key: cord-0905092-sgy7199e
authors: Oh, Jin-Hee; Kim, Gi Beom; Seok, Heeyoung
title: Implication of microRNA as a potential biomarker of myocarditis
date: 2022-03-02
journal: Clin Exp Pediatr
DOI: 10.3345/cep.2021.01802
sha: 18f651f9adbceb37ce02fe403dbfc4c9f97ef9a5
doc_id: 905092
cord_uid: sgy7199e

Myocarditis was previously attributed to an epidemic viral infection. Additional harmful reagents, in addition to viruses, play a role in its etiology. Coronavirus disease 2019 (COVID-19) vaccine-induced myocarditis has recently been described, drawing attention to vaccine-induced myocarditis in children and adolescents. Its pathology is based on a series of complex immune responses, including initial innate immune responses in response to viral entry, adaptive immune responses leading to the development of antigen-specific antibodies, and autoimmune responses to cellular injury caused by cardiomyocyte rupture that releases antigens. Chronic inflammation and fibrosis in the myocardium eventually result in cardiac failure. Recent advancements in molecular biology have remarkably increased our understanding of myocarditis. In particular, microRNAs (miRNAs) are a hot topic in terms of the role of new biomarkers and the pathophysiology of myocarditis. Myocarditis has been linked with microRNA-221/222 (miR-221/222), miR-155, miR-10a*, and miR-590. Despite the lack of clinical trials of miRNA intervention in myocarditis yet, multiple clinical trials of miRNAs in other cardiac diseases have been aggressively conducted to help pave the way for future research, which is bolstered by the success of recently U.S. Food and Drug Administration-approved small-RNA medications. This review presents basic information and recent research that focuses on myocarditis and related miRNAs as a potential novel biomarker and the therapeutics.

Myocarditis is a broad term for inflammatory disorders of the heart muscles. In his work, Traité des Maladies du Coeur (Treatise on Heart Disease) published in 1749, Jean Baptiste Senac identified inflammation in the heart. Later, Joseph Freidrich Sobernheim coined the term myocarditis to describe cardiomyopathy caused by myocyte inflammation, ischemia, and hypertensive heart disease. 1) Various viral infections in the heart, such as coxsackievirus, echovirus, the mumps virus, influenza virus, measles virus, poliovirus, and smallpox, have been reported during epidemic periods, leading to myocarditis becoming a broader term that covers myocardial infarction, chronic ischemic heart disease, and occasionally, pancarditis or myopericarditis. 2, 3) To date, it has been used interchangeably. Recent efforts have been made to clearly describe myocarditis, which is defined as inflammation of the cardiac muscle and recognized as a disease that leads to heart failure. 1, 4) Endomyocardial biopsy (EMB) with quantitative standards (≥14 lymphocytes/mm 2 , including ≤4 monocytes/mm 2 , with the presence of cluster of differentiation 3-positive T lym phocytes, 7 cells/mm 2 ) and immunohistochemistry assays are used to diagnose myocarditis. 3, 5) However, this approach is only acceptable for isolated inflammatory regions, making it difficult to diagnose fulminant myocarditis (FM), which involves widespread inflammation throughout the heart. 6, 7) Quantitative cardiac troponin analysis combined with cardiac magnetic re sonance imaging (MRI) to assess the injured myocardium can be utilized to noninvasively diagnose myocarditis to overcome localized inflammation, spontaneous resolution, and myocar disease (Trypanosoma cruzi) 28) have been reported regularly, as have drug or vaccinerelated cases such as ampicillin or tetracycline 2931) or smallpox vaccines. 32, 33) Amid the recent coronavirus disease 2019 (COVID19) pan demic, cases of myocarditis reported in people vaccinated with the COVID19 mRNA vaccine and the relationship between myocarditis after COVID19 infection and vaccination are under investigation. This finding was supported by 2 major cohort studies. One survey in Israel reported 136 cases of definitive or probable myocarditis within one month of receiving one shot of the vaccine. This study included more than 5 million participants who had received immunization. Of these cases, 135 had a mild or moderate clinical course and one was fatal. After the second dose of the vaccination, a 15 in 100,000 chance of developing myocarditis was assessed in adolescents and young men aged 16-19 years. 30) Similar studies in the United States reported a somewhat lower rate of 5 of 10,000 cases (18 to 24yearold men). However, all of these cases were less severe than myocarditis caused by direct viral infection. Severe acute respiratory syndrome coronavirus 2 infection results in an 18 fold increased risk of myocarditis in the same age group. 31) Two 10year studies of Koreans included cases of myocarditis in children. Park et al. 34 According to the International Classification of Illnesses 9th revision, myocarditis affects approximately 22 per 100,000 individuals worldwide. 12, 13) Systematic reviews of the clinical courses of myocarditis patients from the Lombardy registry (443 patients from the Italian region) and 220 cases in 2018, which used combined diagnostic strategies, revealed that left ventricular systolic dysfunction, ventricular arrhythmias, hemo dynamic instability, and QRS width should be considered the initial diagnostic factors for FM. 14, 15) An estimated, 0.5%-4 % of myocarditis cases progress to heart failure. 13) Myocarditis, which is the leading cause of sudden death among young athletes, is particularly prevalent, accounting for 5%-12% of all deaths. 16) Furthermore, our understanding of the etiology of myocarditis is limited, although we know that it can occasionally resolve spontaneously or result in heart failure, highlighting the need for early diagnosis and accurate comprehension. 4) This review presents basic information and recent research highlights in the field of myocarditis, with a particular focus on diseasespecific microRNA (miRNA) expression patterns and the goal of their potential use as alternative prognostic and diagnostic tools to supplement the current standards.

