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Myocarditis in Clinical Practice—Part II

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Cardiology".

Deadline for manuscript submissions: closed (25 November 2023) | Viewed by 32926

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Dr. Andrea Frustaci

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Guest Editor

Cellular and Molecular Cardiology Lab, National Institute for Infectious Diseases L. Spallanzani, Rome, Italy
Interests: myocarditis; cardiomyopathies; heart failure; endomyocardial biopsy
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Special Issue Information

Dear Colleagues,

Myocarditis continues to receive great attention from researchers among the diseases affecting the cardiovascular system, leading to the potential development of new areas of interest.

Myocardial inflammatory damage from anti-cancer drugs, new infectious agents such as COVID-19, and myopericarditis following COVID-19 vaccination are some of the most pressing issues nowadays. Especially regarding COVID-19 infection, mechanisms of myocarditis derived from a direct action of an involved agent or an immune-mediated pathway, including the intravascular precipitation of immune complexes, are still under investigation. Similarly, around 1% of patients who receive COVID-19 vaccination develop myopericarditis that is usually benign and self-remitting, with the rare occurrence of cardiogenic shock and sudden death. Therefore, it is crucial to determine which patients are potentially susceptible to this complication. Many patients subject to histology have an eosinophilic myocardial infiltration, which begs the question: Is an allergic response to some epitopes of spike proteins that act as Hapten-forming new antigens associated with the molecular complexes of the cardiac cell membrane? Generally, an increase in plasma cationic proteins that may be used to identify this type of myocarditis is observed. These proteins also seem to respond to moderate doses of steroids administered for 3-4 weeks.

A current hot topic regarding myocarditis is the attempted non-invasive diagnosis of myocarditis by analyzing gene expression profiles of cardiomyocytes and peripheral lymphocytes with the intent of identifying common patterns. Molecular investigations of a blood sample could help to establish an early, accessible and safe identification of myocarditis. Hopefully, even the type of myocardial inflammation, whether infectious or auto-immune, could be obtained.

Of course, we are aware of certain difficulties that we are faced with in this research. Nevertheless, these challenges require innovative research. Therefore, we invite researchers to submit articles that cover the latest advances in this field to this Special Issue, which aims to expand and share this important topic with the scientific community.

Dr. Andrea Frustaci
Guest Editor

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Keywords

new insights into myocarditis from anti-cancer drugs
COVID-19-related post-vaccination myopericarditis
non-invasive diagnosis

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Published Papers (9 papers)

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Editorial

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2 pages, 155 KiB

Open AccessEditorial

Remarks on Myocarditis Associated with COVID-19 Infection and Myocarditis Following mRNA COVID-19 Vaccination

by Andrea Frustaci

J. Clin. Med. 2022, 11(21), 6511; https://doi.org/10.3390/jcm11216511 - 2 Nov 2022

Cited by 1 | Viewed by 1900

Abstract

COVID-19 virus infection is responsible for one of the worst reported pandemics as of August 2022 [...] Full article

(This article belongs to the Special Issue Myocarditis in Clinical Practice—Part II)

Research

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22 pages, 4767 KiB

Open AccessArticle

Myocarditis and Pericarditis Post-mRNA COVID-19 Vaccination: Insights from a Pharmacovigilance Perspective

by Abdallah Alami, Paul J. Villeneuve, Patrick J. Farrell, Donald Mattison, Nawal Farhat, Nisrine Haddad, Kumanan Wilson, Christopher A. Gravel, James A. G. Crispo, Santiago Perez-Lloret and Daniel Krewski

