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On the track of new approaches to myocarditis

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Amy Carpenter Aquino

May 2022—Studies show promise for new approaches to biomarkers for myocarditis diagnosis, one of which is circulating micro­RNA mmu-miR-721.

Another biomarker, sera soluble ST2 (sST2), which has been found to be clinically useful in predicting heart failure, could be added to existing biomarkers used to diagnose patients with myocarditis, interpreted according to sex and age.

And serial high-sensitivity troponin measurements might be another approach to diagnosing and monitoring myocarditis.

Authors of the microRNA study investigated the expression of novel miRNAs by Th17 cells, which play an important role in myocarditis and myocardial infarction, and they detected in mice and humans an miRNA (mmu-miR-721 in mice, hsa-miR-Chr8:96 in humans) that could be used to differentiate the two (Blanco-Domínguez R, et al. N Engl J Med. 2021;384[21]:2014–2027). Additional study is needed, and the miR-721 has not yet been evaluated in other cardiac disorders, such as dilated cardiomyopathy, from which myocarditis must be distinguished in the clinical setting, the authors write.

Dr. Li

The miRNA reported in the 2021 study dramatically increased clinical sensitivity and specificity for the diagnosis of myocarditis, says Jieli Shirley Li, MD, PhD, D(ABCC), assistant professor in the Department of Pathology, Ohio State University Wexner Medical Center, who was not involved in the research. Dr. Li highlighted the study in her virtual presentation at last year’s AACC meeting and shared her view about this and more with CAP TODAY recently.

The challenges associated with invasive endomyocardial biopsy have been the impetus for studies on noninvasive methods for diagnosing myocarditis, Dr. Li says. Past studies on miRNA in humans or animals with myocarditis reported that the miRNAs were not specific for myocarditis, the pathophysiology of which is complex, she says. “The inflammation and/or necrosis of cardiac tissues could happen at a very close time or in a certain time order, or mixed, happening at the same time,” Dr. Li explains. “We can see the similar trend of dynamic changes of troponin with the dynamic changes of inflammation biomarkers, but we are not able to confirm that troponin can differentiate myocarditis and myocardial infarction. The finding of novel microRNA”—the human homologue, designated as hsa-miR-Chr8:96—“can make it and fill the hole.”

Myocarditis is an autoimmune inflammatory disorder post a viral infection, and the microRNA study showed that one immune pathway, interleukin-17 in type 17 helper T cells (Th17), is important in causing fibrosis. “And that’s been shown to be important in what happens in some people as they go from myocarditis to dilated cardiomyopathy [DCM],” said DeLisa Fairweather, PhD, director of translational research, Department of Cardiovascular Diseases, Mayo Clinic, Jacksonville, Fla., and a coauthor of the study, in a recent interview.

Acute myocarditis is sometimes missed in the clinical setting and caught later as it progresses to dilated cardiomyopathy, she notes. Th17-type responses facilitate remodeling that leads to dilated cardiomyopathy—“it’s kind of post-acute myocarditis,” she explains. “The animal studies have shown that Th17 responses are important in promoting the transition from myocarditis to DCM.

“So our collaborator in Spain looked at the presence of the miR in people,” she continues. “We also looked for the miR in our viral model, which helped to further establish that this was not just a fluke,” but instead present in patients and virally induced animal models of myocarditis. The collaborator then confirmed the finding of the human miR in several hospitals where they had groups of samples of patients.

All of this connects to soluble ST2, Dr. Fairweather, a coauthor of the ST2 study, says (Coronado MJ, et al. J Am Heart Assoc. 2019;8[2]:e008968). “They’re all in a linear progression,” she explains, referring to the pathogenesis of disease. TLR4 [Toll-like receptor 4] is early in the acute phase and leads to IL-1 beta production, and part of that family is the ST2 receptor. The cytokine that activates the ST2 receptor is IL-33. What follows next is IL-6 and Th17. “You start off with macrophages—TLR4, IL-1 and IL-6, IL-33 and ST2—and that progresses to the next phase of a Th17 response, where you go on to dilated cardiomyopathy, and then the Th17 response becomes really important,” Dr. Fairweather says.

In the ST2 study of myocarditis patients, Dr. Fairweather and her coauthors found that sera sST2 levels were higher in men and women with clinically suspected myocarditis and biopsy-confirmed myocarditis compared with healthy individuals who did not have cardiovascular disease. They found that elevated sST2 levels were associated with worse heart failure symptoms in patients with myocarditis based on New York Heart Association class, similar to the findings of other heart failure studies, but in their study the association was seen only in men (age 50 and under), not women. Myocarditis and DCM are known to occur more often in men than women.

“So the sST2 level,” Dr. Li said in her AACC presentation, “might be the potential diagnostic biomarker for myocarditis with age- and sex-specific criteria.”

