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Special Issue "Myocarditis in Clinical Practice"

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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 (10 June 2022) | Viewed by 36900

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Dr. Andrea Frustaci

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Department of Clinical, Internal, Anesthesiology, and Cardiovascular Sciences, Sapienza University, Rome, Italy
Interests: cardiomyopathies; myocarditis; heart failure
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Dear Colleagues,

Myocarditis is a major cause of cardiovascular disease, the causes, pathway, and treatment of which are in continuous evolution. It is a clinical syndrome which manifests with three major phenotypes: arrhythmic, infarct-like, and cardiomyopathic, which are sometimes difficult to identify with noninvasive tools, including cardiac magnetic resonance. Endomyocardial biopsy is still the gold standard for diagnosis, providing definitive information vital for prognosis and treatment. Indeed, the histology of endomyocardial tissue can be used to identify the various pathologic patterns of inflammatory lesions, while PCR on frozen samples can discriminate between possible agents. Different forms of myocarditis can thus be used as signals to identify various characteristics, such as infectious, hypersensitivity, granulomatous, giant cells, eosinophilic, associated to connective tissue, metabolic disorders, and virus-negative immune-mediated forms. Each form requires a specific treatment through which a partial or complete recovery are possible.

Finally, up to 15% of patients with myocarditis fail to respond to treatments based on accurate morpho-molecular characterizations. In these circumstances, an unnoticed, or possibly still unknown, infectious agent might be the cause. Metagenomics is a valuable approach for the identification of new agents.

Prof. Andrea Frustaci
Guest Editor

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Keywords

describing epidemiology
causes
pathways
treatment
metagenomics

Published Papers (11 papers)

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Editorial

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Open AccessEditorial

New Insights in Human Myocarditis

Andrea Frustaci

J. Clin. Med. 2022, 11(4), 924; https://doi.org/10.3390/jcm11040924 - 10 Feb 2022

Viewed by 1100

Abstract

Myocarditis is an inflammatory heart muscle disease, the incidence of which is likely underestimated, ranging from 10 [...] Full article

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

Research

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Open AccessArticle

Hypersensitivity Myocarditis after COVID-19 mRNA Vaccination

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J. Clin. Med. 2022, 11(6), 1660; https://doi.org/10.3390/jcm11061660 - 16 Mar 2022

Cited by 15 | Viewed by 2719

Abstract

Background: Myocarditis, even in a severe and lethal form, may occur after COVID-19 mRNA (BNT162b2) vaccination. However, its pathway, morphomolecular characterization and treatment are still unknown. Methods: Routine hematochemical screening, ECG, Holter monitoring, 2D echocardiogram cardiac magnetic resonance (CMR) and invasive cardiac studies (cardiac catheterization, selective coronary angiography, left ventriculography and left ventricular endomyocardial biopsy) are reported from three patients (39F-pt1, 78M-pt2, 52M-pt3) with severe compromise of conduction tissue (junctional rhythm and syncope, pt1) or cardiac function compromise (LVEF ≤ 35%, pt2 and pt3) after COVID-19 mRNA (BNT162b2). Results: Hematochemical data and coronary angiography were normal in the patients studied. Histology showed in all three patients extensive myocardial infiltration of degranulated eosinophils and elevation of serum cationic protein directly responsible for cardiomyocyte damage. These findings demonstrate myocarditis hypersensitivity to some component of the vaccine (spike protein?) acting as a hapten to some macromolecules of cardiomyocytes. Steroid administration (prednisone, 1 mg/kg die for 3 days, followed by 0.33 mg/kg for 4 weeks) was followed by complete recovery of cardiac contractility in pt2 and pt3. Conclusions: Eosinophilic myocarditis is a possible adverse reaction to the mRNA COVID-19 vaccine. Its pathway is mediated by release of cationic protein and responds to short courses of steroid administration. Full article

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

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Open AccessArticle

Divergent Impact of Enzyme Replacement Therapy on Human Cardiomyocytes and Enterocytes Affected by Fabry Disease: Correlation with Mannose-6-phosphate Receptor Expression

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J. Clin. Med. 2022, 11(5), 1344; https://doi.org/10.3390/jcm11051344 - 28 Feb 2022