Infection, autoimmune responses, and toxicity are the 3 most common causes of myocarditis. Among them, viral infections are the most common. Several viruses, including coxsackie virus, 17, 18) H1N1 influenza, 19) adenovirus, 20) hepatitis C, 21, 22) cytomegalovirus, 23) echovirus, 24) parvovirus B19, herpes virus, 25) and EpsteinBarr virus 26) were detected in heart autopsy samples on a regular and local basis. 26) In addition to viral infection mediated immune responses, bacterialdriven cases such as Lyme disease (Borrelia burgdorferi) 27) and parasitemediated Chagas Graphical abstract detected. Between 2007 and 2016, another study enrolled 1,462 pediatric cases after health insurance evaluations. The annual occurrence has increased from 1.4 to 2.1. Male patients over the age of 13 years were much more numerous in the 2010-2019 survey. 35) The incidence of myocarditis is bimodal, with peaks during infancy and midadolescence, similar to the 2 peaked cardiac growth signals. 36, 37) These 2 studies reported a similar trend of myocarditis in Korean children: (1) Its proclivity for growth continues to increase annually; and (2) In midadolescence, boys are more prone to its development.

In Korea, COVID19 vaccinations for thirdyear high school students began in July 2021. The incidence of myocarditis was calculated. Myocarditis occurred in 1.97 of every 100,000 cases after the first dose and 3.1 of every 100,000 cases after the second dose per 100,000 vaccine cases. These data were provided concurrently with the incidence in the United States and Israel based on a report from Korea's Disease Control and Prevention Agency (12921 release). According to this report, myocarditis cases in Korea are approximately 7 times higher than that described in the United States or 3 times more than that in Israel for the first dose. However, the incidence after the second immunization dose was comparable to or lower than that of other 2 countries. Notably, Israel's incidence following the second dose is 2.77 times higher than that in Korea. Table 1 illustrates a threenation comparison focusing on midadolescent age cases of the myocarditis after vaccinations.

