Relationship between latent left ventricular contractile dysfunction and signs of immune inflammation in patients with COVID-19 pneumonia.

Aim. To investigate the relationship between echocardiographic parameters and laboratory immune inflammation signs in patients after coronavirus disease 2019 (COVID-19) pneumonia depending on the left ventricular (LV) involvement according to speckle tracking echocardiography (STE). Material and methods. The study included 216 patients (men, 51,1%, mean age, 50,1+/-11,1 years). The examination was carried out in patients 3 months after COVID-19 pneumonia. Patients were divided in 3 groups: group I (n=41) - diffuse decrease (>=4 segments the same LV level) of longitudinal strain (LS) according to STE;group II (n=67) - patients with regional decrease (LS reduction >=3 segments corresponding to systems of the anterior, circumflex or right coronary arteries);group III - patients without visual left ventricle involvement (n=108). Results. There were no significant differences in LV ejection fraction - 68,9+/-4,1% in group I, 68,5+/-4,4% in group II and 68,6+/-4,3 in group III (p=0,934). A decrease in the global longitudinal left ventricle strain was detected significantly more often in groups I and II compared with group III (-17,8+/-2,0, -18,5+/-2,0 and -20,8+/-1,8%, respectively;p<0,001). At the same time, LS depression of LV basal level (-14,9+/-1,5, -16,8+/-1,2% and -19,1+/-1,7%;p<0,001), as well as a decrease in LS of LV inferior-posterior segments in group with diffuse involvement was detected significantly more often than in groups II and III. In addition, we revealed a significant difference in interleukin-6 concentration - 3,1 [2,5;4,0], 3,1 [2,4;3,8] and 2,5 [3,8;1,7] pg/ml, (p=0,033), C-reactive protein - 4,0 [2,2;7,9], 5,7 [3,2;7,9] and 2,4 [1,1;4,7] mg/l, (p<0,001), tumor necrosis factor-alpha - 5,9+/-1,9, 6,2+/-1,9 and 5,2+/-2,0 pg/ml, (p=0,004) and ferritin - 130,7 [56,5;220,0], 92,2 [26,0;129,4] and 51,0 [23,2;158,9] microg/l, respectively (p=0,025). Conclusion. A relationship was found between diffuse and regional left ventricular involvement according to STE and signs of immune inflammation in patients 3 months after COVID-19 pneumonia.Copyright © 2023 Vserossiiskoe Obshchestvo Kardiologov. All rights reserved.

Clinically Suspected and Biopsy-Proven Myocarditis Temporally Associated with SARS-CoV-2 Infection.

We review current data on clinically suspected [European Society of Cardiology (ESC) 2013 criteria] and biopsy-proven [ESC and World Health Organization (WHO) criteria] myocarditis that is temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. ESC/WHO etiological diagnosis of viral myocarditis is based on histological and immunohistological evidence of nonischemic myocyte necrosis and monolymphocytic infiltration, i.e., myocarditis, plus the identification of a specific cardiotropic virus by molecular techniques, in particular polymerase chain reaction (PCR)/in-situ hybridization, on endomyocardial biopsy (EMB)/autopsy tissue. There is not yet definitive EMB/autopsy proof that SARS-CoV-2 causes direct cardiomyocyte damage in association with histological myocarditis. Clinical epidemiology data suggest that myocarditis is uncommon for both SARS-CoV-2-positive and -negative PCR cases. We hypothesize that the rare virus-negative biopsy-proven cases may represent new-onset immune-mediated or latent pre-existing autoimmune forms,triggered or fostered by the hyperinflammatory state of severe COVID-19. We recommend the application of the ESC/WHO definitions and diagnostic criteria in future reports to avoid low-quality scientific information leading to an inaccurate estimate of myocarditis incidence based on misdiagnosis.

Application of Magnetocardiography to Screen for Inflammatory Cardiomyopathy and Monitor Treatment Response.

