Scientists have long been aware that respiratory infections—such as influenza or certain types of coronaviruses—can trigger heart disease. This happens because they cause inflammation, which plays a major role in cardiovascular problems.
Even before the first case of COVID-19 had been confirmed in the U.S., interventional cardiologist Mohammad Madjid began looking into the potential effects of coronaviruses on the cardiovascular system. Madjid, an associate clinical professor of medicine at the University of California, Los Angeles, expected to see a similar increase in heart complications associated with COVID. “I knew that was going to happen because I’d seen this during influenza epidemics,” he says. As far back as 2004, during the avian flu outbreaks in Asia, he urged public health organizations to consider cardiovascular issues in pandemic preparation plans.
Two years into the COVID-19 pandemic, it is becoming clear that the cardiovascular impact of SARS-CoV-2, the coronavirus that causes COVID, is not restricted to people who have had severe COVID. Even those with mild disease appear to be at a higher risk of heart problems one year after infection, according to one of the largest studies to evaluate the long-term cardiovascular outcomes of COVID. The study was published in February in Nature Medicine.
The findings surprised the researchers. “I went into this assuming there was going to be some risk but primarily in people who had very severe disease and needed to be hospitalized in the acute phase of the infection,” says co-author Ziyad Al-Aly, chief of research and development at the U.S. Department of Veterans Affairs (VA) St. Louis Health Care System and a clinical epidemiologist at Washington University in St. Louis.
A Serious Public Health Problem
Al-Aly and his colleagues crunched the numbers on heart and other cardiovascular issues during the first year after infection among 153,760 COVID patients from the national health care databases of the VA. The researchers compared these patients with two control groups: a contemporary cohort who never became infected and a historical group from before the pandemic.
Overall, the risk of any heart complication over the course of one year was 63 percent higher in people who had gotten COVID compared with those in the contemporary control group. At the end of a year, there were 45 additional cardiovascular events—such as stroke or heart failure—per 1,000 people among those who tested positive for COVID. The comparison with historical data yielded similar results: the risk of cardiovascular problems in the group that had COVID was 58 percent higher than what was seen in the prepandemic control group.
When the researchers looked at people with mild COVID specifically, they found that this group had a 39 percent higher risk of developing heart problems, compared with the contemporary control group, or 28 additional cardiovascular problems per 1,000 people in 12 months.
That is a much lower burden than that seen in COVID patients who were hospitalized or admitted to intensive care. Still, the increased risk is not trivial. Compared with those who were not infected, patients with mild disease had more than three times the risk of myocarditis, an inflammation of the heart muscle, and twice the risk of pulmonary embolism, a blood clot that ends up in a lung artery and blocks blood flow.
“It is not only surprising but also profoundly consequential that the risk is evident even in those [who had mild infections],” Al-Aly says. Such cases comprise the vast majority of COVID infections—within the study’s population, 85 percent of those diagnosed with the disease were not hospitalized. “That’s what makes this likely a serious public health problem,” he says.
A much smaller retrospective study, described in a preprint paper that has not yet published or peer-reviewed, also found that COVID patients, including asymptomatic ones, had an increased risk of cardiovascular problems six months after infection. The estimated risk of heart complications after COVID matched that seen in Al-Aly’s study, says cardiologist and biostatistician Larisa Tereshchenko, a researcher at the Cleveland Clinic Lerner Research Institute and lead author of the smaller study. “Despite differences in population and definition of outcomes, [Al-Aly’s team] came to a very similar estimate of absolute risk, which I found quite exciting because it supports the results of each study,” Tereshchenko says.
Interestingly, when another group of researchers searched for cardiovascular abnormalities in patients with mild COVID, they did not find differences in the amount or type of abnormalities in those who had had COVID versus those who had not. Thomas Treibel, an associate professor of cardiology at University College London, and his colleagues at COVIDsortium, a group of immunologists, infectious disease doctors and scientists studying the pandemic in the U.K., recruited 149 otherwise healthy health care workers. “We matched people who never had COVID with people who had COVID and put them all into an MRI [magnetic resonance imaging] scanner to look at cardiovascular damage,” he says. “Across the board, we saw no difference in the cardiac function [or] any evidence of myocarditis or heart damage. And I think that was very reassuring,” Treibel says.
How can scientists reconcile those findings? Tereshchenko believes that looking at patients’ clinical outcomes is more important than cardiac imaging in this context. “When a patient is hospitalized with heart failure, acute infarction, acute arrhythmia, cardiac arrest..., that is always more important than intermediate biomarkers” such as imaging, she says.
COVID’s Long-Term Heart Burden
While it is very likely that inflammation plays a role in the cardiovascular events seen in people with COVID, it is still a mystery why some individuals continue to be at increased risk long after SARS-CoV-2 has left their bodies.
One hypothesis is that the virus simply does not leave. “There are people who proposed the idea that the body might not fully clear the virus and will remain in its ‘preference sites,’ provoking low-grade inflammation,” Al-Aly says. Another hypothesis, he notes, is that the immune response to the virus might go awry, damaging the heart.
An important question is whether SARS-CoV-2 directly infects the heart muscle, Madjid says. Scientists have shown it is possible to infect heart cells grown in a lab dish with the virus. This finding could explain some post-COVID cardiovascular problems. “The interesting distinction between influenza and COVID is that, in COVID, we get less involvement of the heart arteries but more involvement of the heart muscle,” he says.
SARS-CoV-2 also makes the blood clot more. “We see evidence of deep vein thrombosis and pulmonary embolism. And I think that’s important because those people who have these micro clots or big clots might go on to have serious problems for a long, long time,” Al-Aly says.
There is also a growing body of evidence suggesting that COVID affects the vascular endothelium, the inner lining of blood vessels, according to cardiologist Bernard Gersh, a professor of medicine at the Mayo Clinic College of Medicine and Science. “This leads to what is called microvascular dysfunction of the small vessels, which may not dilate or constrict the way they should,” Gersh says. That could explain why long-lasting post-COVID symptoms are not restricted to the heart.
“Suffice it to say, there are many studies ongoing trying to understand the mechanisms of long COVID,” Gersh says. But researchers have yet to pin down the most likely mechanisms causing post-COVID heart disease.
Long COVID and the Heart
When it comes to “long COVID”—a constellation of symptoms, including fatigue, shortness of breath, brain fog and anxiety, that persist for several months—it is still difficult to establish an association with cardiovascular health.
“What we don’t know—and I’m speaking as a cardiologist—is how many of those patients with long COVID actually have cardiac involvement,” Gersh says. “Just because they have palpitations doesn’t mean there’s structural damage to the heart.”
It is definitely plausible that the typical presentation of long COVID, which can include fatigue and shortness of breath, may be intertwined with cardiovascular problems. For example, someone with heart failure may have reduced blood flow to the brain, which may cause brain fog. But at this point, it is difficult to disentangle that relationship, Al-Aly notes.
The problems seen in Al-Aly’s and Tereshchenko’s studies—including stroke, heart failure and acute coronary disease—are not happening only in people with recognizable long COVID. A person might have a mild case of COVID, appear to recover completely and still be at a higher risk for cardiovascular problems months down the road.
“Unfortunately, the risk estimate is high,” says Tereshchenko, adding that these studies suggest the heart risks from COVID may be on par with those from smoking.
Al-Aly agrees. “People think of cholesterol, blood pressure and diabetes as risk factors for heart problems. We need to add COVID-19 to that list,” he says.