New Research Shows Molecular Effects of TNF-α on Cardiomyocytes

March 16, 2021

Heart Institute at UPMC Children’s researcher Anita P. Saraf, MD, PhD, was the lead author of a new study that examined the effects of tumor necrosis factor-alpha (TNF-α) on human cardiomyocytes. 

Dr. Saraf and colleagues’ research (from Emory University) examined the molecular effects of TNF-α on human cardiomyocytes derived from human induced pluripotent stem cells (iPSCs). 

TNF-α is a key cytokine in systemic inflammation including in cytokine storms caused by COVID-19. The study is notable for a number of its findings in how disruption of cardiomyocyte function by TNF-α can be replicated in a sustained in vitro system derived from iPSC-cardiomyocytes. This in vitro system allowed for identification of novel cytokines IL-34 and IL-32 as markers of cardiomyocyte inflammation. Cardiomyocytes exposed to TNF-α showed an increased production of reactive oxygen species (ROS) activity in the cytoplasm that was partially responsible for apoptosis and cellular death in the exposed cardiomyocytes. TNF-α also was shown to upregulate autophagy and cellular stress pathways, while at the same time having a downregulating effect on gene expression regulating calcium ion channel signaling in the cell, but also other ion channels. The research also showed that the disruption to intercellular calcium channels was dose-dependent for TNF-α. Notably, TNF-α exposure also caused a decrease in the contractility of cardiomyocytes.

The models from this study developed by Dr. Saraf and colleagues can be used to further explore molecular aspects of cardiomyopathies and associated inflammatory pathways attributable to IL-32 and IL-34.

The study was published in February in the journal Stem Cell Research and can be accessed at the reference below.

Reference

Saraf A, Rampoldi A, Chao M, Li D, Armand L, Hwang H, Liu R, Jha R, Fu H, Maxwell JT, Xu C. Functional and Molecular Effects of TNF-α on Human iPSC-derived Cardiomyocytes. Stem Cell Res. 2021; Epub ahead of print.

More About Dr. Saraf

Anita Saraf, MD, PhDAnita P. Saraf, MD, PhD, is fellowship-trained in adult congenital heart disease (ACHD) and is a member of the UPMC Adult Congenital Heart Disease Program. Dr. Saraf holds dual academic appointments in the Department of Pediatrics and the Division of Cardiology in the Department of Internal Medicine at the University of Pittsburgh School of Medicine. In addition to her position in the Heart Institute at UPMC Children’s, she also is a member of the UPMC Heart and Vascular Institute

Dr. Saraf’s clinical practice encompasses the full spectrum of ACHD, with a special focus on Fontan patients and women with adult congenital heart disease.

As a physician-scientist, Dr. Saraf studies biomarkers in adult congenital heart disease, and how these biomarkers affect heart function. Her work extends to developing translational models that may lead to new therapies for ACHD. She also has an interest in neurocognitive function in ACHD and outcomes in pregnancy for ACHD patients.

About the UPMC ACHD Program

Decades of advances in pediatric cardiology and cardiothoracic surgery have produced an ever-growing population of adults living long, relatively normal lives with various forms of adult congenital heart disease.

However, the growing population of CHD patients surviving into adulthood requires lifelong, complex cardiac care. Meeting this patient population's needs means expanding services, developing new models of care, and introducing technological advances to lower or remove barriers to care. The UPMC Adult Congenital Heart Disease program is rising to the challenge with a multifaceted approach.

The ACHD program operates on a unified, tri-campus model with UPMC Children’s, UPMC Presbyterian, and UPMC Magee-Womens Hospital serving as the hubs for clinical care for the entire spectrum of ACHD patients — younger or older, male or female.

Collaborations with the UPMC Heart and Vascular Institute and cardiology practices across the UPMC system and outreach to regional and community cardiology providers for referral needs and support are hallmarks of the program. 

New to the UPMC ACHD program is a 24/7 consultation service for any patients admitted to the hospital for care of another condition or surgery, or for any ACHD patient who arrives through the emergency department for any reason.

Patient Referrals and Additional Information

Referring physicians can contact the UPMC Adult Congenital Heart Disease program at 412-692-3158 or by email at achd@upmc.edu.