Background Inflammatory cardiomyopathy is one of the most common causes of sudden cardiac death in young adults. Diagnosis of inflammatory cardiomyopathy remains challenging, and better monitoring tools are needed. We present magnetocardiography as a method to diagnose myocardial inflammation and monitor treatment response. Methods and Results A total of 233 patients were enrolled, with a mean age of 45 (±18) years, and 105 (45%) were women. The primary analysis included 209 adult subjects, of whom 66 (32%) were diagnosed with inflammatory cardiomyopathy, 17 (8%) were diagnosed with cardiac amyloidosis, and 35 (17%) were diagnosed with other types of nonischemic cardiomyopathy; 91 (44%) did not have cardiomyopathy. The second analysis included 13 patients with inflammatory cardiomyopathy who underwent immunosuppressive therapy after baseline magnetocardiography measurement. Finally, diagnostic accuracy of magnetocardiography was tested in 3 independent cohorts (total n=23) and 1 patient, who developed vaccine-related myocarditis. First, we identified a magnetocardiography vector to differentiate between patients with cardiomyopathy versus patients without cardiomyopathy (vector of ≥0.051; sensitivity, 0.59; specificity, 0.95; positive predictive value, 93%; and negative predictive value, 64%). All patients with inflammatory cardiomyopathy, including a patient with mRNA vaccine-related myocarditis, had a magnetocardiography vector ≥0.051. Second, we evaluated the ability of the magnetocardiography vector to reflect treatment response. We observed a decrease of the pathologic magnetocardiography vector toward normal in all 13 patients who were clinically improving under immunosuppressive therapy. Magnetocardiography detected treatment response as early as day 7, whereas echocardiographic detection of treatment response occurred after 1 month. The magnetocardiography vector decreased from 0.10 at baseline to 0.07 within 7 days (P=0.010) and to 0.03 within 30 days (P<0.001). After 30 days, left ventricular ejection fraction improved from 42.2% at baseline to 53.8% (P<0.001). Conclusions Magnetocardiography has the potential to be used for diagnostic screening and to monitor early treatment response. The method is valuable in inflammatory cardiomyopathy, where there is a major unmet need for early diagnosis and monitoring response to immunosuppressive therapy.

Role of Endomyocardial Biopsy in Diagnostics of Myocarditis.

Endomyocardial biopsy as the cornerstone of diagnostics has been re-evaluated throughout the years, leaving unanswered questions on the precedence of it. The reported incidence of myocarditis has increased during the pandemic of coronavirus disease 2019 (COVID-19), reinforcing discussions on appropriate diagnostics of myocarditis. By analysis of evidence-based literature published within the last demi-decade, we aimed to summarize the most recent information in order to evaluate the current role of endomyocardial biopsy in diagnostics and management of myocarditis. For the most part, research published over the last five years showed ongoing uncertainty regarding the use, informativeness, safety and necessity of performing a biopsy. Special circumstances, such as fulminant clinical course or failure to respond to empirical treatment, were reconfirmed as justified indications, with a growing applicability of non-invasive diagnostic approaches for most other cases. We concluded that endomyocardial biopsy, if performed properly and with adjunct diagnostic methods, holds a critical role for treatment correction in specific histological subtypes of myocarditis and for differential diagnosis between immune-mediated myocarditis and secondary infections due to immunosuppressive treatment. A high level of possible misdiagnosing was detected, indicating the need to review terminology used to describe findings of myocardial inflammation that did not meet Dallas criteria.

Intramyocardial Inflammation after COVID-19 Vaccination: An Endomyocardial Biopsy-Proven Case Series.

Myocarditis in response to COVID-19 vaccination has been reported since early 2021. In particular, young male individuals have been identified to exhibit an increased risk of myocardial inflammation following the administration of mRNA-based vaccines. Even though the first epidemiological analyses and numerous case reports investigated potential relationships, endomyocardial biopsy (EMB)-proven cases are limited. Here, we present a comprehensive histopathological analysis of EMBs from 15 patients with reduced ejection fraction (LVEF = 30 (14-39)%) and the clinical suspicion of myocarditis following vaccination with Comirnaty® (Pfizer-BioNTech) (n = 11), Vaxzevria® (AstraZenica) (n = 2) and Janssen® (Johnson & Johnson) (n = 2). Immunohistochemical EMB analyses reveal myocardial inflammation in 14 of 15 patients, with the histopathological diagnosis of active myocarditis according the Dallas criteria (n = 2), severe giant cell myocarditis (n = 2) and inflammatory cardiomyopathy (n = 10). Importantly, infectious causes have been excluded in all patients. The SARS-CoV-2 spike protein has been detected sparsely on cardiomyocytes of nine patients, and differential analysis of inflammatory markers such as CD4+ and CD8+ T cells suggests that the inflammatory response triggered by the vaccine may be of autoimmunological origin. Although a definitive causal relationship between COVID-19 vaccination and the occurrence of myocardial inflammation cannot be demonstrated in this study, data suggest a temporal connection. The expression of SARS-CoV-2 spike protein within the heart and the dominance of CD4+ lymphocytic infiltrates indicate an autoimmunological response to the vaccination.

