Unraveling the Heart of Long COVID
by Amanda Chase, PhD
October 14, 2024
COVID-19 first appeared as a respiratory illness, infecting millions and causing a global pandemic. It has since become clear that COVID-19 has a broader impacts than initially thought, with the potential to affect multiple organs, particularly the cardiovascular system. The lasting effects of COVID-19 have also become an area of increasing concern, with millions of patients experiencing lingering symptoms that can persist for months or years. Much about long COVID remains unknown, and it is imperative that more becomes understood about mechanisms of long COVID to allow treatment or prevention.
In a recent Nature Cardiovascular Research Publication, co-first authors and Stanford Cardiovascular Institute members Dilip Thomas and Chikage Noishiki and senior author Nazish Sayed, used cutting edge techniques to explore the mechanism of long COVID influence on the heart.
To explore how long COVID impacts heart health, researchers in this study used induced pluripotent stem cells (iPSCs) differentiated into heart muscle cells, or cardiomyocytes (iPSC-CMs). Further, these researchers used iPSC-CMs in a sophisticated combination to create 3D organoids to model the heart. This innovative approach let them observe how the virus affects cardiovascular tissue.
Emerging research about long COVID suggests that influence of the virus extends to the heart through an intricate interplay of immune response, inflammation, and endothelial cell (EC) dysfunction. Endothelial cells line the blood vessels and they regulate blood pressure, blood clotting, and immune responses, ensuring the proper function of our circulatory system. EC dysfunction can lead to impaired heart function. Endothelial cells have emerged as key players in cardiovascular complications of long COVID, and understanding how they contribute is crucial for developing treatments and preventative strategies.
A distinctive characteristic of COVID-19 infection is a hyperinflammation state, also referred to as the “cytokine storm”. Cytokines are signaling proteins that are released by immune cells when there is an infection. They function to control inflammation.
In some cases, such as severe cases of COVID-19, there is an overproduction of cytokines that then leads to widespread inflammation, including in blood vessels and the heart.
These cells are important for maintaining healthy blood flow and heart function. In long COVID, endothelial cells become inflamed and dysfunctional. They also release too many CCLs, a chemokine that attracts immune cells and promotes inflammation. This endothelial dysfunction both affects blood vessels and contributes to heart problems by disrupting communication between endothelial cells and cardiomyocytes. In this manuscript, researchers show the role of endothelial cells in driving heart dysfunction in long COVID, with inflammation and oxidative stress generated by endothelial cells contributing to impaired cardiac contractility. Further, the high levels of inflammation can cause long-lasting damage, promoting scaring and remodeling of the heart tissue, which can lead to more severe cardiovascular issues, such as heart failure.
This important study shows the potential of targeting endothelial dysfunction and the associated inflammatory responses for treatment of existing heart issues or to prevent further cardiovascular complications in long COVID patients. The cutting-edge work presented in this manuscript highlights the importance of continued research to understand the full scope of the effect of long COVID on the body. As health challenges posed by long COVID continue to evolve, it becomes more important to move closer to finding ways to treat or prevent the long-term impact.
Other Stanford Cardiovascular Institute members involved in the work presented in this Nature Cardiovascular Research manuscript include David Wu, Amit Manhas, Yu Liu, Dipti Tripathi, Ronald Dalman, Karim Sallam, Jason Lee, and Joseph Wu. They were joined by Nimish Kathale, Jaishree Garhyan, Baohui Xu, Kevin Wang, and Anthony Oro, also from Stanford, and by Elsie Ross at UC San Diego and Chun Liu at Medical College of Wisconsin. Funding was provided by NIH R01 HL158641, R01 HL161002, K01 HL135455 and American Heart Association SFRN grant 869015, Stanford Surgery and SAGE center pilot award.
Chikage Noishiki, MD, PhD
Dilip Thomas, PhD
Nazish Sayed, MD, PhD