J. Clin. Med. 2023, 12(15), 4971; https://doi.org/10.3390/jcm12154971 - 28 Jul 2023

Cited by 4 | Viewed by 7803

Abstract

Concerns remain regarding the rare cardiovascular adverse events, myocarditis and pericarditis (myo/pericarditis), particularly in younger individuals following mRNA COVID-19 vaccination. Our study aimed to comprehensively assess potential safety signals related to these cardiac events following the primary and booster doses, with a specific focus on younger populations, including children as young as 6 months of age. Using the Vaccine Adverse Events Reporting System (VAERS), the United States national passive surveillance system, we conducted a retrospective pharmacovigilance study analyzing spontaneous reports of myo/pericarditis. We employed both frequentist and Bayesian methods and conducted subgroup analyses by age, sex, and vaccine dose. We observed a higher reporting rate of myo/pericarditis following the primary vaccine series, particularly in males and mainly after the second dose. However, booster doses demonstrated a lower number of reported cases, with no significant signals detected after the fourth or fifth doses. In children and young adults, we observed notable age and sex differences in the reporting of myo/pericarditis cases. Males in the 12–17 and 18–24-year-old age groups had the highest number of cases, with significant signals for both males and females after the second dose. We also identified an increased reporting for a spectrum of cardiovascular symptoms such as chest pain and dyspnea, which increased with age, and were reported more frequently than myo/pericarditis. The present study identified signals of myo/pericarditis and related cardiovascular symptoms after mRNA COVID-19 vaccination, especially among children and adolescents. These findings underline the importance for continued vaccine surveillance and the need for further studies to confirm these results and to determine their clinical implications in public health decision-making, especially for younger populations. Full article

(This article belongs to the Special Issue Myocarditis in Clinical Practice—Part II)

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13 pages, 2026 KiB

Open AccessArticle

Comparative Efficacy and Safety of Mycophenolate Mofetil and Azathioprine in Combination with Corticosteroids in the Treatment of Lymphocytic Myocarditis

by Olga Blagova, Ruslan Rud’, Evgeniya Kogan, Alexander Zaitsev and Alexander Nedostup

J. Clin. Med. 2023, 12(15), 4913; https://doi.org/10.3390/jcm12154913 - 26 Jul 2023

Cited by 3 | Viewed by 1762

Abstract

Aims: This paper aimed to study the efficacy and safety of mycophenolate mofetil (MM) in combination with corticosteroids in the treatment of lymphocytic myocarditis (LM) when compared to the standard combination of corticosteroids and azathioprine. Methods. The study included 50 adult patients (47.8 ± 10.8 y.o.) in a NYHA III functional class due to LM who were verified using endomyocardial biopsy. The main group included 29 patients who received MM at 2 g/day. The comparison group comprised 21 patients who received azathioprine at 150 [50; 150] mg/day. Both groups were administered with methylprednisolone. The average follow-up period was 30 [22; 35] months, but no less than 6 months. Results. The groups were comparable in the baseline parameters and standard drug therapy. In both groups, there was a comparable significant increase in the ejection fraction (from 30.6 ± 7.7% to 44.0 ± 9.4% vs. 29.2 ± 7.7% to 46.2 ± 11.8%, p < 0.001), and a decrease in systolic pressure in the pulmonary artery and the dimensions of the left ventricle and atrium. The frequency of death was two (6.9%) and two (9.5%), transplantation was one (3.4%) and one (4.8%) patient and the “death + transplantation” endpoint was three (10.3%) and three (14.3%) without differences between the groups. The presence of the parvovirus B19 in the myocardium in 6/5 patients did not affect the results. The incidence of infectious complications was comparable. The most severe infectious complications were pneumonia and fatal purulent encephalitis (both cases in the azathioprine group), leptospirosis meningitis (in the mycophenolate mofetil group). Conclusions. In the patients with LM, the combination of corticosteroids with MM at a dose of 2 g/day was at least no less effective than with azathioprine. There was a tendency toward a better tolerance using MM. Full article

(This article belongs to the Special Issue Myocarditis in Clinical Practice—Part II)

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13 pages, 3059 KiB

Open AccessArticle

Circulating Anti-GB3 Antibody as a Biomarker of Myocardial Inflammation in Patients with Fabry Disease Cardiomyopathy

by Andrea Frustaci, Romina Verardo, Michele Magnocavallo, Rossella Scialla, Luigi Sansone and Matteo Antonio Russo