Pediatric Myocarditis: What Have We Learnt So Far?

Myocarditis is an inflammatory disease of the myocardium that is troublesome to diagnose and manage, especially in children. Since the introduction of endomyocardial biopsy (EMB), new diagnostic tools have provided useful data. Especially when enhanced with immunohistochemistry and polymerase chain reaction (PCR) studies, EMB remains the gold standard for the diagnosis. Notably, cardiac magnetic resonance (MRI) is a non-invasive tool that can confirm the diagnosis and has a particular usefulness during the follow-up. The causes of myocarditis are heterogeneous (mostly viral in children). The course and outcome of the illness in the pediatric population represent a complex interaction between etiologic agents and the immune system, which is still not fully understood. The clinical presentation and course of myocarditis vary widely from paucisymptomatic illness to acute heart failure refractory to therapy, arrhythmias, angina-like presentation and sudden cardiac death. In this setting, cardiac biomarkers (i.e., troponins and BNP), although unspecific, can be used to support the diagnosis. Finally, the efficacy of therapeutic strategies is controversial and not confirmed by clinical trials. In this review, we summarized the milestones in diagnosis and provided an overview of the therapeutic options for myocarditis in children.

Arrhythmogenic Cardiomyopathy as a Late Complication of COVID-19-Induced Myocarditis.

COVID-19 has become a global health problem. So far, more than 281 million COVID-19 cases have been confirmed. The vast majority of patients diagnosed with COVID-19 infection present only with respiratory signs and symptoms. A small amount of patients, however, show signs and symptoms of cardiovascular involvement like a myocardial injury. Myocarditis is one of the possible complications, and cases of clinically suspected myocarditis have been reported in the setting of COVID-19. Herein, we present a case of inflammatory cardiomyopathy, a different type of arrhythmogenic cardiomyopathy, in a 32-year-old man, 40 days after being diagnosed with COVID-19.

Stemi mimicking post COVID: a case of focal myopericarditis post COVID infection.

Since the beginning of the coronavirus disease 2019 (COVID19) pandemic, several cases of myocarditis related to COVID-19 infection have been reported. These cases range from asymptomatic disease to fulminant heart failure or sudden cardiac death. Cardiac injury has also been found in asymptomatic patients and patients who recovered from the disease. Data regarding cardiovascular involvement due to COVID-19 infection are still limited, and the actual prevalence of myocarditis due to COVID-19 infection is still unknown. We present a case of focal myopericarditis in a patient recently recovered from COVID-19 pneumonia with electrocardiogram showing ST elevation in inferior and lateral leads. This case highlights the need for studying the long-term cardiovascular complications of COVID-19 and reinforces the use of cardiac magnetic resonance (CMR) and cardiac biomarkers in the diagnosis of COVID-19-related myocarditis.

Cardiovascular consequences of viral infections: from COVID to other viral diseases.

Infection of the heart muscle with cardiotropic viruses is one of the major aetiologies of myocarditis and acute and chronic inflammatory cardiomyopathy (DCMi). However, viral myocarditis and subsequent dilated cardiomyopathy is still a challenging disease to diagnose and to treat and is therefore a significant public health issue globally. Advances in clinical examination and thorough molecular genetic analysis of intramyocardial viruses and their activation status have incrementally improved our understanding of molecular pathogenesis and pathophysiology of viral infections of the heart muscle. To date, several cardiotropic viruses have been implicated as causes of myocarditis and DCMi. These include, among others, classical cardiotropic enteroviruses (Coxsackieviruses B), the most commonly detected parvovirus B19, and human herpes virus 6. A newcomer is the respiratory virus that has triggered the worst pandemic in a century, SARS-CoV-2, whose involvement and impact in viral cardiovascular disease is under scrutiny. Despite extensive research into the pathomechanisms of viral infections of the cardiovascular system, our knowledge regarding their treatment and management is still incomplete. Accordingly, in this review, we aim to explore and summarize the current knowledge and available evidence on viral infections of the heart. We focus on diagnostics, clinical relevance and cardiovascular consequences, pathophysiology, and current and novel treatment strategies.