“What we find with myocarditis,” Dr. Fairweather says, “as has been found also with other allergy or inflammatory conditions, is that sST2 is protective and IL-33 makes disease worse. We had published that before—that if you gave recombinant IL-33, it induced a type of eosinophilic myocarditis that is similar to giant cell myocarditis,” a more fatal form of myocarditis. Giving recombinant sST2, on the other hand, “inhibited that process, so that’s kind of the two working together.”

With that background, “we were really interested because sST2 has been shown for a number of other types of heart failure to be a biomarker in the sera,” says Dr. Fairweather, who is also associate professor of medicine, Mayo Clinic College of Medicine and Science.

Nothing had been published about the sex differences related to sST2, she says. “The whole pathway of TLR4/IL-1, and ST2/IL-33, and even Th17 and IL-6/TGFβ/IL-17—all pathways that are found to promote acute myocarditis and progress to dilated cardiomyopathy—are elevated in males and not in females in the animal model. And now as we’re doing translational studies looking at people, we’re finding the same thing.” Finding the age difference (under or over age 50) was also significant, she adds. “We’re trying to understand that better and pursuing studies in that area,” Dr. Fairweather says.

Awareness of myocarditis among the public is higher now because of its relationship with COVID-19, she says. “They didn’t know what it was before, and the cases are much more common and it’s spurred more interest and research.” Myocarditis was always known to be caused by viruses, she says, but the association with SARS-CoV-2 “has proven without any doubt such a direct relationship.”

All that she and others knew from their myocarditis research was seen in COVID-19 patients who had myocarditis, she says—“the type of immune response, involvement of complement and thrombotic responses, elevated cytokines/cytokine storm, and the increased occurrence in males compared with females. It’s the same mechanisms and the same pathway. So I think sST2, as far as the COVID myocarditis, would be the same as what we had been studying for the role of ST2 and other biomarkers.”

Myocarditis has an autoimmune component, she says, “so virus has always been speculated to cause autoimmune disease.” She has written extensively about how viruses can cause autoimmune disease, “but it’s been difficult to prove.” Here too COVID has helped to shed light: “It’s really shown how viruses can cause autoimmune disease.”

Dr. Fairweather

Opinions vary on how much SARS-CoV-2 has caused myocarditis, and the discussion is based on what is known as the Dallas criteria, developed in the 1980s. “It requires that if you take a biopsy, you see both inflammation and necrosis. But from our basic research studies, you don’t need necrosis at all for the presence or development of cardiomyopathy and heart failure related to myocarditis,” she says. “The chances of finding those two together in biopsies are low.” That reduces the number of myocarditis diagnoses found with autopsy or in biopsies. “I think the rate of cardiac inflammation would be much higher post-COVID” without the necrosis requirement, she says.

Dr. Fairweather notes the importance of mitochondria and the role of the virus with mitochondria, which has to do with aging “and why myocarditis is such a beautiful example of this situation with aging.” She is studying how mitochondria drives the sex difference in disease and myocarditis, she says, adding that publications to come will highlight how important it is.

Even though heart failure is the No. 1 killer of women, it happens later in life in women compared with men. “Women are really protected against heart failure by estrogen,” Dr. Fairweather says.

“That’s a big sex difference: Women have a big advantage as far as the heart goes. And we find that estrogen/estrogen receptor and estrogen-related receptor are important in protecting the heart after viral infection during myocarditis in women and women upregulate just about everything that can help the heart including healthy mitochondria.” Testosterone increases the inflammatory response, she says, and estrogen dampens the response and offers protection.

Based on the most recent expert consensus published in 2020, recommended lab tests for suspected acute myocarditis include myocardial damage biomarkers, which are high-sensitivity troponins and CK-MB, Dr. Li said in her AACC presentation, though “there is weak correlation between troponin release and the severity of cardiac function” (Ammirati E, et al. Circ Heart Fail. 2020;13[11]:e007405). Others are CRP, ESR, CBC with differential, serological and virological tests (“rarely informative,” she said), PCR, and autoantibodies. For SARS-CoV-2 vaccination-induced myocarditis, the CDC lists troponin level above normal limit as a laboratory evaluation criterion in its guidelines for diagnosis. “So troponin is a relatively more specific cardiac biomarker in the diagnosis of myocarditis, even in the course of COVID-19 vaccination,” said Dr. Li, who is also co-director of the OSU clinical chemistry and toxicology laboratory.

In a 1997 study, troponin and CK-MB were measured in patients with biopsy-proven myocarditis (Smith SC, et al. Circulation. 1997;95[1]:163–168). “The troponin values were significantly greater in patients with myocarditis. In contrast, CK-MB levels were not significantly elevated,” she said. “So troponin has a better sensitivity than CK-MB for the diagnosis of myocarditis.”

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