Inflammatory Disease Of Heart Muscle Research Articles

Association between anti-cardiac autoantibodies in acute myocarditis and downstream clinical outcomes

Abstract Introduction Myocarditis is an inflammatory heart muscle disease that can result in cardiac dysfunction and arrhythmias. Its aetiology includes infectious, toxic or autoimmune causes. Myocarditis is responsible for sudden cardiac death in young adults (1) and can result in heart failure due to dilated cardiomyopathy in 20% of patients (2). The pathogenesis of myocarditis may involve immune system dysregulation leading to a cascade of inflammation and myocardial damage (3). For those patients that rapidly progress to end-stage dilated cardiomyopathy, an important dilemma is whether there is any prospect of heart function recovery. Therefore, there is an unmet need for a better understanding of key causal pathways and for developing a biological signature of disease progression. Hypothesis The progression of acute myocarditis depends on a persistent adaptive immune response against the heart, leading to ongoing inflammation, myocardial fibrosis and ultimately tissue destruction and remodelling. Aims We sought to explore anti-cardiac IgG serum levels, their temporal profile throughout follow up and their association with clinical and imaging data, in patients presenting with acute myocarditis. Methods We prospectively recruited 80 patients with a clinical diagnosis of acute myocarditis. We measured their total anti-cardiac IgG levels at admisssion, 3- and 12-months follow-up using an enzyme-linked immunosorbent assay (ELISA). We explored the association between the anti-cardiac IgG levels, cardiac MRI parameters (CMR) and clinical data. Results We detect an adaptive immune response against the heart in a subgroup of patients with acute myocarditis. 20% of patients develop high systemic titres of anti-cardiac IgG (OD threshold >0.65), within the first 7 days of presentation (Figure 1a). These patients continue to have persistent and significantly higher anti-cardiac IgG levels at 12 months (Figure 1b). Importantly, patients that mount a strong initial adaptive immune response against the heart, are more likely to show evidence of persistent oedema on CMR at 12 months(Figure 1c). Clinical event rates in our cohort have remained low at five-year follow-up. A small signal exists to indicate potentially higher rates of persistent symptoms (70% vs 47%), hospitalisations for heart failure (12% vs 8%) and new heart failure diagnosis (18% vs 11%), in patients that mount a strong adaptive immune response compared to those that do not. Conclusion A subset of patients with acute myocarditis develops a strong and persistent adaptive immune response against the heart. This may be associated with more myocardial oedema on cardiac MRI, persistent symptoms and higher rates of heart failure diagnoses and hospitalisations. Further work Plasma proteomics (targeted and un-targeted discovery) with validation in myocardial tissue. Analysis of CMR data with a focus on fibrosis assessment. ELISA for IgG subtypes and total IgG against myosin and troponin I.

The Influence of Diagnoses of Specific Viral Infections on In-Hospital Mortality, Length of Stay and Cost in Patients Admitted to Hospital with a Diagnosis of Myocarditis: An Analysis of the National Inpatient Sample.

The influence of different viral infections in patients with myocarditis is unknown. Myocarditis is an inflammatory disease of heart muscle that is commonly caused by viruses. The impact of different viral infections in patients with myocarditis is unknown. We conducted a retrospective cohort study using data between 2016-2020 in the National Inpatient Sample in the USA to evaluate admissions with myocarditis and concomitant viral infection. The outcomes of in-hospital mortality, length of stay (LoS), and cost, among patients hospitalized for myocarditis was evaluated. A total of 27,050 hospital admissions for myocarditis were included and 6750 (25.0%) had a co-diagnosis of viral infection. Patients with myocarditis and viral infection had significantly higher mortality compared to those without viral infection (23.6% vs. 4.4%, p 0.001). Viral infection was associated with increased in-hospital mortality (odds ratio (OR) 2.03, 95% CI 1.51 to 2.73, p 0.001), greater median LoS (7 vs. 3 days, p 0.001) and median hospitalization cost ($21,445 vs. $11,596, p 0.001), compared to patients without viral infection. The rate of death was greatest for patients with a diagnosis of coronavirus disease 2019 (COVID-19), viral pneumonia and herpes zoster, respiratory syncytial virus, chronic hepatitis, and influenza which was 36.0%, 34.3%, 27.3%, 21.4%, 20.0%, and 14.5%, respectively. In conclusion, the diagnosis of viral infection is present in one in four patients hospitalized with myocarditis and is correlated with greater mortality, LoS, and in-hospital cost.