Because viral infection is the most common cause of myo carditis, viral infectionmediated pathology is discussed here. These studies are mostly based on the pathophysiological under standing of the murine model. The first step is linked to viral replication in the heart, resulting in cellular rupture, an antigen independent and innate immune response. Consequently, adap tive immune responses are triggered in antigenpresenting cells, resulting in the production of antigenspecific antibodies. Autoimmune reactions and cellular damage propagate during this stage as cardiac proteins are released through cardiomyocyte rupture. Finally, the replacement of collagen with dead myocar dium results in persistent inflammation and fibrosis. 38) There is also disagreement regarding whether viral infection is a direct pathogenic cause of cardiac injury. It is a situation in which a virus triggers immune responses to cause cardiomyocyte injury, or that cardiomyocyte injury is caused by viral infection. The presence of the viral genome in the myocardium of patients with chronic inflammatory cardiomyopathy, rather than acute myocarditis, is suggested. 39, 40) Reports on FM associated with viral infection frequently adopted nasopharyngeal swabs for the diagnosis of viral infection. 41) The hstroponin level was also elevated in COVID19 patients, suggesting that the virus generated aberrant immunemediated inflammatory responses rather than viraldirected myocyte damage. 4244) Understanding the pathophysiology, whether the virus is directly or indirectly involved, is critical for immunosuppression because its role is also conflicting. 3, 45) The use of immunosuppressive medication should generally be validated by polymerase chain reaction to ensure that the condition is not an active infection in EMB. 3) Patients with acute myocarditis alone or in combination with autoimmune responses were also identified among those who received immunocheckpoint inhibitor (ICI) medications. 46, 47) Since many cancer patients have just begun to utilize ICI treat ment and its estimated correlation with myocarditis is 1.14%, it may become a subtype of myocarditis with distinct age and inflammatory type in the near future. 46) Myocardial inflammation and the cellular compartment Idiopathic, autoimmune, and infectious are the 3 types of myocardial inflammation. 4) Interactions between several cellu lar compartments causes myocardial inflammation. T, B, and lymphoidderived cells, such as macrophages, dendritic cells, granulocytes, mast cells, and immature precursor cells, all contribute to the differentiation of inflammatory cells and myofibroblasts. 4) Caspase1, nterminal PYRIN PAAD DAPIN and cterminal caspaserecruitment domain containing, and nucleotidebinding oligome rization domainlike receptor path ways play a role in the production of proinflammatory cytokines during this process. Tolllike receptors (TLRs) have also been implicated in the activation of innate immune res ponses in the early stages. 48) TLR3 polymorphism have been linked to enteroviral myocarditis. 49) Tumor necrosis factorα (TNFα) and interleukin (IL)1β are also released in the myocar dium by the TLR pathway. 50, 51) Inflammatory cell invasion is aided by macrophages. Because Ly6Chi inflammatory macrophages are found in the early stages of cardiac damage, their blockade has been used to treat autoimmune myocarditis. 5254) The Ly6Clow M2 macrophage is a critical factor in the transition from acute to pathological remodeling via myofibroblast replacement. 55, 56) Thymic resis tance to alphamyosin heavy chain (MyHC) causes, at least in part, Tcell function to quell autoimmune responses after clearing infections. 57, 58) Overexpressing alphaMyHC promoter specific Tcell receptors were designed for a mouse autoimmune While lymphoidderived cells are involved in adaptive immune responses, endothelial cells act as barriers preventing circulating bone marrowderived cells from entering the heart. Interstitial cell types, such as fibroblasts, myofibroblasts, and stromal cells, act as a matrix to modify the inflammatory phenotype via local cues. During pathogenesis, the cardiomyocyte compartment is also involved in early infection and adaptive responses such as altered calcium signaling or hypertrophy. 64, 65) Both direct and indirect crosstalk was used to orchestrate these interactions ( Table 2) . 66) 