Immunomodulatory Role of Tenascin-C in Myocarditis and Inflammatory Cardiomyopathy.

Accumulating evidence suggests that the breakdown of immune tolerance plays an important role in the development of myocarditis triggered by cardiotropic microbial infections. Genetic deletion of immune checkpoint molecules that are crucial for maintaining self-tolerance causes spontaneous myocarditis in mice, and cancer treatment with immune checkpoint inhibitors can induce myocarditis in humans. These results suggest that the loss of immune tolerance results in myocarditis. The tissue microenvironment influences the local immune dysregulation in autoimmunity. Recently, tenascin-C (TN-C) has been found to play a role as a local regulator of inflammation through various molecular mechanisms. TN-C is a nonstructural extracellular matrix glycoprotein expressed in the heart during early embryonic development, as well as during tissue injury or active tissue remodeling, in a spatiotemporally restricted manner. In a mouse model of autoimmune myocarditis, TN-C was detectable before inflammatory cell infiltration and myocytolysis became histologically evident; it was strongly expressed during active inflammation and disappeared with healing. TN-C activates dendritic cells to generate pathogenic autoreactive T cells and forms an important link between innate and acquired immunity.

Targeted treatment in viral-associated inflammatory cardiomyopathy.

Detection of viruses like HHV-6 in endomyocardial biopsy or serum serology of patients with myocarditis or heart failure features unresponsive to conventional heart failure therapies could be a potential targeted treatment especially in refractory cases.

Myocardial Inflammation, Sports Practice, and Sudden Cardiac Death: 2021 Update.

Myocardial inflammation is an important cause of cardiovascular morbidity and sudden cardiac death in athletes. The relationship between sports practice and myocardial inflammation is complex, and recent data from studies concerning cardiac magnetic resonance imaging and endomyocardial biopsy have substantially added to our understanding of the challenges encountered in the comprehensive care of athletes with myocarditis or inflammatory cardiomyopathy (ICM). In this review, we provide an overview of the current knowledge on the epidemiology, pathophysiology, diagnosis, and treatment of myocarditis, ICM, and myopericarditis/perimyocarditis in athletes, with a special emphasis on arrhythmias, patient-tailored therapies, and sports eligibility issues.

Clinically Suspected Myocarditis in the Course of Severe Acute Respiratory Syndrome Novel Coronavirus-2 Infection: Fact or Fiction?

Cardiac complications, including clinically suspected myocarditis, have been described in novel coronavirus disease 2019. Here, we review current data on suspected myocarditis in the course of severe acute respiratory syndrome novel coronavirus-2 (SARS-CoV-2) infection. Hypothetical mechanisms to explain the pathogenesis of troponin release in patients with novel coronavirus disease 2019 include direct virus-induced myocardial injury (ie, viral myocarditis), systemic hyperinflammatory response (ie, cytokine storm), hypoxemia, downregulation of angiotensin-converting enzyme 2, systemic virus-induced endothelialitis, and type 1 and type 2 myocardial infarction. To date, despite the fact that millions of SARS-CoV-2 infections have been diagnosed worldwide, there is no definitive proof that SARS-CoV-2 is a novel cardiotropic virus causing direct cardiomyocyte damage. Diagnosis of viral myocarditis should be based on the molecular assessment of endomyocardial biopsy or autopsy by polymerase chain reaction or in-situ hybridization. Blood, sputum, or nasal and throat swab virology testing are insufficient and do not correlate with the myocardial involvement of a given pathogen. Data from endomyocardial biopsies and autopsies in clinically suspected SARS-CoV-2 myocarditis are scarce. Overall, current clinical epidemiologic data do not support the hypothesis that viral myocarditis is caused by SARS-CoV-2, or that it is common. More endomyocardial biopsy and autopsy data are also needed for a better understanding of pathogenesis of clinically suspected myocarditis in the course of SARS-CoV-2 infection, which may include virus-negative immune-mediated or already established subclinical autoimmune forms, triggered or accelerated by the hyperinflammatory state of severe novel coronavirus disease 2019.