Abstract 13941: RNA-Sequencing Reveals a Distinct Transcriptomic Signature for Giant Cell Myocarditis and Identifies Novel Druggable Targets

Introduction: Giant cell myocarditis (GCM) is a rare inflammatory heart muscle disease that is often rapidly progressive and carries a poor prognosis. The pathogenesis of GCM is incompletely understood, but is thought to be autoimmune in nature. An improved mechanistic understanding of GCM is critical for identifying novel therapeutic targets and improving survival. Hypothesis: We hypothesized that GCM exhibits a distinct transcriptomic profile. By querying database of drug-gene interactions, novel drug targets could be identified. Methods: We performed RNA-seq utilizing FFPE tissues. Results: Demographics and clinical characteristics of the groups are highlighted in Panel A. Principal component analysis (B) based on complete expression profiles and unsupervised hierarchical cluster analysis of significant differentially expressed genes identified a distinct transcriptomic profile for GCM (C). Consistent with shared histological features, overlap is noted between rejection and lymphocytic myocarditis. Pathway enrichment analysis (D) in GCM showed that upregulated pathways were enriched for neutrophil degranulation, multiple cytokine signaling pathways, and phagocytosis, while downregulated pathways included those involved in muscle contraction and cardiac conduction. The most significantly upregulated genes play roles in innate and adaptive immune responses (E). Querying the Drug Gene Interaction Database (DGIdb) identified several novel biologically-plausible therapeutic targets (F). Conclusions: To our knowledge, this is the first study using RNA-seq to interrogate the transcriptomic profile of GCM. Our results demonstrate that GCM has a gene expression profile that mirrors clinical and histopathological features of GCM, and is distinct from the transcriptomic profiles seen in other healthy and inflammatory cardiac diseases. By querying a drug-gene interaction database, several novel drug targets were identified.

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.

Long non-coding RNAs in cardiac hypertrophy.

Cardiac hypertrophy (CH) is generally considered adaptive responses that may occur after myocardial infarction, pressure overload, volume overload, inflammatory heart muscle disease, or idiopathic dilated cardiomyopathy, whereas long-term stimulation eventually leads to heart failure (HF). However, the current molecular mechanisms involved in CH are unclear. Recently, increasing evidences reveal that long non-coding RNAs (lncRNAs) play vital roles in CH. Different lncRNAs can promote or inhibit the pathological process of CH by different mechanisms, while the regulation of lncRNAs expression can improve CH. Thus, CH-related lncRNAs may become a novel field of research on CH.

Dynamic changes of heart structural and functional condition in patients with acute myocarditis

Diagnosis and prognosis of myocarditis course, which is an inflammatory heart muscle disease, has been and remains one of the most urgent, complex and unresolved problem in modern cardiology. The purpose of the study – to investigate the dynamic changes in the structural and functional heart state in patients with acute myocarditis and reduced left ventricular ejection fraction. Materials and methods. In total, 74 patients with clinically suspected acute myocarditis (AM) with reduced left ventricular (LV) ejection fraction (EF) ≤40 % and NYHA heart failure (HF) functional class II or higher were examined three times: in the first month of myocarditis debut, after 6 and 12 months of observation. All the patients underwent echocardiography and speckle-tracking echocardiography, Holter electrocardiogram monitoring and cardiac magnetic resonance imaging (MRI). Results. It was found that the debut of AM was characterized by the presence of active inflammatory process according to the cardiac MRI - edema and hyperemia of the myocardium were detected in 54.0 % and 70.2 % of cases, respectively, followed by LV dilation and systolic dysfunction as well as by a significant decrease in longitudinal and circumferential LV global systolic strain. After 12 months of observation, there was a significant increase in LV EF, decrease in end-diastolic volume index and an improvement in the parameters of longitudinal and circumferntial LV systolic strain by 30.8 % and 36.8 %, respectively, (P < 0.01), the frequency of active inflammatory changes in the myocardium was significantly reduced, herewith in 41.8 % of cases, delayed enhancement was noted, indicating fibrotic changes in the myocardium. The presence of delayed enhancement in cardiac MRI after 12 months since myocarditis onset was correlated with the presence of unstable ventricular tachycardia episodes (r = 0.62; P < 0.02) and with the frequency of ventricular extrasystoles (r = 0.53; P < 0.05). A significant influence of fibrotic changes in the myocardium on the presence of unstable ventricular tachycardia episodes in 12 months after the disease onset was confirmed by determining Fisher's exact test, its value was: P = 0.016 (P < 0.05). Conclusions. It was established that the debut of myocarditis was characterized by a significant violation of the structural and functional heart state: an active inflammatory process in the myocardium causedLV dilatation and contractile dysfunction. After 12 months, a decrease in detection of active inflammatory myocardial changes followed by regression ofLV dilation and its contractile function improvement was observed. It was proved that the presence of fibrotic changes in the myocardium in patients with myocarditis was associated with the persistence of ventricular rhythm disorders.

