Serum Proteomic Analysis of Peripartum Cardiomyopathy Reveals Distinctive Dysregulation of Inflammatory and Cholesterol Metabolism Pathways

Jana P Lovell; Kevin Bermea; Jinsheng Yu; Sylvie Rousseau; Charles D Cohen; Aashik Bhalodia; Marcelle Dina Zita; Richard D Head; Roger S Blumenthal; Rami Alharethi; Julie Damp; John Boehmer; Jeffrey Alexis; Dennis M McNamara; Garima Sharma; Luigi Adamo; IPAC; IMAC2 Investigators

doi:10.1016/j.jchf.2023.05.031

Serum Proteomic Analysis of Peripartum Cardiomyopathy Reveals Distinctive Dysregulation of Inflammatory and Cholesterol Metabolism Pathways

JACC Heart Fail. 2023 Sep;11(9):1231-1242. doi: 10.1016/j.jchf.2023.05.031. Epub 2023 Aug 2.

Authors

Jana P Lovell¹, Kevin Bermea¹, Jinsheng Yu², Sylvie Rousseau¹, Charles D Cohen¹, Aashik Bhalodia¹, Marcelle Dina Zita¹, Richard D Head¹, Roger S Blumenthal³, Rami Alharethi⁴, Julie Damp⁵, John Boehmer⁶, Jeffrey Alexis⁷, Dennis M McNamara⁸, Garima Sharma⁹, Luigi Adamo¹⁰; IPAC; IMAC2 Investigators

Collaborators

Dennis M aaaMcNamara, James D Fett, Jessica Pisarcik, Charles McTiernan, Karen Hanley-Yanez, John Gorcsan 3rd, Erik Schelbert, Rami Alharethi, Kismet Rasmusson, Kim Brunisholz, Amy Butler, Deborah Budge, A G Kfoury, Benjamin Horne, Joe Tuinei, Heather Brown, Julie Damp, Allen J Naftilan, Jill Russell, Darla Freehardt, Eileen Hsich, Cynthia Oblak, Greg Ewald, Donna Whitehead, Jean Flanagan, Anne Platts, Uri Elkayam, Jorge Caro, Stephanie Mullin, Michael M Givertz, M Susan Anello, Navin Rajagopalan, David Booth, Tiffany Sandlin, Wendy Wijesiri, Leslie T Cooper, Lori A Blauwet, Joann Brunner, Mary Phelps, Ruth Kempf, Kalgi Modi, Tracy Norwood, Joan Briller, Decebal Sorin Griza, G Michael Felker, Robb Kociol, Patricia Adams, Gretchen Wells, Vinay Thohan, Deborah Wesley-Farrington, Sandra Soots, Richard Sheppard, Caroline Michel, Nathalie Lapointe, Heather Nathaniel, Angela Kealey, Marc Semigran, Maureen Daher, John Boehmer, David Silber, Eric Popjes, Patricia Frey, Todd Nicklas, Jeffrey Alexis, Lori Caufield, John W Thornton 3rd, Mindy Gentry, Vincent J B Robinson, Gyanendra K Sharma, Joan Holloway, Maria Powell, David Markham, Mark Drazner, Lynn Fernandez, Mark Zucker, David A Baran, Martin L Gimovsky, Natalia Hochbaum, Bharati Patel, Laura Adams, Gautam Ramani, Stephen Gottlieb, Shawn Robinson, Stacy Fisher, Joanne Marshall, Jennifer Haythe, Donna Mancini, Rachel Bijou, Maryjane Farr, Marybeth Marks, Henry Arango, Biykem Bozkurt, Mariana Bolos, Paul Mather, Sharon Rubin, Raphael Bonita, Susan Eberwine, Hal Skopicki, Kathleen Stergiopoulos, Ellen McCathy-Santoro, Jennifer Intravaia, Elizabeth Maas, Jordan Safirstein, Audrey Kleet, Nancy Martinez, Christine Corpoin, Donna Hesari, Sandra Chaparro, Laura J Hudson, Jalal K Ghali, Zora Injic, Ilan S Wittstein, Dennis M McNamara, Karen Janosko, Charles McTiernan, Barry London, Karen Hanley-Yanez, John Gorcsan, Hidekazu Tanaka, Mathew Suffoletto, Randall C Starling, Cynthia Oblak, Leslie T Cooper, Annette McNallan, LuAnne Koenig, Paul Mather, Natalie Pierson, Sharon Rubin, Yanique Bell, Alicia Ervin, John Boehmer, Patricia Frey, Jeffrey Alexis, Janice Schrack, Pam LaDuke, Guillermo Torre-Amione, Jeannie Arredondo, Daniel F Pauly, Pamela C Smith, Richard Sheppard, Stephanie Fuoco, Ilan S Wittstein, Elayne Breton, Vinay Thohan, Deborah Wesley, G William Dec, Diane Cocca-Spofford, David W Markham, Lynn Fernandez, Colleen Debes, Mark J Zucker, Laura Adams, Peter Liu, Judith Renton, Jagat Narula, Byron Allen, Elizabeth Westberg