Cited by 2 | Viewed by 1990

Abstract

Background: The impact of enzyme replacement therapy (ERT) on cardiomyocytes and intestinal cells, affected by Fabry disease (FD), is still unclear. Methods: Six patients with FD, including five family members with GLA mutation c.666delC and one with GLA mutation c.658C > T, manifesting cardiomyopathy and intestinal symptoms (abdominal pain, diarrhea and malabsorption) were included in the study. Clinical outcome, cardiac magnetic resonance (CMR), endomyocardial and gastro-intestinal biopsies were evaluated before and after 2 years of treatment with agalsidase-α (0.2 mg/kg every other week). Immunohistochemistry and Western blot assessments of mannose-6-phosphate receptors (IGF-II-R) on intestinal and myocardial frozen tissue were obtained at diagnosis and after 2 years of ERT. Results: After ERT left ventricular maximal wall thickness, ranging from pre (<10.5 mm) to mild (<15 mm) and moderate hypertrophy (16 mm), was not associated with significant changes at CMR. Degree of dyspnea, mean cardiomyocyte diameter and % vacuolated areas of cardiomyocytes, representing intracellular GL3, remained unmodified. In contrast, intestinal symptoms improved with disappearance of diarrhea, recovery of anemia and weight gain, correlating with near complete clearance of the enterocytes from GL3 inclusions. IGF-II-R expression was remarkably higher even at histochemistry in intestinal tissue compared with myocardium (p < 0.001) either at baseline and after ERT, thus justifying intestinal recovery. Conclusions: Human cells affected by FD may respond differently to ERT: while cardiomyocytes retain their GL3 content after 2 years of treatment, gastro-intestinal cells show GL3 removal with recovery of function. This divergent response may be related to differences in cellular turnover, as well as tissue IGF-II-R expression. Full article

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

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Open AccessArticle

More than 50% of Persistent Myocardial Scarring at One Year in “Infarct-like” Acute Myocarditis Evaluated by CMR

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J. Clin. Med. 2021, 10(20), 4677; https://doi.org/10.3390/jcm10204677 - 13 Oct 2021

Cited by 2 | Viewed by 1263

Abstract

Background: Cardiac magnetic resonance (CMR) has emerged as a reference tool for the non-invasive diagnosis of myocarditis. However, its role in follow-up (FU) after the acute event is unclear. The objectives were to assess the evolution of CMR parameters between the acute phase of infarct-like myocarditis and 12 months thereafter and to identify the predictive factors of persistent myocardial scarring at one year. Methods: All patients with infarct-like acute myocarditis confirmed by CMR were included. CMR was performed within 8 days following symptom onset, at 3 months and at one year. One-year FU included ECG, a cardiac stress test, Holter recording, biological assessments, medical history and a quality-of-life questionnaire. Patients were classified according to the presence or absence of complete recovery at one year based on the CMR evaluation. Results: A total of 174 patients were included, and 147 patients had three CMR. At one year, 79 patients (54%) exhibited persistent myocardial scarring on CMR. A multivariate analysis showed that high peak troponin at the acute phase (OR: 3.0—95%CI: 1.16–7.96—p = 0.024) and the initial extent of late gadolinium enhancement (LGE) (OR: 1.1—95%CI: 1.03–1.19—p = 0.006) were independent predictors of persistent myocardial scarring. Moreover, patients with myocardial scarring on the FU CMR were more likely to have premature ventricular contractions during the cardiac stress test (25% versus 9%, p = 0.008). Conclusion: Less than 50% of patients with infarct-like acute myocarditis showed complete recovery at one year. Although major adverse cardiac events were rare, ventricular dysrhythmias at one year were more frequent in patients with persistent myocardial scarring. Full article

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

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Open AccessArticle

Serum Anti-Heart and Anti-Intercalated Disk Autoantibodies: Novel Autoimmune Markers in Cardiac Sarcoidosis

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J. Clin. Med. 2021, 10(11), 2476; https://doi.org/10.3390/jcm10112476 - 02 Jun 2021

