Danielle Huff was on her treadmill when she first noticed the pain in her chest. She had just recovered from a terrible case of COVID-19 about two or three weeks earlier, during which she’d had just about every symptom imaginable: sore throat, headache, congestion, coughing, loss of smell, body aches, a mild case of pinkeye, and a constant heaviness in her chest like there was a bowling ball weighing it down.
But this feeling in her chest was different—it was a sharper pain that came on suddenly. Huff, an Illinois school administrator in her 30s, has a family history of heart issues, and she worried that it might signal something serious. Although she’d always tried to live a healthy lifestyle—doing yoga or walking every day—she soon found herself too frightened to exercise.
“It got to the point where I just couldn’t,” she says. “I was scared of the chest pain because I didn’t know what it was.” Ultimately, her doctor referred her to a cardiologist who specializes in treating patients who have recovered from COVID-19 but still experience cardiac symptoms.
From the earliest months of the pandemic, scientists have suspected that COVID-19 is not just a disease of the lungs, but also a disease of the heart and blood vessels. “We realized very, very early that clotting was playing a major role,” says Jeffrey Berger, director of New York University Langone’s Center for the Prevention of Cardiovascular Disease. Even in March 2020, physicians were seeing unexpectedly high rates of blood clots in their patients, leading to a rise in heart attacks and strokes. Autopsies also revealed masses of tiny blood clots in places where doctors don’t normally see them, such as the liver and the kidneys.
Now it has become clear that COVID-19’s cardiovascular damage doesn’t resolve as soon as a patient recovers from the initial infection. For some patients, MRI scans show signs of inflammation months after clearing the virus. Others continue to have elevated levels of troponin, a chemical that’s released into the blood whenever there’s damage to the heart muscle.
Oddly, Huff took a battery of heart-related tests and the results came back normal. Still, she found herself so short of breath she had to step out of a yoga class and couldn’t walk across her school building without needing to sit down. And about a month after she recovered from COVID-19, she began feeling random heart palpitations.
Adding to the mystery, some people who had only mild or even asymptomatic cases of COVID-19 also report long-lasting symptoms such as heart palpitations, chest pain, shortness of breath, and extreme fatigue. Scientists are still baffled about what’s causing them.
“To me there’s no question these individuals are suffering real symptoms,” says James de Lemos, a cardiologist at the University of Texas Southwestern Medical Center and a co-chair of the American Heart Association’s COVID-19 CVD registry steering committee. “The question is, is there some injury to the heart that’s leading to symptoms that we’re not seeing?”
There is reason for hope. Researchers have made strides toward understanding how to prevent COVID-19 from attacking the heart and blood vessels. Meanwhile, physicians are learning more every day about how to treat long COVID symptoms—and rigorous investigations are underway to help shed light on why they occur.
How COVID-19 attacks the cardiovascular system
Physicians quickly learned in early 2020 that the use of blood thinners, which help keep blood from clotting, improved the chances of survival for moderately ill COVID-19 patients. But Berger says it also became clear that there was more to the deadly blood clotting than what they could treat with these anticoagulant therapies alone.
“One in four patients were still dying or requiring organ support,” he says.
In the last five to 10 years, scientists have begun to understand that platelets play a role in promoting unwanted clotting and inflammation in other diseases such as HIV, psoriasis, lupus, and rheumatoid arthritis. These tiny round blood cells serve one major purpose: to stop bleeding by binding to a damaged blood vessel and forming a clot. With that in mind, Berger and a team of researchers set out to investigate what role the platelets might play in COVID-19.
“We found it was nothing like we would have expected,” Berger says. “It was like somebody changed the genetic architecture of these platelets.”
In a study published in Science Advances, the researchers showed that the virus can enter megakaryocytes, the bone marrow cells that make platelets. The infected cell then alters the genetic material in the platelets so that they become more active and give off protein signals that make the lining of the blood vessels sticky and inflamed. This makes the vessels prone to developing clots that can spread throughout the body.
Scientists also learned that the virus weakens connections in the tissue that lines blood vessels, making them leaky instead of sealing them up, as you might expect when clots are present.
“It’s like a double-edged sword,” says Ben Maoz, a biomedical engineer at Tel Aviv University and lead author of a recent study that identified the SARS-CoV-2 proteins that cause the most damage to the blood vessel lining. Somehow, he says, COVID-19 affects the blood vessels “in a dual and opposite way.”
Leaky vessels allow blood and other chemicals in the body to spill into places they’re not supposed to go—including the air sacs of the lungs and the tissues of other organs. That can have a cascade of downstream effects, from the flooded lungs seen in many severe COVID-19 cases to complications of the liver, kidneys, and, of course, the heart.
“Things we’re supposed to be protected from are suddenly coming in,” Maoz says. He likens the harm this causes to a garbage bag with holes in it: Those holes will allow some waste to seep back into your home. Some of the subsequent damage, like the smell and the foul liquid, will be noticeable right away. But others—like, say, a resulting rat infestation—may not be evident for months. The extent of that harm will depend on how bad the leak was and how long it lasted.