J. Clin. Med. 2023, 12(12), 4068; https://doi.org/10.3390/jcm12124068 - 15 Jun 2023

Cited by 2 | Viewed by 1555

Abstract

Background: Fabry disease cardiomyopathy (FDCM) has manifested some resistance to enzyme replacement therapy (ERT), particularly in its advanced phase. Recently, myocardial inflammation of autoimmune origin has been demonstrated in FDCM. Aims: The objective of this study was the assessment of circulating anti-globotriaosylceramide (GB3) antibodies as potential biomarkers of myocardial inflammation in FDCM, defined by the additional presence of ≥CD3+ 7 T lymphocytes/low-power field associated with focal necrosis of adjacent myocytes. Its sensitivity was based on the evidence of overlapping myocarditis at left ventricular endomyocardial biopsy. Methods and Results: From January 1996 to December 2021, 85 patients received a histological diagnosis of FDCM in our department and 48 (56.5%) of them had an overlapping myocardial inflammation with negative PCR for common cardiotropic viruses, positive antiheart, and antimyosin abs. The presence of anti-GB3 antibodies was evaluated with an in-house ELISA assay (BioGeM scarl Medical Investigational Research, MIR—Ariano Irpino, Italy), along with antiheart and antimyosin abs, in the FDCM patients and compared with control healthy individuals. The correlation between levels of circulating anti-GB3 autoantibody myocardial inflammation and FDCM severity was assessed. Anti-Gb3 antibodies were above the positivity cut-off in 87.5% of FDCM subjects with myocarditis (42 out of 48), while 81.1% of FDCM patients without myocarditis were identified as negative for Gb3 antibodies. Positive anti-Gb3 abs correlated with positive antiheart and antimyosin abs. Conclusions: The present study suggests a potential positive role of anti-GB3 antibodies as a marker of overlapping cardiac inflammation in patients with FDCM. Full article

(This article belongs to the Special Issue Myocarditis in Clinical Practice—Part II)

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13 pages, 3181 KiB

Open AccessArticle

Interleukin-17A-Correlated Myocarditis in Patients with Psoriasis: Cardiac Recovery following Secukinumab Administration

by Andrea Frustaci, Nicola Galea, Lorenzo Dominici, Romina Verardo, Maria Alfarano, Rossella Scialla and Antonio Giovanni Richetta

J. Clin. Med. 2023, 12(12), 4010; https://doi.org/10.3390/jcm12124010 - 12 Jun 2023

Cited by 6 | Viewed by 1922

Abstract

(1) Background: Psoriasis (PS) is a common immune-mediated disease of the skin with possible extension to joints, aorta and eye. Myocardial inflammation has rarely been suggested. (2) Aims: Report of PS-related myocarditis. (3) Methods and Results: One hundred consecutive patients with PS were screened for cardiac involvement. Among them, five male patients (aged 56 ± 9.5 years) with a moderate–severe form of PS showed dilated cardiomyopathy (LVEF < 35%) with normal coronary arteries and valves. They underwent a left-ventricular endomyocardial biopsy for evaluation of myocardial substrate. Endomyocardial samples were processed for histology and immunohistochemistry, including myocardial expression of Toll-Like Receptor 4 (TLR4) and interleukin-17A (IL-17A), which play a major role in PS pathogenesis. Real-time PCRs were carried out for cardiotropic viruses, and Western blot analysis was conducted for myocardial expression of IL-17A. Patients’ sera were tested for anti-heart autoantibodies. Active lymphocytic myocarditis was revealed in all five patients, characterized by an absence of viral genomes with PCR, positive anti-heart autoantibodies, overexpression of TLR-4 and enhancement of IL-17-A during western blot analysis, showing a 2.48-fold increase in psoriatic myocarditis compared with no psoriatic myocarditis and a six-fold increase compared to myocardial controls. Treatment included combination of prednisone (1 mg/kg daily for 4 weeks, tapered to 0.33 mg/kg) and azathioprine (2 mg/kg, daily) in 3 pts or secukinumab (SK, 150 mg/weekly for 4 weeks followed by 150 mg/monthly) in 2 pts for 6 months. LVEDD and LVEF improved in the first 3 pts (−14% and + 118%, respectively), while they completely recovered (LVEF > 50%) in the last 2 pts on SK. (4) Conclusions: IL-17A-related myocarditis can occur in up to 5% of patients with PS. It manifests as progressive dilated cardiomyopathy. It may completely recover following SK administration. Full article

(This article belongs to the Special Issue Myocarditis in Clinical Practice—Part II)

