Natural History of Myocardial Injury After COVID-19 Vaccine-Associated Myocarditis.

BACKGROUND: Acute myocarditis is a rare complication of mRNA-based COVID-19 vaccination. Little is known about the natural history of this complication. METHODS: Baseline and convalescent (≥ 90 days) cardiac magnetic resonance (CMR) imaging assessments were performed in 20 consecutive patients meeting Updated Lake Louise Criteria for acute myocarditis within 10 days of mRNA-based vaccination. CMR-based changes in left ventricular volumes, mass, ejection fraction (LVEF), markers of tissue inflammation (native T1 and T2 mapping), and fibrosis (late gadolinium enhancement [LGE] and extracellular volume [ECV]) were assessed between baseline and convalescence. Cardiac symptoms and clinical outcomes were captured. RESULTS: Median age was 23.1 years (range 18-39 years), and 17 (85%) were male. Convalescent evaluations were performed at a median (IQR) 3.7 (3.3-6.2) months. The LVEF showed a mean 3% absolute improvement, accompanied by a 7% reduction in LV end-diastolic volume and 5% reduction in LV mass (all P < 0.015). Global LGE burden was reduced by 66% (P < 0.001). Absolute reductions in global T2, native T1, and ECV of 2.1 ms, 58 ms, and 2.9%, repectively, were documented (all P ≤ 0.001). Of 5 patients demonstrating LVEF ≤ 50% at baseline, all recovered to above this threshold in convalescence. A total of 18 (90%) patients showed persistence of abnormal LGE although mean fibrosis burden was < 5% of LV mass in 85% of cases. No patient experienced major clinical outcomes. CONCLUSIONS: COVID-19 mRNA vaccine-associated myocarditis showed rapid improvements in CMR-based markers of edema, contractile function, and global LGE burden beyond 3 months of recovery in this young patient cohort. However, regional fibrosis following edema resolution was commonly observed, justifying need for ongoing surveillance.

Lymphohistiocytic Myocarditis Possibly Due to Moderna mRNA-1273 Vaccine.

OBJECTIVES: Despite the clear benefits of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in mitigating the impact of the coronavirus disease 2019 pandemic, there are emerging reports of postvaccination myocarditis, the majority of which are diagnosed based on the clinical and radiologic findings without biopsy confirmation. We report a case of biopsy-confirmed lymphohistiocytic myocarditis after Moderna mRNA-1273 vaccination. METHODS: We describe a case of a previously healthy 45-year-old woman who had palpitations, exercise intolerance, and syncope 1 week after her first mRNA-1273 vaccine dose. Laboratory tests and cardiac imaging were compatible with myocarditis. Given her unusual clinical presentation, an endomyocardial biopsy was performed to exclude other potential etiologies. RESULTS: The endomyocardial biopsy specimen showed patchy endocardial and intramyocardial lymphohistiocytic infiltrates with scattered eosinophils and focal myocyte injury. CD3 and CD68 immunostains confirmed the lymphocytic and histiocytic nature of the infiltrate, respectively. A focal histiocytic collection suggestive of an ill-defined granuloma was present. The histologic and immunohistochemical findings of a lymphohistiocytic myocarditis were highly suggestive of a postvaccination hypersensitivity reaction. CONCLUSIONS: Myocarditis following SARS-CoV-2 vaccination is a rare adverse event. The findings of a lymphohistiocytic myocarditis with scattered eosinophils and a possible ill-defined granuloma are highly suggestive of a hypersensitivity reaction. The mechanism by which this inflammation occurs remains uncertain. Despite our findings, the benefits of SARS-CoV-2 vaccination far outweigh the risks.

Commentary on an inflammatory discussion: Society for Cardiovascular Pathology journal club.

The histologic criteria for myocarditis are a focal point of scientific debate in the wake of the SARS-CoV-2 pandemic. Variable methodologies have evolved in an evaluation already plagued by high intraobserver variability and low sensitivity. In this commentary, two topical manuscripts are reviewed in the context of this unfolding discussion.

RLMD-PA: A Reinforcement Learning-Based Myocarditis Diagnosis Combined with a Population-Based Algorithm for Pretraining Weights.

