J.D.R.); Hassenfeld Scholars Award (to J.D.R.); American Heart Association (940166 and 979465 to M.C.H.; 18SFRN34110082 to P.T.E.; and AHA MERIT Award to A.R.); Department of Defense (W81XWH18 to Z.A.); European Union (MAESTRIA 965286 to P.T.E.); Deutsche Forschungsgemeinschaft KFO 311 (HI 842/10-2 to D.H.-K. and M.R.-H., RI2531/2-2 to M.R.-H., and RI2531/4-1 to M.R.-H.); Foundation Leducq (19CVD02 to D.H.-K.); Lower Saxony Ministry of Science and Culture REBIRTH I/II (ZN3400 to D.H.-K. and M.R.-H.); Connor Fund (to J.L.K.); Robert J and Theresa Ryan Fund (to J.L.K.); and the Noaber Foundation (to J.L.K.).

About Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. MGH is a founding member of the Mass General Brigham healthcare system.

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