Getting to the heart of COVID-19-related cardiac injury
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The ability of COVID-19 to cause cardiac injury and myocarditis has been well documented since the pandemic began, and data continue to accumulate.
“We certainly know that COVID-19 has a long-term effect, or ‘long COVID’, which is the systemic disease that even patients with mild COVID-19 can develop,” Howard J. Eisen, MD, senior advanced heart failure specialist at Penn State Medical Center, told Cardiology Today. “They can be fatigued, have a shortness of breath, drops in blood pressure, elevated heart rates. And a lot of that is thought to maybe be due to autoimmune phenomena and enhanced inflammation. But one thing we know is that myocarditis can, in some patients, develop into heart failure. A lot of these patients who we see who have what we call idiopathic dilated cardiomyopathy ... we suspect that they have myocarditis.”
As research continues and new information evolves, Cardiology Today spoke with experts in the field about COVID-19-related outcomes on the heart, the risks for myocardial injury as a result of COVID-19 and with vaccination, based on the current knowledge base, and more.
‘A spectrum of injury’
Numerous studies have reported cardiac injury as a result of COVID-19.
Early reports uncovered evidence of cardiac injury in 25% to 30% of patients hospitalized for COVID-19, Biykem Bozkurt, MD, PhD, FHFSA, FACC, FAHA, FESC, Mary and Gordon Cain Chair and Professor of Medicine, director of the Winters Center for HF Research and associate director of the Cardiovascular Research Institute at Baylor College of Medicine, said during a presentation at the Heart in Diabetes meeting in September. Additionally, cardiac injury was most common among patients with preexisting CVD, and elevated levels of CVD biomarkers such as troponin were associated with mortality, Bozkurt said.
“COVID-19 myocarditis is in many ways similar to myocarditis caused by other viruses, but the SARS-CoV-2 virus stands out through its predilection for ACE2 receptors, present in the endothelium as well as in many other organs,” Mariska Kemna, MD, heart failure and transplant cardiologist at Seattle Children’s Hospital and professor of pediatrics at the University of Washington School of Medicine, told Cardiology Today. “SARS-CoV-2 also appears to be more immunogenic than other viruses, leading to severe multi-organ disease in adults and multisystem inflammatory syndrome in children and teens. A hyperimmune response to vaccinations may be part of that clinical picture as well.”
In a study published in the European Heart Journal in May, myocardial injury was detected in more than half of patients hospitalized with severe COVID-19, and elevated cardiac troponin persisted months after hospital discharge.
“Troponin levels are easy to obtain. While an elevated level indicates cardiac injury, it does not necessarily equate to myocarditis,” Kemna told Cardiology Today. “Myocarditis can present in many different ways. For COVID-19, cardiac inflammation may be part of a multi-organ inflammatory response or there may be endotheliitis leading to cardiac injury, and it can be challenging to distinguish between those and true myocarditis.”
Researchers continue to investigate the mechanisms underlying COVID-19-related myocardial injury as well as the direct effect of COVID-19 on the heart.
In the Sept. 3 issue of the CDC’s Morbidity and Mortality Weekly Report, researchers reported the incidence of myocarditis in a database of more than 900 hospitals was 42% higher in 2020 compared with 2019, and from March 2020 to January 2021, the risk for myocarditis in patients with COVID-19 was 16 times greater compared with patients without COVID-19.
In another analysis published in JAMA Cardiology in May, researchers evaluated the prevalence of post-COVID-19 myocarditis among collegiate athletes using the Big Ten COVID-19 Cardiac Registry. After cardiac MRI, approximately 2.3% of athletes were diagnosed with clinical or subclinical myocarditis.
In that study, “It became clear that a small percentage of people, maybe 4.5% in the older population with preexisting heart disease and a smaller percentage of young athletes, could actually have myocarditis as defined by a cardiac MRI, and that the majority of the cardiac injury was due to other mechanisms,” Leslie T. Cooper Jr., MD, FAHA, professor of medicine and chair of the cardiovascular department at Mayo Clinic in Jacksonville, Florida, and past president of the Myocarditis Foundation, told Cardiology Today. “Other mechanisms of cardiac injury include blocked large and small arteries, demand ischemia or cytokine storm, in which the heart function is depressed because of systemic inflammatory mediators, as well as another, not yet defined group of novel mechanisms, which could be virus-specific. We and others have shown that the spike protein, which is produced by the virus, can cause cardiac damage directly in isolated heart cells, but without any myocarditis. There’s a spectrum of injury mechanisms, a minority of which is due to classic myocarditis.”