Cited by 7 | Viewed by 2265

Abstract

Background: Sarcoidosis is an immune-mediated disease. Cardiac involvement, a granulomatous form of myocarditis, is under-recognized and prognostically relevant. Anti-heart autoantibodies (AHAs) and anti-intercalated disk autoantibodies (AIDAs) are autoimmune markers in nonsarcoidosis myocarditis forms. Objective: The aim was to assess serum AHAs and AIDAs as autoimmune markers in cardiac sarcoidosis. Methods: This is a cross-sectional study on AHA and AIDA frequency in: 29 patients (aged 46 ± 12, 20 male) with biopsy-proven extracardiac sarcoidosis and biopsy-proven or clinically suspected and confirmed by 18-fluorodeoxyglucose positron emission tomography and/or cardiovascular magnetic resonance (CMR) cardiac involvement; 30 patients (aged 44 ± 11, 12 male) with biopsy-proven extracardiac sarcoidosis without cardiac involvement (no cardiac symptoms, normal 12-lead electrocardiogram, echocardiography and CMR), and control patients with noninflammatory cardiac disease (NICD) (n = 160), ischemic heart failure (IHF) (n = 141) and normal blood donors (NBDs) (n = 270). Sarcoidosis patients were recruited in two recruiting tertiary centers in the USA and Italy. AHAs and AIDAs were detected by indirect immunofluorescence on the human myocardium and skeletal muscle. Results: AHA and AIDA frequencies were higher in sarcoidosis with cardiac involvement (86%; 62%) than in sarcoidosis without cardiac involvement (0%; 0%), NICD (8%; 4%), IHF (7%; 2%) and NBD (9%; 0%) (p = 0.0001; p = 0.0001, respectively). Sensitivity and specificity for cardiac sarcoidosis were 86% and 92% for positive AHAs and 62% and 98% for positive AIDAs, respectively. AIDAs in cardiac sarcoidosis were associated with a higher number of involved organs (p = 0.04). Conclusions: Serum AHAs and AIDAs provide novel noninvasive diagnostic autoimmune markers for cardiac sarcoidosis. Full article

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

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Open AccessArticle

Outcomes of Mechanical Circulatory Support for Giant Cell Myocarditis: A Systematic Review

Preethi R. Pirlamarla

René J. Alvarez

Leslie T. Cooper

J. Eduardo Rame

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Vakhtang Tchantchaleishvili

J. Clin. Med. 2020, 9(12), 3905; https://doi.org/10.3390/jcm9123905 - 01 Dec 2020

Cited by 7 | Viewed by 1698

Abstract

Treatment of giant cell myocarditis (GCM) can require bridging to orthotopic heart transplantation (OHT) or recovery with mechanical circulatory support (MCS). Since the roles of MCS and immunotherapy are not well-defined in GCM, we sought to analyze outcomes of patients with GCM who required MCS. A systematic search was performed in June 2019 to identify all studies of biopsy-proven GCM requiring MCS after 2009. We identified 27 studies with 43 patients. Patient-level data were extracted for analysis. Median patient age was 45 (interquartile range (IQR): 32–57) years. 42.1% (16/38) were female. 34.9% (15/43) presented in acute heart failure. 20.9% (9/43) presented in cardiogenic shock. Biventricular (BiVAD) MCS was required in 76.7% (33/43) of cases. Of the 62.8% (27/43) of patients who received immunotherapy, 81.5% (22/27) used steroids combined with at least one other immunosuppressant. Cyclosporine was the most common non-steroidal agent, used in 40.7% (11/27) of regimens. Immunosuppression was initiated before MCS in 59.3% (16/27) of cases, after MCS in 29.6% (8/27), and not specified in 11.1% (3/27). Immunosuppression started prior to MCS was associated with significantly better survival than MCS alone (p = 0.006); 60.5% (26/43) of patients received bridge-to-transplant MCS; 39.5% (17/43) received bridge-to-recovery MCS; 58.5% (24/41) underwent OHT a median of 104 (58–255) days from diagnosis. GCM recurrence after OHT was reported in 8.3% (2/24) of transplanted cases. BiVAD predominates in mechanically supported patients with GCM. Survival and bridge to recovery appear better in patients on immunosuppression, especially if initiated before MCS. Full article

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

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Open AccessArticle

Inflammation of Conduction Tissue in Patients with Arrhythmic Phenotype of Myocarditis

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J. Clin. Med. 2020, 9(11), 3470; https://doi.org/10.3390/jcm9113470 - 29 Oct 2020