Entzündliche Herzmuskelerkrankung als Ursache einer Herzinsuffizienz

Myocarditis is an inflammatory disease of the cardiac muscle caused by myocardial infiltration of immunocompetent cells following any kind of cardiac injury. Myocarditis is a challenging diagnosis due to the heterogeneity of clinical presentations. It can be caused by infections, drugs, toxic substances, and autoimmune diseases. Chronic inflammatory events may survive successful clearance of initial cardiotoxic agents, be triggered or amplified by autoimmunological processes, or develop in the context of systemic diseases. Progression of myocarditis to its sequela, dilated cardiomyopathy, has been documented in 25 % of cases and is pathogenically linked to chronic inflammation and viral persistence. Therapeutic decisions must be based on the results of endomyocardial biopsy studies while taking account of the individual patient's clinical course. Moreover, specific immunosuppressive and antiviral treatment can help only if a treatable cause is present (e. g., a viral infection, or inflammatory process), and only if the myocardium still has regenerative potential. Once irreversible myocardial injury has occurred then the development or progression of heart failure in the long term can no longer be prevented. The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management of aetiology-driven treatment in inflammatory heart muscle disease.

Acute viral hepatitis e is associated with the development of myocarditis.

Myocarditis, an inflammatory disease of heart muscle, is an important cause of dilated cardiomyopathy worldwide. Viral infection is an important cause of myocarditis. This condition presents with various symptoms, ranging from minimally symptomatic cases to fatal arrhythmia and cardiogenic shock, and may develop chronic myocarditis and dilated cardiomyopathy in some patients. We report the case of a 26-year-old patient with acute viral hepatitis E who developed symptomatic myocarditis. As far as we could search, this is probably the 3rd case report of this rare association.

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

In this position statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviews the current knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposes new diagnostic criteria for clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms. The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management and provide a common reference point for future registries and multicentre randomised controlled trials of aetiology-driven treatment in inflammatory heart muscle disease.

Myocarditis and dilated cardiomyopathy: possible connections and treatments

Myocarditis is an inflammatory heart muscle disease, resulting from various etiologies, both noninfectious and infectious, which may be associated or not with cardiac dysfunction. Its course is unpredictable: it may spontaneously resolve or evolve into dilated cardiomyopathy and heart failure. A possible connection between myocarditis and dilated cardiomyopathy has long been postulated, but the intimate mechanisms linking these two conditions are still poorly understood. Viral myocarditis could induce a dilated cardiomyopathy through viral persistence and/or by triggering an autoimmune process. Understanding the mechanisms underlying the relationship between myocarditis and dilated cardiomyopathy will help in identifying an effective strategy of treatment aimed to stop and prevent cardiac damage. Specifically, we need to (a) evaluate the potential role of autoantibodies in disease prevention and progression, and understand their importance as markers of disease progression; (b) clarify the role of immunoregulation in exacerbating the disease.

Viral Genomic Detection and Outcome in Myocarditis

Myocarditis, particularly in children, remains a major cause of morbidity and mortality worldwide. This article discusses diagnosis of viral infection, molecular and alternative diagnostic techniques, association between detection of virus and outcome, and therapeutics of myocarditis. The detection of viral genomic sequences seems to correlate with adverse outcomes in patients who have inflammatory heart muscle disease and treatment regimens that result in viral clearance seem to be effective. Until alternative techniques become available, analysis of endomyocardial biopsy samples for virus and by histology will remain important for the diagnosis and potentially treatment of this disease.