There has been research on the posttranscriptional modula tion of cardiac immunological responses, including miRNA mediated controls. MiRNAs are 22nt singlestrand RNAs that complementarily base pair with mRNAs, primarily but not exclusively in the 3′ untranslated region, to govern transla tion by a minimum 6mer basepairing. This is generally a translational repressor. 67, 68) The importance of miRNAs in myocardial specification and cardiac development, as well as in cardiac disorders such as cardiac hypertrophy, myocardial infarction, arrhythmia, myocarditis, coronary artery disease, and heart failure, has been recognized. 6971) Circulating miRNAs in the blood have been used to identify novel biomarkers in addition to their role in the heart. 72, 73) MED13 and miR208a are 2 of the most notable regulators of metabolic homeostasis via systemic control. 74) Table 3 summarizes the miRNAs in heart disorders, including myocarditis.

Several miRNA profiling studies have been conducted. A total of 107 miRNAs were dysregulated in human right ventricular myocarditis samples. 75) The inhibition of miR155, miR21, and miR146b, for example, reduced cardiac inflammation and myocardial damage in a coxsackievirus B3 (CVB3) animal model and mouse autoimmune studies. 7679) Furthermore, miR www.e-cep.org 5903p overexpression reduced disease by repressing nuclear factor kappa B (NFκB) expression and turning off IL6/TNFα expression by targeting NFκB. 80) Patients with myocarditis were profiled for various CVB3 clearance conditions. Patients with defective cardiac function under protracted viral accumulation (CVB3) had a greater expression of 8 miRNAs, including miR135b, 155, 190, 422a, 489, 590, 601, and 1290. 81) Circulating miRNAs in the blood have been investigated as a means of diagnosis or prognosis, while myocarditis is present. miR208 and miR499 were overexpressed in the blood plasma during acute myo carditis. However, misregulation of these 2 miRNAs has been documented in acute ischemia and hypertensive disorders, implying that other defining factors may be required. 82, 83) Cellu lar release in response to inflammation could explain the mixed expression of these 2 miRNAs. 82) In mouse myocarditis model studies involving enterovirus CVB3, the dysregulation of miR221/222 by targeting ETS1/2, interferon regulatory factor 2, and Bcell lymphoma 2 (Bcl2) like11 maintained prolonged cardiac viremic states and ac tivate inflammatory and injury pathways by targeting ETS1/2, interferon regulatory factor 2, and Bcl2like11. 84) MiR155 uses a similar regulatory mechanism to activate immune responses such as T cells and monocytes by targeting PU.1 and suppressor of cytokine signaling 1. 84, 85) Recent studies using a murine myocarditis model revealed the induction of cardiac myosinspecific Th17 lymphocytes in a myocarditisspecific manner, turning on as early as 3 days after onset, which differs from the response of myocardial infarction, which also showed Th17 cell upregulation later in the disease course. Using a murine model, the authors validated Th17 cell upregulation of mmumiR721 from 27 dysregulated miRNAs. The authors stated that dysregulation of the human version of miR721, hasmiRChr8:96, was confirmed in a large human cohort study that included 42 myocarditis patients (based on cardiac MRI diagnosis), 90 myocardial infarction patients, and 80 healthy participants, implying that it could be used as a biomarker for acute myocarditis. 86) A total of 113 miRNAs were differentially expressed in a murine myocarditis model using Trypanosoma cruzi. The authors reported that miR146b, miR21, miR1423p, miR 1425p, miR1455p, and miR1495p were correlated with disease severity. 79) 

