Early in the coronavirus pandemic, alarming reports suggested that COVID-19 was more than just a severe respiratory disease. Clinicians quickly learned that the disease could have a dire impact on cardiovascular health and sometimes seemed to attack the heart directly.

Over the following months, hypotheses and speculation gave way to a solid understanding of the cardiovascular risks associated with a COVID-19. Viral infections are notorious for putting added pressure on the system in the form of inflammation, which in turn leads to adverse health outcomes such as cardiovascular injury or disease and strokes, but early data suggested that SARS-CoV-2 is exceptional.

It turns out that COVID-19 can involve a variety of cardiovascular health outcomes. Scientists from the CDC COVID-19 Response Team found that COVID-19 patients have a 16-fold increase in the risk of developing the inflammatory conditions myocarditis and pericarditis while they had COVID-19. Research published in JAMA Neurology in July 2020 identified 31 strokes among 1,683 COVID-19 patients admitted to the emergency room at two New York City hospitals, a 7.6-fold greater risk than for those who were admitted for flu. This estimate has fallen a bit as more data have accrued, but the trend is holding that SARS-CoV-2 presents a greater risk of stroke than other viruses, especially among older patients with preexisting health complications, study author and Weill Cornell Medical College neurologist Alexander Merkler tells The Scientist. Similarly, research published in The Lancet in July found that COVID-19 patients are three times more likely to have a heart attack in the week after their diagnosis than healthy controls. Many of these cardiovascular outcomes have the potential to become chronic health issues, especially among older patients or those with medical conditions such as diabetes and hypertension, according to a literature review published in Circulation Research.

“It’s not uncommon to see these cardiovascular manifestations take effect in patients with underlying heart disease or patients with severe COVID,” Aeshita Dwivedi, an assistant professor of cardiology at Lenox Hill Hospital in New York tells The Scientist.

Throughout the pandemic, scientists have been probing health records, examining patient tissue, and analyzing viral genomes in order to understand how SARS-CoV-2 affects the cardiovascular system. In addition to the high levels of inflammation associated with COVID-19, the disease can also cause hearts to enlarge as a result of how much harder they have to work during the infection, which can in turn lead to heart failure, notes Northwestern University cardiology professor Robert Bonow, who is also the editor-in-chief of JAMA Cardiology. And several studies involving autopsies and biopsies of the heart muscle and stem cell models found evidence of heart cells infected with SARS-CoV-2, indicating that the coronavirus seems to be able to injure the heart directly as well as indirectly. Meanwhile, scientists are still grappling with the possible implications of long COVID, which remains enigmatic because reliable data sets are only now starting to emerge. Also unknown is whether Omicron, now the dominant variant in the United States, will affect the heart any differently than prior variants—the best data available are still too preliminary to draw conclusions.

Manish Bansal, a cardiologist at the Medanta hospital in India, points out that overall rates of cardiovascular events related to COVID-19 are low. “So, these figures should not lead to ‘fear’,” he writes in an email, “but yes, at [the] population level, they are worrisome because COVID-19 has affected millions of people and therefore the absolute burden of cardiovascular events is going to be large.”

Runaway inflammation

SARS-CoV-2 may be unique in the level of risk it poses to the heart, but like other viruses, many of the cardiovascular risks associated with COVID-19 stem from severe inflammation, researchers tell The Scientist. UVA Health emergency cardiologist William Brady says the increase in cardiovascular health problems that doctors report encountering likely stems from the fact that COVID-19 causes particularly severe inflammation compared to other viruses. Even in the absence of a direct assault on the heart, severe inflammation is bad news for the cardiovascular system due to the added strain it imposes on the heart and the body’s vasculature.

Indeed, viral inflammation like that caused by the coronavirus seems to increase one’s risk of dying “from any cause” by accelerating the aging process, Brigham and Women’s Hospital physician and infectious disease specialist John Ross tells The Scientist over email. He cites a 2015 study in PLOS ONE that scoured the health records of 160,481 patients to link biomarkers of an inflammatory response—including C-reactive protein, albumin, and neutrophils—to a heightened risk of all-cause mortality. In the case of SARS-CoV-2, the inflammation occurs all around the body, not just in the lungs as seen with the respiratory inflammation caused by the flu. “That inflammation doesn’t spare any part of your body,” Dwivedi says.

In addition to injuring the body directly, this inflammatory response can also trigger programmed cell death: infection activates the apoptosis-directing gene caspase-8, according to an analysis of postmortem lung samples published last October.

Early on in the pandemic, SARS-CoV-2 became notorious for its ability to cause cytokine storms, severe immunological responses to infection that attack a pathogen so ferociously that they damage the body’s organs. A literature review published last March in Frontiers in Immunology suggests that the cytokine storms caused by SARS-CoV-2 are different from and more dangerous than those caused by influenzas and other coronaviruses. These storms are “unusually bad” in COVID-19, J. David Spence, a neurologist and stroke prevention expert at the Robarts Research Institute, tells The Scientist. Specifically, a Science study determined how SARS-CoV-2 infections cause dysregulation of the antimicrobial type-I interferons secreted by immune cells to fight pathogens. That leads to not only a greater number but also a greater variety of cytokines being released into the system, which results in greater immunological havoc than with other infections.

Direct infection of the heart—an open question

The inflammation caused by COVID-19 may be more severe than that caused by other viruses, but inflammation alone can’t explain all of COVID-19’s cardiovascular effects. COVID-19 causes symptoms that are different from and more diverse than those of other respiratory diseases, “which is why it’s much more complicated than the average pneumonia or influenza,” says Bonow.