Molecular Aspects of Myocarditis.

Myocarditis is an acquired form inflammatory heart muscle disease, manifested as acute and chronic conditions. While many etiologies have been reported, the most common cause of this disease is infection, primarily viral. Typically, the specific causative agent(s) and mechanism(s) are elusive. Over the past several years, various new findings have added to our understanding of myocarditis. These include the identification of adenoviruses as important causative agents, a new receptor protein likely to play an important role in the virulence of certain agents affecting the myocardium, and the effect of viruses on the cardiac cytoskeleton. This report reviews the current understanding of myocarditis, proposes a hypothesis about the long-term sequelae, and suggests possible new therapeutic strategies.

Prevalence of viral genome in endomyocardial biopsies from patients with inflammatory heart muscle disease.

In the report of the 1995 World Health Federation/International Society and Federation of Cardiology (WHF/ISFC) Task Force on the Definition and Classification of Cardiomyopathies, the definition of heart muscle diseases was updated. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy are now recognized in this definition. Enteroviruses, adenoviruses and cytomegaloviruses are considered as main etiopathological factors in the pathogenesis of inflammatory heart disease. A wide range of different assays have been and are currently being used, either alone or in combination, to assay for the presence of enteroviral RNA and/or DNA of cytomegalo- and adenoviruses in endomyocardial biopsy and explanted heart samples. The prevalence of cardiotropic viruses in endomyocardial biopsies of patients with clinically suspected inflammatory cardiomyopathy varies widely: enteroviral genome was detected in endomyocardial biopsies of 3 to 53% of patients, cytomegaloviral DNA was detected in 3 to 40% of patients with inflammatory heart disease and adenoviruses in 3 to 23% of the patients. This report summarizes the methods that have been used and the results of molecular biological investigation with polymerase chain reaction, which were reported by several groups over the last years. Taking this together it seems to be clear that the improvement of molecular biological techniques and the experience of people working with these methods will lead to more reliable results on prevalence, persistence and the diagnostic value of these investigations. These findings have to be taken into account in future diagnostic and therapeutic studies in the field of cardiomyopathies.

Detection of viral and bacterial protein in endomyocardial biopsies of patients with inflammatory heart muscle disease?

The development of highly sensitive molecular biological methods such as in-situ hybridization and polymerase chain reaction (PCR) made it possible to detect viral/bacterial nucleic acid in human endomyocardial biopsies. However, only a few investigations addressed the problem of latent persistence of viral and bacterial genome and the detection of the corresponding proteins, which could have important consequences for the clinical course of the disease. The purpose of this study was to determine whether protein of various viruses (adenovirus, enterovirus, cytomegalovirus, influenza A and B virus, herpes simplex virus 1 and 2) and bacteria (chlamydia pneumonia) can be detected in endomyocardial biopsies of patients with myocarditis and dilated cardiomyopathy with and without inflammation by use of an immunofluorescence assay and to compare the frequency of its detection with the results of PCR, immunohistology and serology. Thirty-nine patients with myocarditis and dilated cardiomyopathy with and without inflammation were examined by a direct immunofluorescence assay using the endomyocardial biopsy as antigen. Each of the samples was additionally studied by immunohistological methods and PCR for the detection of infiltrating cells and the genome of cardiotropic viruses or bacteria. Fourteen of patients were considered to have myocarditis (group 1), 9 dilated cardiomyopathy with inflammation (group 2), 10 dilated cardiomyopathy (group 3), 6 to have no myocarditis or dilated cardiomyopathy (group 4). Using a direct immunofluorescence assay we could show only that 1 patient without histological myocarditis or dilated cardiomyopathy (group 4) was positive for influenza B and chlamydia pneumonia antigens in the endomyocardial biopsy. In addition we have determined influenza B-specific antibodies, such as IgG (marginal titer) and IgA (high titer) and chlamydia pneumonia-specific antibodies, such as IgG (marginal titer) in serum of this patient. A second patient with dilated cardiomyopathy was found to be positive for protein of chlamydia pneumonia, who was shown to have chlamydia pneumonia-specific antibodies, such as IgG (high titer) in serum. There was no correlation with PCR results, but good correlation with influenza B and chlamydia pneumonia-specific antibodies in sera of these patients. In this investigation we have determined viral/bacterial-specific antibodies using serological methods and proteins of these agents using immunoflourescence. Despite the detection of virus or bacteria-specific antibodies in the sera and detection of viral and/or bacterial protein in the biopsies of some of the patients viral and/or bacterial genome was not found in the biopsy. This may be explained by the focal character of myocarditis and sampling error, because for technical reasons we use different biopsies for immunohistochemical and molecular biological investigations.