Affiliations

¹ Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
² Department of Genetics, McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
³ Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
⁴ Intermountain Heart Institute, Murray, Utah, USA.
⁵ Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁶ Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA.
⁷ Division of Cardiology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
⁸ Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
⁹ Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. Electronic address: https://twitter.com/GarimaVSharmaMD.
¹⁰ Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address: ladamo2@jhmi.edu.

PMID: 37542511
DOI: 10.1016/j.jchf.2023.05.031

Abstract

Background: The pathophysiology of peripartum cardiomyopathy (PPCM) and its distinctive biological features remain incompletely understood. High-throughput serum proteomic profiling, a powerful tool to gain insights into the pathophysiology of diseases at a systems biology level, has never been used to investigate PPCM relative to nonischemic cardiomyopathy.

Objectives: The aim of this study was to characterize the pathophysiology of PPCM through serum proteomic analysis.

Methods: Aptamer-based proteomic analysis (SomaScan 7K) was performed on serum samples from women with PPCM (n = 67), women with nonischemic nonperipartum cardiomyopathy (NPCM) (n = 31), and age-matched healthy peripartum and nonperipartum women (n = 10 each). Serum samples were obtained from the IPAC (Investigation of Pregnancy-Associated Cardiomyopathy) and IMAC2 (Intervention in Myocarditis and Acute Cardiomyopathy) studies.

Results: Principal component analysis revealed unique clustering of each patient group (P for difference <0.001). Biological pathway analyses of differentially measured proteins in PPCM relative to NPCM, before and after normalization to pertinent healthy controls, highlighted specific dysregulation of inflammatory pathways in PPCM, including the upregulation of the cholesterol metabolism-related anti-inflammatory pathway liver-X receptor/retinoid-X receptor (LXR/RXR) (P < 0.01, Z-score 1.9-2.1). Cardiac recovery by 12 months in PPCM was associated with the downregulation of pro-inflammatory pathways and the upregulation of LXR/RXR, and an additional RXR-dependent pathway involved in the regulation of inflammation and metabolism, peroxisome proliferator-activated receptor α/RXRα signaling.

Conclusions: Serum proteomic profiling of PPCM relative to NPCM and healthy controls indicated that PPCM is a distinct disease entity characterized by the unique dysregulation of inflammation-related pathways and cholesterol metabolism-related anti-inflammatory pathways. These findings provide insight into the pathophysiology of PPCM and point to novel potential therapeutic targets.

Keywords: heart failure; inflammation; pregnancy; proteomics; serum proteomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cardiomyopathies*
Cholesterol
Female
Heart Failure*
Humans
Inflammation
Peripartum Period
Pregnancy
Pregnancy Complications, Cardiovascular* / therapy
Proteomics
Puerperal Disorders* / therapy

Substances

Cholesterol

Abstract

Publication types

MeSH terms

Substances

Grants and funding