Myocarditis is heart muscle inflammation that is becoming more prevalent these days, especially with the prevalence of COVID-19. Noninvasive imaging cardiac magnetic resonance (CMR) can be used to diagnose myocarditis, but the interpretation is time-consuming and requires expert physicians. Computer-aided diagnostic systems can facilitate the automatic screening of CMR images for triage. This paper presents an automatic model for myocarditis classification based on a deep reinforcement learning approach called as reinforcement learning-based myocarditis diagnosis combined with population-based algorithm (RLMD-PA) that we evaluated using the Z-Alizadeh Sani myocarditis dataset of CMR images prospectively acquired at Omid Hospital, Tehran. This model addresses the imbalanced classification problem inherent to the CMR dataset and formulates the classification problem as a sequential decision-making process. The policy of architecture is based on convolutional neural network (CNN). To implement this model, we first apply the artificial bee colony (ABC) algorithm to obtain initial values for RLMD-PA weights. Next, the agent receives a sample at each step and classifies it. For each classification act, the agent gets a reward from the environment in which the reward of the minority class is greater than the reward of the majority class. Eventually, the agent finds an optimal policy under the guidance of a particular reward function and a helpful learning environment. Experimental results based on standard performance metrics show that RLMD-PA has achieved high accuracy for myocarditis classification, indicating that the proposed model is suitable for myocarditis diagnosis.

T2 mapping in myocardial disease: a comprehensive review.

Cardiovascular magnetic resonance (CMR) is considered the gold standard imaging modality for myocardial tissue characterization. Elevated transverse relaxation time (T2) is specific for increased myocardial water content, increased free water, and is used as an index of myocardial edema. The strengths of quantitative T2 mapping lie in the accurate characterization of myocardial edema, and the early detection of reversible myocardial disease without the use of contrast agents or ionizing radiation. Quantitative T2 mapping overcomes the limitations of T2-weighted imaging for reliable assessment of diffuse myocardial edema and can be used to diagnose, stage, and monitor myocardial injury. Strong evidence supports the clinical use of T2 mapping in acute myocardial infarction, myocarditis, heart transplant rejection, and dilated cardiomyopathy. Accumulating data support the utility of T2 mapping for the assessment of other cardiomyopathies, rheumatologic conditions with cardiac involvement, and monitoring for cancer therapy-related cardiac injury. Importantly, elevated T2 relaxation time may be the first sign of myocardial injury in many diseases and oftentimes precedes symptoms, changes in ejection fraction, and irreversible myocardial remodeling. This comprehensive review discusses the technical considerations and clinical roles of myocardial T2 mapping with an emphasis on expanding the impact of this unique, noninvasive tissue parameter.

Management of myocarditis in clinical practice.

Myocarditis is an inflammatory heart muscle disease characterized by heterogeneous clinical presentation and outcome. Clinical heterogeneity of myocarditis, ranging from acute onset chest pain with electrocardiographic changes resembling an acute coronary syndrome, to arrhythmic storm and chronic decompensated heart failure, makes diagnosis challenging. However, a correct diagnosis is fundamental to proper patients' management and should always be seeked. Although a definite diagnosis is only provided by endomyocardial biopsy, the European Society of Cardiology task force on myocardial and pericardial diseases provided specific criteria for the diagnosis of clinically suspected myocarditis, which has been facilitated by the advent of noninvasive imaging tests (i.e. cardiovascular magnetic resonance based myocardial tissue characterization). Due to the heterogeneous presentation and disease course of myocarditis, a tailored treatment would be the best strategy, but a standardized management is still not available. However, over the years, new, promising therapies, such as antiviral and immune-suppressive treatment, have come side by side to the standard pharmacological heart treatment, i.e. antiheart failure medications. In this paper we will review the basic principles of myocarditis management in clinical practice, including diagnostic work-up, conventional and disease-specific therapy and patients' follow-up.

Morphological changes without histological myocarditis in hearts of COVID-19 deceased patients.