Cardiac injury in pediatric patients
In the MMWR study, risk for myocarditis in patients with COVID-19 was higher among men than women (0.187% vs. 0.109%), was higher in children younger than 16 years (0.133%) and was elevated in adults aged 50 to 64 years (0.155%), 65 to 74 years (0.186%) or 75 years or older (0.238%).
“As of July 9, 2021, there were more than 4 million cases of COVID-19 in children and at least 335 deaths. As of October 14, the total number of COVID-19 cases in children was even higher at 6.2 million,” Sandra Adamson Fryhofer, MD, adjunct professor of medicine at Emory University School of Medicine, and the AMA liaison to the CDC Advisory Committee on Immunization Practices, told Cardiology Today. “Young people with COVID-19 are at risk for multisystem inflammatory syndrome in children and for post-COVID-19 conditions, including persisting symptoms, such as fatigue, insomnia, rhinorrhea, muscle pain, headache, lack of concentration, exercise intolerance, dyspnea and chest pain. It seems adolescents and young adults can have long COVID-19, too.”
The American Heart Association July scientific statement on the diagnosis and management of myocarditis in children indicated that myocarditis in children is most commonly caused by viral infection, although there are a variety of noninfectious causes, and this risk is highest among infants and young adults. According to the statement, pediatric myocarditis is typically acute or sudden-onset and less likely to be chronic compared with adult myocarditis.
Multisystem inflammatory syndrome in children (MIS-C) is a serious potential complication after COVID-19 infection, according to a report published by Nemours Children’s Health.
“Children with COVID-19 can present with MIS-C around 4 to 6 weeks after they’ve had COVID-19 and sometimes they didn’t even realize they had COVID-19,” Kemna told Cardiology Today. “There are instances when they can get critically ill from MIS-C, and require inotropic support or mechanical ventilation, all due to an overactivation of their immune system. Fortunately, it responds well to anti-inflammatory therapy such as IV immunoglobin and steroids. While they can become extremely ill quickly, sometimes even overnight, they often recover just as quickly.”
Causes of myocarditis
COVID-19 is not the only cause of myocarditis.
According to the Myocarditis Foundation, although the leading trigger is viral infections, cancer, bacterial infections and exposure to environmental toxins can also cause myocarditis.
“Common causes of ‘traditional’ myocarditis include infectious agents — viral, bacterial, fungal, parasitic, protozoal — and noninfectious agents, including toxins, certain medications and immunological syndromes,” Fryhofer told Cardiology Today. “In general, we see a gradual increase in the incidence of myocarditis with age, with 76% of adult cases in males. However, children can also suffer myocarditis. The annual incidence in children is 0.8 per 100,000 and is more common in males.”
Compared with myocarditis as a result of H1N1 influenza or coxsackie B myocarditis, “COVID-19-related myocarditis is not as severe. Overall, COVID-19 tends to cause a milder injury with faster recovery,” Cooper told Cardiology Today. “Although, there is a small percentage of people who are critically ill and there is also a small percentage of people who go on to have a more chronic recurrent pattern over months to years of chest pain. That is true for all forms of myocarditis, including, as far as we know, COVID-19-related myocarditis.”
Troponin testing and cardiac MRI are not routinely conducted for most other viral infections, according to a commentary by Maleszewski and colleagues published in Circulation in September 2020. There is a need for more clinical data to effectively compare COVID-19-related myocarditis with myocarditis caused by other infections and diseases.
“It’s well known that the flu and a number of other viruses [can cause myocarditis], so there’s no reason why COVID-19 couldn’t either,” Eisen said. “It’s thought COVID-19 may do a number of things. It may directly damage the heart muscle cells, and we can actually see that on MRI. It can also directly affect the endothelial cells, and therefore can damage to the circulation and can cause clots in those arteries, too.”
According to the AHA scientific statement on myocarditis, the signs of fulminant myocarditis can vary with or without manifestations of an inflammatory disorder or infection. Timely diagnosis and treatment are critical. The first test for myocarditis should be echocardiography, which can rapidly process a diagnosis, and cardiac MRI in this population should be considered secondary since most patients would be too sick to have an MRI, and biopsy is more important.
Vaccines and myocarditis
On May 27, the CDC issued a statement on the possible association between COVID-19 vaccination and risk for myocarditis for both of the available messenger RNA (mRNA) vaccines.
