Since emerging in China in late 2019, COVID-19 has claimed more than one million lives and infected more than 30 million people around the world. Initially viewed as a respiratory infection, scientists soon realized the virus was also capable of causing serious heart damage, including arrhythmias, heart attacks, and heart failure.
While COVID-19 clearly contributes to significant cardiovascular problems in many patients, a mystery has lingered: is the heart a bystander victim of inflammation triggered by the body’s response to the virus – or is the virus capable of infecting heart cells directly?
That question is at the center of an ongoing research effort led the Murry Lab in the University of Washington Institute for Stem Cell and Regenerative Medicine (ISCRM). In the investigation, the Murry Lab partnered with the lab of ISCRM faculty member Nate Sniadecki and with the Gale Lab in the Department of Immunology to expose stem cell-derived cardiomyocytes to the SARS-CoV-2 virus.
Their initial findings, published on the preprint server bioRxiv, could have major implications for patient care and help explain why front-line providers are seeing cardiovascular complications even when inflammation seems to be under control. The investigation also further validates the use of stem cells and 3D-tissue engineering technology as models for studying the effect of COVID-19 on the heart.
Studying COVID-19’s Trojan Horse
One focus of the study is a protein known as ACE2, an enzyme found on the surface of cells in multiple organs, including the lungs and heart. Normally, ACE2 helps keep the body healthy by regulating blood pressure and other biological processes. However, scientists learned early in the pandemic that the SARS-CoV-2 virus uses its distinctive spikes to latch on to ACE2 and turn the protein into the trojan horse it needs to invade and infect healthy cells in the lungs.
In March, the ISCRM team, led by Silvia Marchiano, a Senior Research Fellow in the Murry Lab, showed that heart cells derived from pluripotent stem cells also expressed ACE2. To understand whether the virus was capable of infecting heart cells directly, the researchers obtained live SARS-CoV-2 from the Gale Lab and set up a new base of operations in a secure biosafety lab.
Armed with remote technology originally developed in part by Nate Sniadecki to allow earthbound scientists to monitor experiments on the International Space Station, Marchiano and her colleagues exposed heart cells to the virus for one hour, still unsure how susceptible the cells would be to infection.
Alessandro Bertero, an Acting Assistant Professor in Lab Medicine and Pathology and a contributor to the study, summarizes the eye-popping results. “Not only does the virus infect heart cells, but it alters their ability to generate and conduct electrical signals and to contract, basically all they do for a living. Most worryingly, eventually the virus can kill them.”
The Strongest Evidence Yet
The havoc that COVID-19 can play on the heart was captured in a series of high-resolution images, akin to a brain CT, produced in collaboration with Behzad Najafian, Associate Professor of Laboratory Medicine and Pathology. “We could clearly see the virus particles inside the cell,” says Marchiano. “Which is the strongest evidence yet that the virus can replicate inside heart cells. It took us all by surprise.”
The results of the ISCRM study reinforce similar revelations from an investigation led by the lab of Todd DcDevitt at the Gladstone Institutes, setting the stage for a planned co-submission of a peer-reviewed paper.
“The stunning loss of healthy heart cells we saw is a particular concern because the heart is one of the least regenerative organs in the human body,” says Chuck Murry, Director of the Institute for Stem Cell and Regenerative Medicine. “If similar infection happens inside the human body, that means the damage done by the virus is essentially irreversible.”
For this reason, Murry stresses the need for more research to back up the ISCRM findings, to study the long term effects of COVID-19 on the heart, and to understand how risk varies in different patients.
Still, there is reason for hope, says Bertero. “The good news is that we have sophisticated tools that allow us to model the impact of the virus on the heart and to test many different drugs and combinations of drugs in the lab, which is much faster and safer than relying on animal or human subjects.”