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17 pages, 468 KiB

Open AccessArticle

Fulminant Myocarditis and Cardiogenic Shock Following COVID-19 Infection Versus COVID-19 Vaccination: A Systematic Literature Review

by Maya E. Guglin, Aniekeme Etuk, Chirag Shah and Onyedika J. Ilonze

J. Clin. Med. 2023, 12(5), 1849; https://doi.org/10.3390/jcm12051849 - 25 Feb 2023

Cited by 6 | Viewed by 4558

Abstract

Background: Myocarditis, diagnosed by symptoms and troponin elevation, has been well-described with COVID-19 infection, as well as shortly after COVID-19 vaccination. The literature has characterized the outcomes of myocarditis following COVID-19 infection and vaccination, but clinicopathologic, hemodynamic, and pathologic features following fulminant myocarditis have not been well-characterized. We aimed to compare clinical and pathological features of fulminant myocarditis requiring hemodynamic support with vasopressors/inotropes and mechanical circulatory support (MCS), in these two conditions. Methods: We analyzed the literature on fulminant myocarditis and cardiogenic shock associated with COVID-19 and COVID-19 vaccination and systematically reviewed all cases and case series where individual patient data were presented. We searched PubMed, EMBASE, and Google Scholar for “COVID”, “COVID-19”, and “coronavirus” in combination with “vaccine”, “fulminant myocarditis”, “acute heart failure”, and “cardiogenic shock”. The Student’s t-test was used for continuous variables and the χ2 statistic was used for categorical variables. For non-normal data distributions, the Wilcoxon Rank Sum Test was used for statistical comparisons. Results: We identified 73 cases and 27 cases of fulminant myocarditis associated with COVID-19 infection (COVID-19 FM) and COVID-19 vaccination (COVID-19 vaccine FM), respectively. Fever, shortness of breath, and chest pain were common presentations, but shortness of breath and pulmonary infiltrates were more often present in COVID-19 FM. Tachycardia, hypotension, leukocytosis, and lactic acidosis were seen in both cohorts, but patients with COVID-19 FM were more tachycardic and hypotensive. Histologically, lymphocytic myocarditis dominated both subsets, with some cases of eosinophilic myocarditis in both cohorts. Cellular necrosis was seen in 44.0% and 47.8% of COVID-19 FM and COVID-19 vaccine FM, respectively. Vasopressors and inotropes were used in 69.9% of COVID-19 FM and in 63.0% of the COVID-19 vaccine FM. Cardiac arrest was observed more in COVID-19 FM (p = 0.008). Venoarterial extracorporeal membrane oxygenation (VA-ECMO) support for cardiogenic shock was also used more commonly in the COVID-19 fulminant myocarditis group (p = 0.0293). Reported mortality was similar (27.7%) and 27.8%, respectively) but was likely worse for COVID-19 FM as the outcome was still unknown in 11% of cases. Conclusions: In the first series to retrospectively assess fulminant myocarditis associated with COVID-19 infection versus COVID-19 vaccination, we found that both conditions had a similarly high mortality rate, while COVID-19 FM had a more malignant course with more symptoms on presentation, more profound hemodynamic decompensation (higher heart rate, lower blood pressure), more cardiac arrests, and higher temporary MCS requirements including VA-ECMO. In terms of pathology, there was no difference in most biopsies/autopsies that demonstrated lymphocytic infiltrates and some eosinophilic or mixed infiltrates. There was no predominance of young males in COVID-19 vaccine FM cases, with male patients representing only 40.9% of the cohort. Full article

(This article belongs to the Special Issue Myocarditis in Clinical Practice—Part II)

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Review

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32 pages, 1934 KiB

Open AccessReview

Advancing Precision Medicine in Myocarditis: Current Status and Future Perspectives in Endomyocardial Biopsy-Based Diagnostics and Therapeutic Approaches

by Christian Baumeier, Dominik Harms, Ganna Aleshcheva, Ulrich Gross, Felicitas Escher and Heinz-Peter Schultheiss

J. Clin. Med. 2023, 12(15), 5050; https://doi.org/10.3390/jcm12155050 - 31 Jul 2023

Cited by 3 | Viewed by 2355

Abstract

The diagnosis and specific and causal treatment of myocarditis and inflammatory cardiomyopathy remain a major clinical challenge. Despite the rapid development of new imaging techniques, endomyocardial biopsies remain the gold standard for accurate diagnosis of inflammatory myocardial disease. With the introduction and continued development of immunohistochemical inflammation diagnostics in combination with viral nucleic acid testing, myocarditis diagnostics have improved significantly since their introduction. Together with new technologies such as miRNA and gene expression profiling, quantification of specific immune cell markers, and determination of viral activity, diagnostic accuracy and patient prognosis will continue to improve in the future. In this review, we summarize the current knowledge on the pathogenesis and diagnosis of myocarditis and inflammatory cardiomyopathies and highlight future perspectives for more in-depth and specialized biopsy diagnostics and precision, personalized medicine approaches. Full article