He explains that COVID-19 cytokine storms cause a “hyper coagulable state” that increases the risk of blood clots, stroke, and heart attacks. In this storm-induced coagulable state, Spence says that platelets aggregate together, creating “plugs” that can get stuck in the heart or elsewhere in the circulatory system and restrict or block blood flow, although the mechanism behind the formation of these plugs hasn’t been determined yet. Bonow suggests that cytokine storms contribute in some way to this coagulable state and what he calls “intense blood clotting” during COVID-19.

See “The Specter of Endothelial Injury in COVID-19

There’s also accumulating evidence that the coronavirus can infect human cardiomyocytes, the heart’s muscle cells. However, several of the studies probing this direct infection phenomenon were inconclusive, experts say. It’s difficult to draw conclusions from stem cell models because the human body behaves very differently from cells in a dish, Cincinnati Children’s Hospital molecular cardiovascular biologist Kelly Grimes tells The Scientist in an email, and “squirting a ton of virus on some cardiomyocytes” isn’t a good model for how those cells might encounter the virus in the body.

As of yet, it’s unclear whether viral infection of heart cells is causing any of COVID-19’s symptoms or factoring into disease severity, Grimes adds. “Determining if the cells get directly infected by the virus will allow us to understand if the dysfunction we’re finding in them is a primary or secondary effect of the virus.”

“So, is there a direct injury effect of the virus on the myocardium?” says Brady. “I think the thought is yes there is, but . . . we need to understand more about the direct effect of the virus on the myocardium. That’s not conclusively sorted out.”

Long-term implications

However the damage is inflicted, if the heart muscle, or myocardium, suffers injury, it could lead to a “large number of people with weak hearts” over time, potentially leading to chronic health conditions or an uptick in heart attacks in the future, Bonow says.

Multiple researchers tell The Scientist that they expect to see the bulk of these problems among patients who had underlying health issues before catching COVID-19. But Brady notes that there’s not a scientific consensus regarding whether COVID-19 causes new cardiovascular issues that wouldn’t have happened on their own or if it’s inducing these health problems among those who had preexisting risk factors.

More generally, as they look toward the future of the pandemic and beyond, researchers are now trying to chase down the disease’s long-term implications, Bonow says. “I think there’s still a lack of understanding of what long COVID is all about,” he says. “Everybody’s in the knowledge-gathering stage regarding longer-term effects at this point.”

See “Mechanisms of Long COVID Remain Unknown but Data Are Rolling In

However, the general consensus within the scientific literature is that COVID-19 cases are associated with an uptick in cardiovascular health problems in the long run. An April 2021 paper from the American College of Cardiology highlights patient reports of cardiopulmonary symptoms such as fatigue long after their coronavirus infections waned, and an October review in Nature Reviews Cardiology suggests that long COVID can cause an increased risk of heart palpitations and arrhythmias.

“Maybe it shouldn’t be that surprising that COVID, which causes a very severe and very prolonged inflammatory state, is associated with a high risk of heart problems over a long period of time,” Ross says. However, Bonow notes, determining whether a cardiovascular complication was caused by an acute injury that happened to manifest later on or if it’s actually tied to long COVID is difficult. Part of the difficulty, says Dwivedi, is that “long COVID is really a diagnosis of exclusion,” meaning that clinicians need to rule out the myriad other explanations for a patient’s symptoms before attributing them to a past SARS-CoV-2 infection.

Several clinicians tell The Scientist that they’ve witnessed an increase in cardiovascular health issues among the general population as the pandemic progressed. Indeed, research published in the American Heart Association journal Circulation in May of last year identified an atypical annual increase in deaths caused by heart disease and cerebrovascular diseases in 2020. These could stem from a drop in the number of doctor visits among people who wanted to avoid hospitals lest they get exposed to the coronavirus, experts say.

The confusion surrounding long COVID illustrates how much is left to learn about COVID-19 across the board. The first cases of the disease emerged at the end of 2019, and while it may not feel that way to those living through the pandemic, two years is an extremely short time when it comes to determining the long-term effects of a new disease.

“For most other diseases, we have years and years of data,” says Dwivedi. “This disease—barely any time has passed by.”

What about vaccines?

When it comes to prevention and mitigation of cardiovascular outcomes caused by COVID-19, all eyes are on the continued performance of the various vaccines approved for use.

As with the long-term effects of COVID-19, it’s too early in the pandemic to know whether vaccines will help stave off secondary health outcomes such as cardiovascular complications in people who get breakthrough infections. Figuring out whether that’s the case is a top priority for many researchers and clinicians, experts tell The Scientist, but not nearly enough time has passed since the vaccine rollout began to offer a definitive answer. Still, many offered up the hypothesis that vaccination will, in fact, help prevent problems including strokes, heart attacks, and heart disease, pointing to the vaccines’ ability to lessen the severity of SARS-CoV-2 infections.

“If I were to be a betting person, I would say the incidence of cardiovascular complications should be lower in patients after vaccination,” says Aeshita Dwivedi, an assistant professor of cardiology at Lenox Hill Hospital in New York. “The vaccine kind of blunts the severity of the disease, so it can be hypothesized that vaccination should reduce the cardiovascular burden of COVID. But it’s a little too soon to say.”

Columbia University neurologist Mitchell Elkind, a former president of the American Heart Association, agrees. He tells The Scientist that “most complications are associated with the course of the disease. It stands to reason that vaccination will lessen the chance of any secondary cardiovascular complication of COVID.”