“There is risk for myocarditis after mRNA COVID-19 vaccines, but myocarditis can also occur with COVID-19 infection, and it occurs at higher rates after COVID-19 infection than after mRNA vaccination,” Fryhofer told Cardiology Today. “Data reviewed at the recent Advisory Committee on Immunization Practices meeting on Aug. 30, 2021, revealed patients with COVID-19 had 16 to 18 times higher risk for myocarditis compared to those without COVID-19. Risk did vary by age and sex. Risk of myocarditis due to COVID-19 infection was six to 34 times higher compared to those who received an mRNA vaccine.”
Researchers continue to investigate the link. Recent research suggests that although COVID-19 mRNA vaccines can be associated with myocarditis, particularly in male adolescents and young adults, the incidence is very low, and the severity is usually less than that of COVID-19-induced myocarditis and other cardiac injuries.
Some of the recent research includes a nationwide study published in October in The New England Journal of Medicine. The Pfizer-BioNTech mRNA COVID-19 vaccine was not associated with risk for most adverse events; however, the vaccine was associated with risk for myocarditis of between one and five events per 100,000 persons.
In October, a retrospective analysis published in NEJM utilized the Clalit Health Services database to identify 2.5 million individuals in Israel who received the Pfizer-BioNTech mRNA vaccine, of whom 54 met the criteria for myocarditis. The estimated incidence of myocarditis among individuals who received at least one dose of the vaccine was 2.13 per 100,000 persons, with the highest incidence reported among young men aged 16 to 29 years.
The researchers acknowledged the incidence rates were higher than those reported elsewhere. “Although we cannot directly compare the incidence of myocarditis after vaccination in our study with the incidence in other studies, our data may provide points of reference,” Guy Witberg, MD, interventional cardiologist at the Rabin Medical Centre in Petah-Tikva, Israel, and colleagues wrote. “On the basis of data from the Vaccine Adverse Event Reporting System, the CDC has estimated that the incidence of myocarditis after any COVID-19 vaccination is 0.48 cases per 100,000 overall and 1.2 cases per 100,000 among vaccine recipients between the ages of 18 and 29 years. These estimates are lower than those in our study, possibly due to different methods that were used to identify cases (passive reporting to the CDC vs. electronic health records in our health care organization).”
A similar study from Israel, also published in NEJM in October, estimated that the rate ratio of myocarditis at 30 days after the second dose of the Pfizer-BioNTech vaccine was 2.35 compared with unvaccinated individuals. Again, the incidence was highest for young men aged 16 to 19 years, compared with unvaccinated young men.
A research letter published in October in JAMA Internal Medicine evaluated excess risk for myocarditis as a result of COVID-19 vaccination among more than 2.3 individuals who received at least one dose of the Pfizer-BioNTech or Moderna vaccine. The researchers reported a myocarditis incidence of 5.8 per 1 million individuals after the second dose, or one case per 172,414 fully vaccinated individuals. However, due to the observational nature of this analysis, the researchers stated that no associations between COVID-19 vaccination and incident myocarditis can be established.
“One hypothesis that has been postulated is so-called molecular mimicry, in which parts of the spike proteins that are being expressed as a result of mRNA vaccination are similar to some myocardial proteins, and the antibodies we make in response to the spike protein could cross-react with myocardial proteins,” Kemna told Cardiology Today. “The other hypothesis is that the spike proteins that we produce as a result of mRNA vaccination could bind directly to the ACE2 receptors, activating the inflammatory response in the same manner the virus can.”
According to a presentation at the Aug. 30 CDC Advisory Committee on Immunization Practices meeting by John R. Su, MD, PhD, MPH, Vaccine Adverse Event Reporting System (VAERS) team lead at the CDC and a member of the Vaccine Safety Team of the CDC’s COVID-19 Vaccine Task Force, there had been more than 2,500 reports to VAERS of myocarditis or pericarditis (out of more than 350 million doses of mRNA COVD-19 vaccines administered).
These reports were primarily in younger males, after the second mRNA vaccine dose, and within several days after vaccination. Research and conversations about the impact of COVID-19 on the heart continue.
“It is important to consider myocarditis in young people who experience chest pain, shortness of breath or palpitations after mRNA vaccination,” Fryhofer told Cardiology Today. “Report all cases to VAERS. In the initial evaluation, consider checking ECG, troponin and inflammatory markers like C-reactive protein and erythrocyte sedimentation rate.”
In October, the FDA delayed its decision on approving the Moderna vaccine for adolescents aged 12 to 17 years to further review data on vaccine-induced myocarditis risk in that population. The Pfizer-BioNTech vaccine is approved for that age group, and in October was approved for children aged 5 to 11 years.
