Maybe we should think of Covid-19 as a heart disease.
When SARS-CoV-2 virus was added to human heart cells grown in lab dishes, the long muscle fibers that keep hearts beating were diced into short bits, alarming scientists at the San Francisco-based Gladstone Institutes, especially after they saw a similar phenomenon in heart tissue from Covid-19 patients’ autopsies.
Their experiments could potentially explain why some people still feel short of breath after their COVID infections clear and add to worries that survivors may be at risk for future heart failure.
The new study was posted as a preprint on bioRxiv, meaning it has not yet been peer-reviewed or otherwise vetted by a scientific journal. The authors said they felt an urgent need to share their work so others could help them understand the mechanisms causing heart damage and work on ways to prevent or treat it.
“When we saw this disruption in those microfibers, … that was when we made the decision to pull the trigger and put out this preprint,” said Todd McDevitt, a senior investigator at Gladstone and a co-author of the study. “I’m not a scientist who likes to stoke these things [but] I did not sleep, honestly, while we were finishing this paper and putting it out there.”
His colleague Bruce Conklin, a senior investigator at Gladstone and a co-author, said the “carnage in the human cells” they saw was unlike anything that’s been previously described with other diseases. “Nothing that we see in the published literature is like this in terms of this exact cutting and precise dicing. We should think about this as not only a pulmonary disease, but also potentially a cardiac one.”
Looking like they were surgically sliced, fiber fragments known as sarcomeres bore no resemblance to the disintegration seen in other acquired or hereditary diseases of the heart muscle, the scientists said. And in another mystery, there were black holes where DNA should have been in the nucleus of these cells, leaving just an empty shell. Their observations were made using high-magnification imaging to capture what happens in the first 48 hours after exposure to the virus that causes Covid-19.
The scientists first presented small amounts of virus to three types of human heart cells derived from stem cells: cardiomyocytes, cardiac fibroblasts, and endothelial cells. Only cardiomyocytes — the muscle cells — showed signs of viral infection that spread to adjacent muscle cells. They then obtained autopsy specimens from three COVID-positive patients and saw similar, though not identical, changes.
Together, the sarcomere and DNA damage caused by infection could explain earlier findings of heart damage as well as case reports of lingering weakness in patients who recovered from even mild COVID-19 — if they hold up to further scrutiny and are confirmed in more patient samples.
“I think it’s really important and elegant work, helping to define the potential mechanisms by which SARS-CoV-2 is leading to the observed heart damage and clinical manifestations,” said Gregg Fonarow, interim chief of the UCLA Division of Cardiology and director of the Ahmanson-UCLA Cardiomyopathy Center. “There was a real question, other than just a few case reports, as to whether the heart muscle cells themselves could be infected. This shows that at least in vitro, that absolutely can occur and that those cells engender a response that is damaging and disruptive to those cells.”
Caveats abound when extrapolating from lab-dish studies with human cells to patients, but the striking cell culture images add to a limited but growing body of evidence from autopsy reports and clinical studies of hearts in people infected by SARS-2. Balancing the “only in cell culture” limitation is one advantage of studying infection in a dish: Scientists can watch one possible causal factor at a time in isolation, rather than trying to tease out what’s happening during a viral infection that finds its way into every system in the body. Is it inflammation? Is it pulmonary stress? Did the patient have previous heart damage?
“This is the virus itself damaging the heart,” said UCLA’s Fonarow, who was not involved in the research. “There are no other ones in that test tube. There is no systemic inflammation.”
Sahil Parikh, an interventional cardiologist at Columbia University Irving Medical Center who was not involved in the Gladstone study, says the jury is still out.
“The data are provocative: It suggests that cardiomyocytes, the heart muscle cells, in a Petri dish are damaged in ways that are potentially irretrievable,” he said. “The challenge here is that this paper has not been peer-reviewed by people who are experts in cardiology, who have not had a chance to tear it apart. I am reluctant to make a lot out of a pre-publication manuscript, no matter how provocative the finding.”
The Gladstone scientists concede the need for outside experts, and they have submitted the manuscript to a leading journal. Since the pandemic began, doctors and basic scientists have been documenting how the virus — initially viewed as primarily a respiratory illness — reaches into many parts of the body, from the nose to the toes. It can trigger an overwhelming immune response called a cytokine storm in some people, multisystem inflammation in some children, neurological problems, and abnormal blood clotting in the brain, heart, and lungs.
Concern about long-term damage to the heart stems from the fact that unlike the liver, for example, it cannot regenerate its tissues. Doctors in Germany reported earlier this summer that 39 autopsies and cardiac MRIs of 100 patients showed damage to the hearts of older people who died (average age of 85) and younger people (average age of 49) who weren’t even hospitalized for their apparently mild Covid-19 infections.
The cardiac MRI study has since been corrected to amend statistical errors, but Fonarow, who co-authored an editorial that accompanied the two articles published in July in JAMA Cardiology, said the main message of heart damage still held true, raising the specter of heart failure for patients as they grow older and their hearts become weaker.
Patients who heard about that German study are asking for cardiac MRIs, Parikh said.
“We worry that those patients who did demonstrate heart damage during the acute illness, or in the near term afterward, may have long-term sequelae that they will not recover from,” he said. “Many patients are just anxious and come to get checked out. To say there’s a clear pattern of acute and then chronic convalescent heart disease would be premature.”
The Gladstone scientists still don’t know if the heart can reassemble sarcomeres once they’ve been cut, perhaps after the infection clears. The heart cells in the three autopsy samples they studied looked different than what they saw in the lab dish 48 hours after exposure to the virus. In the patient samples, there were just hints of a disorderly rearrangement of the muscle fibers, Conklin said.
To learn more, the scientists said, autopsy data need to tell more of the story than current post-mortem exams do. They think that problem can be solved with available immunohistochemistry tests that can detect the sarcomere disarray they’ve seen in their experiments.
For patients actively fighting Covid-19 infections, there is a highly specific test that shows damage to heart muscle. Widely used when a heart attack is suspected, the blood test looks for troponin, which leaks into the blood when heart muscle dies.
Conklin and McDevitt hope their work will pave the way for discovering drugs that might target an as-yet-unidentified enzyme in the virus that so efficiently slashes the sarcomeres. They propose high-throughput screening of available drugs that could possibly benefit patients, using an assay they developed. Further research would establish a timeline for when to intervene, which could be early in infection.
Different heart medications are being tested to see if they can protect the hearts of Covid-19 patients, including drugs designed to lower blood pressure or treat diabetes, UCLA’s Fonarow said. And Columbia’s Parikh points out that there are treatments to help people whose hearts aren’t pumping strongly.
“Just because the heart isn’t squeezing well now doesn’t mean it can’t improve its squeezing function with appropriate medical therapy,” Parikh said.
Gladstone’s Conklin thinks of his late father, who had scarlet fever and strep throat in the 1930s, before the advent of antibiotics. He suffered heart valve damage that didn’t bother him for most of his life, but it did eventually “take him down” in his 80s.
“Fifty years from now, what are we going to be seeing?” Conklin asked.