Although antisense RNAs as a novel mechanism for medica tion have been explored since 1978, 87) the success of partisiran, a short RNA drug that mimics siRNAs with pharmacological features to treat polyneuropathy, has only recently become beneficial for treatment. 8890) Small RNA therapies, either inhibiting or activating, are likely to be actively developed for the medical intervention of heart disorders. 9093) In the pharmaceutical industry, there are 2 primary types of antitechnologies that repress miRNAs. The first is antagomir, 94) a cholesterolbased modified RNA, while the second is locked nucleic acid (LNA)modified RNA. 70, 95) Anti miR92a, also known as MRG110, is an LNA/DNA mixed, phosphorothiorate linkage, and 16nucleic acid medication that was administered intravenously and had a repressive efficacy of up to 2 weeks with a single dose in healthy humans. 96) Taubel et al. 97) used an antisense LNA method to block miR1323p in patients with heart failure. This group previously demonstrated that LNAbased chemical modification approaches effectively lowered miRNA levels while maintaining WatsonCrick base pairing. 98) Furthermore, scientists demonstrated that miR1323p re pression clearly improved the heart failure mouse model, 99) which was then expanded into a large animal setting as a pre clinical trial to determine the dosage with enhanced cardiac functions. 100) With this excellent research background, the authors assessed the efficacy of LNAmiR1323p (CDR132L) for the first time by examining heart failure biomarkers, cardiac fibrosis, QRS narrowing, and left ventricular ejection fraction. For 28 patients, 4 dosage groups with a maximum dose of 10 mg/kg administered every 4 weeks were created. Efficacy assess ments were underpowered in the phase 1b trial due to the research design and small patient cohort, but this study clearly demonstrated the safety of a dosedependent reduction of plasma miR1323p expression level and encouraged the next stage in the development of this innovative drug. 97) 

In both experimental animals and humans, miRNA expres sion profiling has been shown to reflect disease status and/ or progression. Misregulation of miR195 and miR21 was observed for the first time in mouse models of heart hyper trophy. 101) Since then, a large amount of miRNA profiling data has been amassed in various cardiovascular disease models and patients, leading to current active clinical trials. 73) In heart failure patients, for example, profiling miRNA expression as biomarkers from patients receiving U.S. Food and Drug Admi nistration (FDA)-approved medications has been de scribed. Table 4 contains detailed information on miRNA investigations in clinical trials.

Myocarditis remains a challenge, and the recent COVID19 outbreak has brought it back to the forefront. Although its exact pathophysiology remains unknown, new research is seeking to improve our understanding and lay the groundwork for newer treatment methods. MiRNAs offer further insights into this understanding.

Over the past several years, miRNA studies on cardiac dis eases have been ongoing. There are 6 records of miRNAs in coronary heart disorders, myocardial infarction, heart failure, and unstable angina on the clinical trial list, spanning early phases 1-4. There were 40 studies on miRNAs in heart disorders if the searches were widened to include nonFDAdefined phase trials. To date, no direct clinical studies have investigated miRNAs in myocarditis; nevertheless, the role of miRNAs has been investigated and specific miRNAs have been identified, paving the way for future innovative interventions and/or diagnostics.

Acute viral myocarditis

Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases

The fate of acute myocarditis between spontaneous improvement and evolution to dilated cardiomyopathy: a review

Myocarditis: the Dallas criteria

Recognition and initial management of fulminant myocarditis: a scientific statement from the American Heart Association

Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis

Longterm evolution and prognostic stratification of biopsyproven active myocarditis

Predictors of outcome in patients with suspected myocarditis

A prospective study of biopsyproven myocarditis: prognostic relevance of clinical and aetiopathogenetic features at diagnosis

The efficacy and safety of electroanatomic mappingguided endomyocardial biopsy: a systematic review

Global Burden of Disease Study C. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 19902013: a systematic analysis for the Global Burden of Disease Study

The global burden of myocarditis: part 1: a systematic literature review for the Global Burden of Diseases, Injuries, and Risk Factors 2010 study

Clinical presentation and outcome in a contemporary cohort of patients with acute myocarditis: multicenter lombardy registry

Fulminant versus acute nonfulminant myocarditis in patients with left ventricular systolic dysfunction

Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 3: hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardio myopathy and other cardiomyopathies, and myocarditis: a scientific statement from the American Heart Association and American College of Cardiology

Enteroviral RNA replication in the myocardium of patients with left ventricular dysfunction and clinically suspected myocarditis