But it’s not clear exactly how this blood vessel damage is connected to the lingering cardiovascular symptoms in patients who have recovered from COVID-19. Maoz points out that the virus causes harm in many complex ways that are difficult to disentangle. Yet physicians have continued to see signs of damaged heart tissue such as myocarditis, inflammation of the heart muscle, or high levels of troponin months after hospitalization from COVID-19.
Berger says it’s not unusual for a virus that causes such severe inflammation to have residual consequences post-recovery—particularly among patients who had moderate or severe disease and needed to be hospitalized. Worryingly, some patients who had asymptomatic, mild, or moderate disease—including children—also have similar evidence of heart damage. (The real risk of heart inflammation to kids is from COVID-19—not the vaccine.)
Yet mounting evidence suggests that myocarditis due to COVID-19 is more rare than initially believed, de Lemos says. In September a Centers for Disease Control and Prevention study showed that the risk of myocarditis is nearly 16 times higher in patients with COVID-19 than those without. However, the study concluded that the condition is uncommon for both populations—and the risk of myocarditis from COVID-19 is just 0.146 percent. De Lemos says the condition also does heal within months.
“Most of those hearts look fairly normal when reevaluated during follow-up,” he says.
Then there are patients like Huff. Amanda Verma, a cardiologist who treated Huff at the Washington University School of Medicine’s post-COVID clinic in St. Louis, says that some patients come in with chest pain but their stress tests are normal. Others complain of palpitations, yet when equipped with heart rate monitors, their heart rhythms appear normal. Still, Verma says those tests aren’t telling the whole story.
“If you dig a little deeper, you’ll notice that the heart rate pattern isn’t quite normal,” she says. Although it’s expected for a person’s heart rate to rise while walking, it’s not normal for the heart rates of younger and athletic patients to jump from 60 to 120 just from walking across a room or while they’re asleep—which is what was happening to Huff.
This abnormal increase suggests COVID-19 triggered dysfunction in the autonomic nervous system, the pathways of nerve cells that automatically control vital functions such as breathing and the heartbeat, Verma says. It’s part of the evolutionary “fight or flight” response that allows your body to function without having to be consciously instructed. For COVID-19 long-haulers, that system appears to be out of whack.
“People often tell me they’re exhausted by the end of the day—and, yeah, who wouldn’t be if your heart rate was up that high all day?” Verma says. “It’s like you’ve been running all day.”
Scientists have yet to understand how COVID-19 might be causing this type of dysfunction. Some hypotheses suggest it could be a result of the body’s excessive inflammatory response to the virus, or perhaps it could even be related to sex hormones, since women are more likely than men to become COVID-19 long-haulers. Either way, the inability to name the syndrome makes it challenging to get insurance companies to cover treatments—and is maddening for patients who feel their symptoms are not being taken seriously.
“It’s unbelievably frustrating for patients who suffer from this because they don’t get answers,” de Lemos says. “To some extent validating that this is real is the first step. This is real illness, and we just don’t understand it yet.”
Reasons for hope
Researchers are making progress on finding treatments that could reduce the severity of COVID-19—and ultimately improve cardiovascular outcomes. Berger and his team are studying drugs that target the platelets to prevent them from activating and causing clotting.
Meanwhile, Maoz and his team have identified the five virus proteins that cause the most harm to the blood vessel lining. They are testing a model that will allow researchers to identity the proteins that inflict damage on other parts of the body. This molecular understanding will help to develop drugs that can block the specific proteins from attacking the blood vessels and causing critical illness.
“It’s amazing to see how fast we’ve been able to adapt and answer fundamental questions,” Berger says. “The speed of science has dramatically improved.”
However, he acknowledges that none of these potential drugs that would prevent the platelets from clotting or block the virus proteins from attacking the blood vessels will help people who are already suffering from long COVID. To do that, scientists ultimately need to figure out what’s behind their strange constellation of symptoms.
Earlier this year, the National Institutes of Health launched a collaborative research initiative that will support large-scale studies of long COVID-19 in children and adults. And Verma says that physicians who specialize in long COVID-19 are starting to find ways to treat it, from prescribing anti-inflammatories for chest pain to beta blockers for reducing a patient’s blood pressure when their heart rate is out of control. Even exercise—when carefully monitored and structured so that it doesn’t exacerbate fatigue—can help.
There’s also anecdotal evidence that long COVID can resolve over time—even if that may take a year to 18 months. Verma says she’s been able to take some of her patients off their medication, and many of those who haven’t recovered completely do eventually feel better after treatment
“The big question though is, is this going to impact their health in 10 or 15 years down the road?” she says. “Did it do something we just can’t see?”
For Huff, things have gotten better. After taking medications for her high blood pressure and elevated heart rate, the palpitations and shortness of breath have dissipated. Intriguingly enough, so did the frequent migraines that she’s had since she was 13. She’s still too afraid of the chest pain to go back to exercising, but she’s hopeful for the answers that ongoing research and open communication between doctors and their patients may yield as they learn together about the long-term implications of COVID-19.
“There’s a lot to learn, and I can understand the frustration with not knowing what’s going on,” she says. “But I’m at a point of acceptance that I’m just not going to have all the answers right now.”