Viewed by 1355

Abstract

Background: Myocarditis can manifest with lone ventricular tachyarrhythmias (LVT). Elective inflammation of conduction tissue (CT) is supposed but unproved. Methods: Forty-two of 420 patients with biopsy proven myocarditis presented with LVT. Twelve of them included CT sections in endomyocardial biopsies. Real-time polymerase chain reaction (PCR) for viral genomes, immunohistochemistry for viral antigens and Toll like receptor 4 (TLR4) were performed. Twelve myocarditis patients with infarct-like or cardiomyopathic phenotype and CT included in tissue section were used as controls. Results: Four of the 12 patients presented non-sustained ventricular tachycardia (nsVT), six with sustained ventricular tachycardia (sVT), two with ventricular fibrillation. CT was inflamed in all LVT patients and not in controls (p < 0.001). PCR was positive for influenza-A virus in two, herpes simplex virus type 2 (HSV2) in one and adenovirus in one with positive CT immunostaining for viral antigens. In eight patients, negative PCR and TLR4 overexpression suggested an immune-mediated pathway. Patients with influenza-A myocarditis and CT infection responded to oseltamivir, those with HSV2 (Herpes Virus 2) and adenovirus infection died. The eight patients with immune-mediated myocarditis were treated with steroids and azathioprine. Seven of them had no more VT(ventricular tachyarrhythmias)during six-month follow-up. Conclusions: Arrhythmic phenotype of myocarditis is associated with CT inflammation/infection. Molecular characterization of CT damage may lead to pharmacologic control of arrhythmias in 75% of cases. Full article

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

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Open AccessArticle

Evaluation of Myocardial Gene Expression Profiling for Superior Diagnosis of Idiopathic Giant-Cell Myocarditis and Clinical Feasibility in a Large Cohort of Patients with Acute Cardiac Decompensation

J. Clin. Med. 2020, 9(9), 2689; https://doi.org/10.3390/jcm9092689 - 19 Aug 2020

Cited by 7 | Viewed by 2191

Abstract

Aims: The diagnostic approach to idiopathic giant-cell myocarditis (IGCM) is based on identifying various patterns of inflammatory cell infiltration and multinucleated giant cells (GCs) in histologic sections taken from endomyocardial biopsies (EMBs). The sampling error for detecting focally located GCs by histopathology is high, however. The aim of this study was to demonstrate the feasibility of gene profiling as a new diagnostic method in clinical practice, namely in a large cohort of patients suffering from acute cardiac decompensation. Methods and Results: In this retrospective multicenter study, EMBs taken from n = 427 patients with clinically acute cardiac decompensation and suspected acute myocarditis were screened (mean age: 47.03 ± 15.69 years). In each patient, the EMBs were analyzed on the basis of histology, immunohistology, molecular virology, and gene-expression profiling. Out of the total of n = 427 patient samples examined, GCs could be detected in 26 cases (6.1%) by histology. An established myocardial gene profile consisting of 27 genes was revealed; this was narrowed down to a specified profile of five genes (CPT1, CCL20, CCR5, CCR6, TLR8) which serve to identify histologically proven IGCM with high specificity in 25 of the 26 patients (96.2%). Once this newly established profiling approach was applied to the remaining patient samples, an additional n = 31 patients (7.3%) could be identified as having IGCM without any histologic proof of myocardial GCs. In a subgroup analysis, patients diagnosed with IGCM using this gene profiling respond in a similar fashion to immunosuppressive therapy as patients diagnosed with IGCM by conventional histology alone. Conclusions: Myocardial gene-expression profiling is a promising new method in clinical practice, one which can predict IGCM even in the absence of any direct histologic proof of GCs in EMB sections. Gene profiling is of great clinical relevance in terms of (a) overcoming the sampling error associated with purely histologic examinations and (b) monitoring the effectiveness of therapy. Full article

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

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Open AccessEditor’s ChoiceReview

“Heart in DRESS”: Cardiac Manifestations, Treatment and Outcome of Patients with Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome: A Systematic Review

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J. Clin. Med. 2022, 11(3), 704; https://doi.org/10.3390/jcm11030704 - 28 Jan 2022