Importance of vaccination
“It’s clear that vaccination reduces your chance of getting myocarditis,” Kemna told Cardiology Today. “You can get myocarditis from the vaccine, but you can also get myocarditis from COVID-19, even if you’re not in the hospital, you’re not terribly ill and you might never have known that you had it unless you had an MRI.”
The AHA/American Stroke Association released a statement in early November urging adults and children aged 5 years and older to receive a COVID-19 vaccine.
“Vaccination at the individual and the population level is essential to minimize the impact of COVID-19 and people should not avoid vaccination because of a fear of vaccine-related cardiac injury,” Cooper told Cardiology Today.
“In rare occasions, the vaccine may cause some inflammation in the heart, but not anything like what COVID-19 does, and COVID-19 does all sorts of other horrible things,” Eisen told Cardiology Today. “We know that 99% of patients who are dying, hospitalized, intubated and on ventilators in this country are unvaccinated. There’s a certain amount of fatigue among nurses and physicians taking care of people who could prevent all of this by just getting vaccinated. We’ve conquered other diseases such as polio and smallpox, all of which were catastrophic in their day, and we did it through vaccination. I urge people to get vaccinated.” – by Scott Buzby
- References:
- 3rd COVID-19 vaccine dose recommended for heart transplant patients and others with weakened immune systems. newsroom.heart.org/news/3rd-covid-19-vaccine-dose-recommended-for-heart-transplant-patients-and-others-with-weakened-immune-systems. Published Aug. 17, 2021. Accessed Oct. 3, 2021.
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- Bozkurt B. COVID-19. Presented at: Heart in Diabetes Annual Meeting; Sept. 10-12, 2021; New York (hybrid meeting).
- Cooper LT. COVID-19 and mRNA Vaccine Related Cardiac Injury. Presented at: Orlando Heart Grand Rounds. Sep. 16, 2021; Orlando.
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- Discover Myocarditis Causes, Symptoms, Diagnosis and Treatment. www.myocarditisfoundation.org/about-myocarditis. Accessed Oct. 12, 2021.
- FDA. Vaccines and Related Biological Products Advisory Committee Sept. 17, 2021, Meeting Announcement. www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-september-17-2021-meeting-announcement. Accessed Oct. 4, 2021.
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- Merck and Ridgeback’s investigational oral antiviral molnupiravir reduced the risk of hospitalization or death by approximately 50 percent compared to placebo for patients with mild or moderate COVID-19 in positive interim analysis of phase 3 study. www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/. Published Oct. 1, 2021. Accessed Oct. 3, 2021.
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- MIS and COVID-19. www.cdc.gov/mis/index.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fmis-c%2Findex.html. Page last re-viewed June 25, 2021. Accessed Oct. 3, 2021.
- NCDR Chest Pain – MI Registry, CathPCI Registry to collect COVID-19 data. www.acc.org/latest-in-cardiology/articles/2020/05/11/10/42/ncdr-chest-pain-mi-registry-cathpci-registry-to-collect-covid-19-coronavirus-disease-2019-data. Published May 11, 2020. Accessed Oct. 3, 2021.
- Pfizer and BioNTech submit initial data to U.S. FDA from pivotal trial of COVID-19 vaccine in children 5 to <12 years of age. www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-submit-initial-data-us-fda-pivotal. Published Sept. 28, 2021. Accessed Oct. 4, 2021.
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- A serious complication of COVID-19: Multisystem inflammatory syndrome in children (MIS-C). www.nemours.org/content/nemours/wwwv2/health-professionals/covid-info-for-community-physicians/mis-c.html. Accessed Oct. 3, 2021.
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- What you need to know about COVID-19 vaccines with Sandra Fryhofer, MD. www.ama-assn.org/delivering-care/public-health/what-you-need-know-about-covid-19-vaccines-sandra-fryhofer-md. Published Sep. 30, 2021. Accessed Oct. 3, 2021.
- Witberg G, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2110737.
- For more information:
- Leslie T. Cooper Jr., MD, FAHA, can be reached at cooper.leslie@mayo.edu.
- Howard J. Eisen, MD, can be reached at heisen@pennstatehealth.psu.edu.
- Sandra Adamson Fryhofer, MD, can be reached at sandra@drsandrafryhofer.com; Twitter: @DrSandyFryhofer.
- Mariska Kemna, MD, can be reached at mariska.kemna@seattlechildrens.org.
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