(This article belongs to the Special Issue Myocarditis in Clinical Practice—Part II)

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27 pages, 2328 KiB

Open AccessReview

COVID-19 Related Myocarditis in Adults: A Systematic Review of Case Reports

by Szymon Urban, Michał Fułek, Mikołaj Błaziak, Gracjan Iwanek, Maksym Jura, Katarzyna Fułek, Mateusz Guzik, Mateusz Garus, Piotr Gajewski, Łukasz Lewandowski, Jan Biegus, Piotr Ponikowski, Przemysław Trzeciak, Agnieszka Tycińska and Robert Zymliński

J. Clin. Med. 2022, 11(19), 5519; https://doi.org/10.3390/jcm11195519 - 21 Sep 2022

Cited by 11 | Viewed by 6052

Abstract

Despite the progress of its management, COVID-19 maintains an ominous condition which constitutes a threat, especially for the susceptible population. The cardiac injury occurs in approximately 30% of COVID-19 infections and is associated with a worse prognosis. The clinical presentation of cardiac involvement can be COVID-19-related myocarditis. Our review aims to summarise current evidence about that complication. The research was registered at PROSPERO (CRD42022338397). We performed a systematic analysis using five different databases, including i.a. MEDLINE. Further, the backward snowballing technique was applied to identify additional papers. Inclusion criteria were: full-text articles in English presenting cases of COVID-19-related myocarditis diagnosed by the ESC criteria and patients over 18 years old. The myocarditis had to occur after the COVID-19 infection, not vaccination. Initially, 1588 papers were screened from the database search, and 1037 papers were revealed in the backward snowballing process. Eventually, 59 articles were included. Data about patients’ sex, age, ethnicity, COVID-19 confirmation technique and vaccination status, reported symptoms, physical condition, laboratory and radiological findings, applied treatment and patient outcome were investigated and summarised. COVID-19-related myocarditis is associated with the risk of sudden worsening of patients’ clinical status, thus, knowledge about its clinical presentation is essential for healthcare workers. Full article

(This article belongs to the Special Issue Myocarditis in Clinical Practice—Part II)

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Other

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19 pages, 2287 KiB

Open AccessConference Report

Meeting the Challenges of Myocarditis: New Opportunities for Prevention, Detection, and Intervention—A Report from the 2021 National Heart, Lung, and Blood Institute Workshop

by Daniela Čiháková, Yang Shi, Bishow Adhikari, W. Patricia Bandettini, Madeleine W. Cunningham, Narasimhan Danthi, Matthias G. Friedrich, Peter Liu, Lisa Schwartz Longacre, Douglas L. Mann, Filip K. Swirski, W. H. Wilson Tang, Guofei Zhou and Leslie T. Cooper, Jr.

J. Clin. Med. 2022, 11(19), 5721; https://doi.org/10.3390/jcm11195721 - 27 Sep 2022

Cited by 5 | Viewed by 3993

Abstract

The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of international experts to discuss new research opportunities for the prevention, detection, and intervention of myocarditis in May 2021. These experts reviewed the current state of science and identified key gaps and opportunities in basic, diagnostic, translational, and therapeutic frontiers to guide future research in myocarditis. In addition to addressing community-acquired myocarditis, the workshop also focused on emerging causes of myocarditis including immune checkpoint inhibitors and SARS-CoV-2 related myocardial injuries and considered the use of systems biology and artificial intelligence methodologies to define workflows to identify novel mechanisms of disease and new therapeutic targets. A new priority is the investigation of the relationship between social determinants of health (SDoH), including race and economic status, and inflammatory response and outcomes in myocarditis. The result is a proposal for the reclassification of myocarditis that integrates the latest knowledge of immunological pathogenesis to refine estimates of prognosis and target pathway-specific treatments. Full article

(This article belongs to the Special Issue Myocarditis in Clinical Practice—Part II)

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