Objective. Patients with underlying heart diseases have a higher risk of dying from Covid-19. It has also been suggested that Covid-19 affects the heart through myocarditis. Despite the rapidly growing research on the management of Covid-19 associated complications, most of the ongoing research is focused on the respiratory complications of Covid-19, and little is known about the prevalence of myocarditis. Design. This study aimed to characterize myocardial involvement by using a panel of antibodies to detect hypoxic and inflammatory changes and the presence of SARS-CoV-2 proteins in heart tissues obtained during the autopsy procedure of Covid-19 deceased patients. Thirty-seven fatal COVID-19 cases and 21 controls were included in this study. Results. Overall, the Covid-19 hearts had several histopathological changes like the waviness of myocytes, fibrosis, contract band necrosis, infiltration of polymorphonuclear neutrophils, vacuolization, and necrosis of myocytes. In addition, endothelial damage and activation were detected in heart tissue. However, viral replication was not detected using RNA in situ hybridization. Also, lymphocyte infiltration, as a hallmark of myocarditis, was not seen in this study. Conclusion. No histological sign of myocarditis was detected in any of our cases; our findings are thus most congruent with the hypothesis of the presence of a circulating endothelium activating factor such as VEGF, originating outside of the heart, probably from the hypoxic part of the Covid-19 lungs.

A case of vaccine-associated myocarditis following pneumococcal immunization leading to acute mitral regurgitation.

Vaccine-associated myocarditis (VAM) is a rare entity but can result in potentially serious sequelae if left untreated. However, the mechanisms of the complications of VAM and its treatment remain unclear. Herein, we report the first case of VAM related to pneumococcal immunization, presenting as a local and systemic inflammatory reaction, in which the patient developed significant secondary mitral regurgitation, resulting in acute heart failure. Finally, the patient recovered completely following corticosteroid treatment. This case highlights the value of cardiac magnetic resonance and the pitfall of endomyocardial biopsy in establishing the definitive diagnosis of VAM and emphasizes the importance of optimal management in understanding the mechanism and instituting the treatment for secondary mitral regurgitation caused by VAM.

Microthrombosis as a cause of fulminant myocarditis-like presentation with COVID-19 proven by endomyocardial biopsy.

Myocardial injury has been reported as a complication of COVID-19. Although several mechanisms have been proposed as its cause, they are mostly based on autopsy studies, We report a 49-year-old male with COVID-19-associated myocardial injury presented like fulminant myocarditis. We performed endomyocardial biopsy on day 2 and we confirmed the presence of microthrombosis histologically. He died on day 5 due to cardiogenic shock.

Pathological findings of clinically suspected myocarditis temporally associated with COVID-19 vaccination.

Reports on the pathological findings of patients with myocarditis after coronavirus disease 2019 (COVID-19) vaccination are limited. We present a case series of four patients with clinically suspected myocarditis temporally associated with COVID-19 vaccination who underwent endomyocardial biopsy with no evidence of viral genomes in tissue specimens. Two patients had fulminant myocarditis with marked inflammatory cell infiltration comprised mostly of CD8+ T-cells and macrophages, and the other two had suspected myocarditis based on the biochemical evidence of myocardial injury and ST changes on an electrocardiogram. However, they did not meet the histological criteria of myocarditis. Immunosuppressive therapy effectively reduced myocardial damage, and all four patients had improved clinical courses. Temporal association does not prove causation, and it cannot be excluded that the two biopsy-proven cases reported are simply a random association of a naturally occurring virus-negative immune-mediated lymphocytic myocarditis occurring after vaccination.

COVID-19 and myocarditis: a brief review.

Cardiovascular complications (especially myocarditis) related to COVID-19 viral infection are not well understood, nor do they possess a well recognized diagnostic protocol as most of our information regarding this issue was derived from case reports. In this article we extract data from all published case reports in the second half of 2020 to summarize the theories of pathogenesis and explore the value of each diagnostic test including clinical, lab, ECG, ECHO, cardiac MRI and endomyocardial biopsy. These tests provide information that explain the mechanism of development of myocarditis that further paves the way for better management.

Myocarditis following mRNA COVID-19 vaccination: call for endomyocardial biopsy.