Viral causes of human myocarditis

Myocarditis associated with 2009 influenza A (H1N1) virus in children

Detection of viruses in myocardial tissues by polymerase chain reaction. evidence of adenovirus as a common cause of myocarditis in children and adults

Hepatitis C virus from the hearts of patients with myocarditis and cardiomyopathy

Core protein of hepatitis C virus induces cardiomyopathy

Cytomegalovirus myocarditis

A largescale outbreak of echovirus 30 in Gansu Province of China in 2015 and its phylodynamic characterization

Fatal myocarditis associated with acute parvovirus B19 and human herpesvirus 6 coinfection

Acute EpsteinBarr related myocarditis: an unusual but lifethreatening disease in an immunocompetent patient

Suspected inflammatory cardio myopathy. Prevalence of Borrelia burgdorferi in endomyocardial biopsies with positive serological evidence

Pathogenesis of chronic Chagas heart disease

Hypersensitivity myocarditis in heart transplant candidates

Myocarditis after BNT162b2 mRNA vaccine against Covid19 in Israel

BNT162b2 mRNA Covid19 vaccine in a nationwide mass vaccination setting. Reply

Myopericarditis following smallpox vaccination

Myopericarditis following smallpox vaccination among vaccinianaive US military personnel

Epidemiology and clinical features of myocarditis/pericarditis before the introduction of mRNA COVID19 vaccine in Korean children: a multicenter study

Acute myocarditis in children: a 10year nationwide study (20072016) based on the Health Insurance Review and Assessment Service Database in Korea

Hypertrophic cardiomyopathy in infants from the perspective of cardiomyocyte maturation

Dynamics of cell generation and turnover in the human heart

Update on acute myocarditis

Relevance of cardiac parvovirus B19 in myocarditis and dilated cardiomyopathy: review of the literature

Learning from myocarditis: mimicry, chaos and black holes

Fulminant myocarditis associated with pandemic H1N1 influenza A virus in children

Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID19)

Myocardial localization of coronavirus in COVID19 cardiogenic shock

Management of myocarditisrelated cardiomyopathy in adults

Myocarditis in patients treated with immune checkpoint inhibitors

Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs

A nonsteroid antiinflammatory drug exacerbates Coxsackie B3 murine myocarditis

Complete AV block in Lyme carditis: an important differential diagnosis

Outcomes, longterm quality of life, and psychologic assessment of fulminant myocarditis patients rescued by mechanical circulatory sup port

Extracorporeal membrane oxygenation for the support of infants, children, and young adults with acute myocarditis: a review of the Extracorporeal Life Support Organization registry

The European Study of Epidemiology and Treatment of Cardiac Inflam matory Diseases (ESETCID). First epidemiological results

Controlled trial of intravenous immune globulin in recentonset dilated cardiomyopathy

Gammaglobulin treatment of acute myocarditis in the pediatric population

Effect of protein A immunoadsorption on T cell activation in patients with inflammatory dilated cardiomyopathy

Randomized, placebocontrolled study for immunosuppressive treatment of inflammatory dilated cardiomyo pathy: twoyear followup results

From infection to autoimmunity

Impaired thymic tolerance to alphamyosin directs autoimmunity to the heart in mice and humans

Long term follow up of patients with dilated heart muscle disease treated with human leucocytic interferon alpha or thymic hormones initial results

Immunomodulating treatment in advanced heart failureeffect of intravenous immunoglobulin

Immunosuppressive therapy for active lymphocytic myocarditis: virolo gical and immunologic profile of responders versus nonresponders

Intravenous immunoglobulin therapy for patients with idiopathic cardiomyopathy and endomyocardial biopsyproven high PVB19 viral load

Diagnosis of myocarditis: death of Dallas criteria

High doses of digitalis increase the myocardial production of proinflam matory cytokines and worsen myocardial injury in viral myocarditis: a possible mechanism of digitalis toxicity