Cited by 13 | Viewed by 3010

Abstract

Cardiac involvement in drug reaction with eosinophilia and systemic symptoms (DS) is rare but associated with high mortality. The aim of this research was to systematically review case reports by PRISMA guidelines in order to synthetize the knowledge of cardiac manifestations of DS. We identified 42 cases from 36 case reports. Women were two times more affected than men. Two-thirds of patients had cardiac manifestation in the initial phase of the disease, while in one-third of cases cardiac manifestations developed later (mean time of 70 ± 63 days). The most common inciting medications were minocycline (19%) and allopurinol (12%). In 17% of patients, the heart was the only internal organ affected, while the majority (83%) had at least one additional organ involved, most commonly the liver and the kidneys. Dyspnea (55%), cardiogenic shock (43%), chest pain (38%), and tachycardia (33%) were the most common cardiac signs and symptoms reported. Patients frequently had an abnormal ECG (71.4%), and a decrease in left ventricular ejection fraction was the most common echocardiographic finding (45%). Endomyocardial biopsy or histological examination at autopsy was performed in 52.4%, with the predominant finding being fulminant eosinophilic myocarditis with acute necrosis in 70% of those biopsied. All patients received immunosuppressive therapy with intravenous steroids, while non-responders were more likely to have received IVIG, cyclosporine, mycophenolate, and other steroid-sparing agents (60%). Gender and degree of left ventricular systolic dysfunction were not associated with outcomes, but short latency between drug exposure and the first DRESS symptom onset (<15 days) and older age (above 65 years) was associated with death. This underscores the potential importance of heightened awareness and early treatment. Full article

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

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Open AccessReview

Viral Myocarditis—From Pathophysiology to Treatment

Heinz-Peter Schultheiss

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J. Clin. Med. 2021, 10(22), 5240; https://doi.org/10.3390/jcm10225240 - 11 Nov 2021

Cited by 17 | Viewed by 6688

Abstract

The diagnosis of acute and chronic myocarditis remains a challenge for clinicians. Characterization of this disease has been hampered by its diverse etiologies and heterogeneous clinical presentations. Most cases of myocarditis are caused by infectious agents. Despite successful research in the last few years, the pathophysiology of viral myocarditis and its sequelae leading to severe heart failure with a poor prognosis is not fully understood and represents a significant public health issue globally. Most likely, at a certain point, besides viral persistence, several etiological types merge into a common pathogenic autoimmune process leading to chronic inflammation and tissue remodeling, ultimately resulting in the clinical phenotype of dilated cardiomyopathy. Understanding the underlying molecular mechanisms is necessary to assess the prognosis of patients and is fundamental to appropriate specific and personalized therapeutic strategies. To reach this clinical prerequisite, there is the need for advanced diagnostic tools, including an endomyocardial biopsy and guidelines to optimize the management of this disease. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has currently led to the worst pandemic in a century and has awakened a special sensitivity throughout the world to viral infections. This work aims to summarize the pathophysiology of viral myocarditis, advanced diagnostic methods and the current state of treatment options. Full article

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

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Open AccessEditor’s ChoiceReview

Epidemiological Impact of Myocarditis

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J. Clin. Med. 2021, 10(4), 603; https://doi.org/10.3390/jcm10040603 - 05 Feb 2021

Cited by 38 | Viewed by 11051

Abstract

Myocarditis is an inflammatory disease of the heart muscle with a wide range of potential etiological factors and consequently varying clinical patterns across the world. In this review, we address the epidemiology of myocarditis. Myocarditis was considered a rare disease until intensified research efforts in recent decades revealed its true epidemiological importance. While it remains a challenge to determine the true prevalence of myocarditis, studies are underway to obtain better approximations of the proportions of this disease. Nowadays, the prevalence of myocarditis has been reported from 10.2 to 105.6 per 100,000 worldwide, and its annual occurrence is estimated at about 1.8 million cases. This wide range of reported cases reflects the uncertainty surrounding the true prevalence and a potential underdiagnosis of this disease. Since myocarditis continues to be a significant public health issue, particularly in young adults in whom myocarditis is among the most common causes of sudden cardiac death, improved diagnostic and therapeutic procedures are necessary. This manuscript aims to summarize the current knowledge on the epidemiology of myocarditis, new diagnostic approaches and the current epidemiological impact of the COVID-19 pandemic. Full article

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

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