Acute myocarditis following mRNA COVID-19 vaccination was reported by the European Medicine Agency safety committee as a rare adverse event. We present a case series of three young male patients with suspected acute myocarditis following BNT162b2 mRNA COVID-19 vaccination including results of endomyocardial biopsies (EMB). Additionally, we analysed EMB of another 21 patients with clinically suspected acute myocarditis following vaccination to determine the pathohistological pattern. Overall, EMB revealed acute lymphocytic myocarditis in 5 (20.8%), chronic lymphocytic myocarditis in 6 (25%), cardiac sarcoidosis in 1 (4.2%), healed myocarditis in 6 (25%), and other diagnoses with cardiac damage of unclear aetiology in 6 (25%) cases. Our findings support the necessity of EMB in patients with suspected acute myocarditis following mRNA COVID-19 vaccination presenting with reduced EF to establish a correct and definite diagnosis. Concerns of these rare severe adverse events after COVID-19 immunization should not undermine its value for the global community.

Morphologically, immunohistochemically and PCR proven lymphocytic viral peri-, endo-, myocarditis in patients with fatal COVID-19.

BACKGROUND: Despite a reported cardiac injury in patients with new coronavirus infection, the possibility and specifics of genuine viral myocarditis in COVID-19 remains not fully clear. PURPOSE: To study the presence of SARS-CoV-2 in the myocardium and the morphological properties of myocarditis in patients with severe coronavirus infection (COVID-19). METHODS: Autopsy data of eight elderly patients (75.6 ± 7.4 years), four male and four female, with severe new coronavirus infection were studied. The lifetime diagnosis of COVID-19 is based on a positive result of the PCR study. The inclusion criterion was the presence of morphological signs of myocarditis according to the Dallas criteria. A standard histological examination included staining by hematoxylin and eosin, toluidin blue and Van Gieson. An immunohistochemical study was performed using antibodies to CD3, CD 68, CD20, perforin, toll-like receptor (TLR) types 4 and 9. PCR in real-time was performed to determine the viral RNA in the myocardium. RESULTS: All patients had severe bilateral viral pneumonia. In all cases, myocarditis was not clinically diagnosed. Morphological examination of the heart found signs of active lymphocytic myocarditis. PCR identified the SARS-Cov2 RNA in all cases. There were also signs of destructive coronaritis in all cases, thrombovasculitis, lymphocytic pericarditis (in 3 cases) and endocarditis (in 2 cases). The absence of neutrophils confirms the aseptic nature of inflammation. An immunohistochemical study showed the CD3-positive T lymphocytes in the infiltrates. Increased expression of TLR type 4 and less 9 was also detected. CONCLUSION: Morphological and immunohistochemical evidence of myocarditis in COVID-19 was presented. Lymphocytic infiltrations and positive PCR confirm the viral nature of inflammation. Myocarditis in COVID-19 is also characterized by coronaritis with microvascular thrombosis and associated with lymphocytic endo- and pericarditis.

Sex-Specific Effects of Plastic Caging in Murine Viral Myocarditis.

BACKGROUND: Myocarditis is an inflammatory heart disease caused by viral infections that can lead to heart failure, and occurs more often in men than women. Since animal studies have shown that myocarditis is influenced by sex hormones, we hypothesized that endocrine disruptors, which interfere with natural hormones, may play a role in the progression of the disease. The human population is exposed to the endocrine disruptor bisphenol A (BPA) from plastics, such as water bottles and plastic food containers. METHODS: Male and female adult BALB/c mice were housed in plastic versus glass caging, or exposed to BPA in drinking water versus control water. Myocarditis was induced with coxsackievirus B3 on day 0, and the endpoints were assessed on day 10 post infection. RESULTS: We found that male BALB/c mice that were exposed to plastic caging had increased myocarditis due to complement activation and elevated numbers of macrophages and neutrophils, whereas females had elevated mast cell activation and fibrosis. CONCLUSIONS: These findings show that housing mice in traditional plastic caging increases viral myocarditis in males and females, but using sex-specific immune mechanisms.