Antiinflammatory effects of eplerenone on viral myocarditis

Beneficial effects of amlodipine in a murine model of congestive heart failure induced by viral myocarditis. A possible mechanism through inhibition of nitric oxide production

Regulation of microRNA biogenesis

Overview of MicroRNA biogenesis, mechanisms of actions, and circulation

miRNAS in cardiovascular diseases: potential biomarkers, therapeutic targets and challenges

Development of microRNA therapeutics is coming of age

MicroRNAs in skeletal and cardiac muscle development

Systematic review of microRNA biomarkers in acute coronary syndrome and stable coronary artery disease

Circulating noncoding RNAs as biomarkers of cardiovascular disease and injury

A cardiac microRNA governs systemic energy homeostasis by regulation of MED13

The quest for new approaches in myocarditis and inflammatory cardiomyopathy

MicroRNA profiling identifies microRNA155 as an adverse mediator of cardiac injury and dysfunction during acute viral myocarditis

Inhibition of microRNA155 ameliorates experimental autoimmune myocarditis by modulating Th17/Treg immune response

Silencing microRNA155 attenuates cardiac injury and dysfunction in viral myocarditis via promotion of m2 phenotype polarization of macro phages

MicroRNA transcriptome profiling in heart of trypanosoma cruziinfected mice: parasitological and cardiological outcomes

miR5903p is a Novel MicroRNA in myocarditis by targeting nuclear factor kappaB in vivo

Differential cardiac microRNA expression predicts the clinical course in human enterovirus cardiomyopathy

Circulating microRNA208b and microRNA499 reflect myocardial damage in cardiovascular disease

Use of circulating microRNAs to diagnose acute myocardial infarction

The microRNA221/222 cluster balances the antiviral and inflammatory response in viral myocarditis

Macrophage microRNA155 promotes cardiac hypertrophy and failure

A novel circulating microRNA for the detection of acute myocarditis

Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide

an RNAi therapeutic for the treatment of hereditary transthyretinmediated amyloidosis

an RNAi therapeutic, for hereditary trans thyretin amyloidosis

The potential for microRNA therapeutics and clinical research

The current state and future directions of RNAibased therapeutics

Therapeutic siRNA: state of the art

Silencing of microRNAs in vivo with 'antagomirs'

RNA therapeutics in cardiovascular disease

Efficiency and target derepression of antimiR92a: results of a first in human study

Novel antisense therapy targeting microRNA132 in patients with heart failure: results of a firstinhuman Phase 1b randomized, doubleblind, placebo controlled study

MiR484 promotes nonsmallcell lung cancer (NSCLC) progression through inhibiting Apaf1 associated with the suppression of apoptosis

Vascular importance of the miR212/132 cluster

Preclinical development of a miR132 inhibitor for heart failure treatment

A signature pattern of stressresponsive microRNAs that can evoke cardiac hypertrophy and heart failure

Enterovirus induced miR141 contributes to shutoff of host protein translation by targeting the translation initiation factor eIF4E

MiR10a* upregulates coxsackievirus B3 biosynthesis by targeting the 3Dcoding sequence

A role of premir10a coding region variant in host susceptibility to coxsackie virusinduced myocarditis

MicroRNA 1 represses Cx43 expression in viral myocarditis

MiR126 promotes coxsackievirus replication by mediating crosstalk of ERK1/2 and Wnt/betacatenin signal pathways

The role of microRNAs in enteroviral infections

Circulating exosomes control CD4(+) T cell immunometabolic functions via the transfer of mir142 as a novel mediator in myocarditis

Implication of microRNA as a potential biomarker of myocarditis

There is no conflict of interests to declare.Funding: This work is supported by NRF2020R1A2C1013377 and NRF2017R1D1A1B03030852 for H Seok.ORCID: JinHee Oh iD http://orcid.org/0000000228930563 Gi Beom Kim iD http://orcid.org/000000027880280X Heeyoung Seok iD https://orcid.org/0000000326999935