Sites other than nucleotide 234 determine cardiovirulence in natural isolates of coxsackievirus B3

The genetic site(s) that naturally determine the cardiovirulence phenotype of coxsackievirus B3 (CVB3) have yet to be mapped. Using two closely related CVB3 strains that differed in terms of cardiovirulence phenotype in mice, we previously reported the difference in phenotype mapped to a single site, nucleotide 234 (nt234) in the 5' non-translated region (NTR) of the CVB3 genome. When nt234 was C, the virus was attenuated and when U, the virus was cardiovirulent. To determine whether this finding was applicable to other strains of CVB3, we examined 13 different naturally occurring CVB3 strains isolated in different years in the United States. We determined that only two isolates induced severe inflammatory heart muscle disease in C3H/HeJ male mice. Using PCR products as sequencing templates, we determined the 5' NTR sequence from each viral genome. Alignment of these sequences and other published CVB3 5' NTR sequences suggests as many as four separate lineages, with commonly used laboratory strains clustering closely in one branch. An examination of the sequences showed that regardless of cardiovirulence phenotype, nt234 was invariably uridine. Thus, the previously reported cytidine at nt234 is most likely the result of a rare mutation and is not a naturally occurring variation and other sites must account for the variance in virulence seen in natural isolates of CVB3.

Genetics of coxsackievirus virulence.

The first reported isolate of the coxsackieviruses occurred in the upstate New York town of Coxsackie (Dalldorf and Sickles 1948). By the mid-late 1950s (Dalldorf 1955), the coxsackie B viruses (CVBs) had been shown to be agents of severe human inflammatory heart muscle disease (myocarditis) (Montgomery et al. 1955; Gear et al. 1956; Javett et al. 1956; van Creveld and de Jager 1956; Verlinde et al. 1956; Fletcher and Brennan 1957; Kibrick and Benirschke 1958; Simenhoff and Ulys 1958). In the intervening years, the CVBs have been confirmed as etiologic agents of, or etiologically linked to, a host of human diseases ranging from flu-like illness through severe inflammatory diseases of the heart and central nervous system (Melnick 1990; Chaps. 2–4 ). Based on molecular detection data, it is estimated that enteroviruses (likely in most cases to be CVBs) are etiologic agents in perhaps 20%–25% of the cases of inflammatory heart disease (or myocarditis) and dilated cardiomyopathy (DCM), although individual reports range from 0%–53% (Bowles et al. 1986; Easton and Eglin 1988; Tracy et al. 1990; Kandolf and Hofschneider 1991; Grasso et al. 1992; reviewed in Martino et al. 1995). DCM alone afflicts approximately five to eight per 100 000 per year worldwide (Williams and Olsen 1985; Manolio et al. 1992). In the aggregate, these data indicate that there are at least 5000 or more occurrences of enterovirus-induced DCM alone per year in the United States.

A non-cardiovirulent strain of coxsackievirus B3 causes myocarditis in mice with severe combined immunodeficiency syndrome.

The most extensively studied animal model of coxsackievirus B3 (CVB3)-induced inflammatory heart muscle disease is the murine model. In the acute and chronic phase of the disease, it has been suggested that autoimmune mechanisms play a major role in the pathogenesis of the disease. In this study, C3H mice without functional T- and B-lymphocytes (C3H SCID) were inoculated either with a cardiovirulent (CVB3/20) or a non-cardiovirulent (CVB3/0) strain of coxsackievirus B3. Both viruses caused myocarditis in SCID mice. Furthermore, it could be demonstrated, that CVB3/0 had mutated to a cardiovirulent phenotype, able to cause myocarditis in immunocompetent mice.