Inflammatory Cardiomyopathy Research Articles

Myocardial inflammation is associated with impaired mitochondrial oxidative capacity in ischaemic cardiomyopathy.

Myocardial inflammation and impaired mitochondrial oxidative capacity are hallmarks of heart failure (HF) pathophysiology. The extent of myocardial inflammation in patients suffering from ischaemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) and its association with mitochondrial energy metabolism are unknown. We aimed at establishing a relevant role of cardiac inflammation in the impairment of mitochondrial energy production in advanced ischaemic and non-ischaemic HF. We included 81 patients with stage D HF (ICM, n=44; DCM, n=37) undergoing left ventricular assist device implantation (n=59) or heart transplantation (n=22) and obtained left ventricular tissue samples during open heart surgery. We quantified mitochondrial oxidative capacity, citrate synthase activity (CSA) and fibrosis and lymphocytic infiltration. We considered infiltration of >14 CD3+ cells/mm2 relevant inflammation. Patients with ICM or DCM did not differ regarding age (61.5±5.7 vs. 56.5±12.7years, P=0.164), sex (86% vs. 84% male, P=0.725), type 2 diabetes mellitus (34% vs. 18%, P=0.126) or chronic kidney disease (8% vs. 11%, P=0.994). ICM exhibited oxidative capacity reduced by 23% compared to DCM (108.6±41.4 vs. 141.9±59.9pmol/(s*mg), P=0.006). Maximum production of reactive oxygen species was not significantly different between ICM and DCM (0.59±0.28 vs. 0.69±0.36pmol/(s*ml), P=0.196). Mitochondrial content, detected by CSA, was lower in ICM (359.6±164.1 vs. 503.0±198.5nmol/min/mg protein, P=0.002). Notably, relevant inflammation was more common in ICM (27% vs. 6%, P=0.024), and the absolute number of infiltrating leucocytes correlated with lower oxidative capacity (r=-0.296, P=0.019). Fibrosis was more prevalent in ICM (20.9±21.2 vs. 7.2±5.6% of area, P=0.002), but not associated with oxidative capacity (r=-0.13, P=0.327). More than every fourth ICM patient with advanced HF displays myocardial inflammation in the range of inflammatory cardiomyopathy associated with reduced mitochondrial oxidative capacity. Future studies may evaluate inflammation in ICM at earlier stages in standardised fashion to explore the therapeutic potential of immunosuppression to influence trajectories of HF in ICM.

High prevalence of cardiotropic viruses in endomyocardial biopsies from patients with inflammatory cardiomyopathy demonstrated by a novel targeted NGS approach

Abstract Background Viral infection of the heart muscle is a common cause of myocarditis and viral persistence can lead to chronic inflammatory cardiomyopathies (DCMi). A number of viruses including parvovirus B19 (B19V), adenovirus (AdV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes virus 6 (HHV-6) and enteroviruses (EV) are known to infect the myocardium, but their prevalence and role in persisting DCMi are not well understood. Virological etiologies can only be determined via endomyocardial biopsy (EMB), but the low tissue amount limits the number of conventional viral nucleic acid tests (virus-specific PCR) that can be performed in parallel. This study aimed to detect known and novel cardiotropic viruses in EMB of DCMi patients using a targeted next generation sequencing (NGS) approach. Methods A cohort of 33 patients with inflammatory cardiomyopathy (DCMi) (LVEF=29±12%) were retrospectively analyzed and compared to previous results of virus-specific PCR. DNA and RNA extracted from EMB were used for sequencing library preparation, and viral nucleic acids were enriched via a custom myBaits hybridization capture approach. Enriched libraries were sequenced on an Illumina MiSeq-platform in paired-end mode (500.000 reads/sample), and reads were taxonomically classified via Kraken2 and mapped against viral reference genomes using BWA-MEM2 or HiSat2, and subsequently deduplicated. Viral reads detected via both Kraken2 and mapping were classified as valid. Results Targeted NGS confirmed 19 out of 22 (86%) of the previous PCR-based viral detections. However, NGS was able to detect B19V DNA and RNA in an additional 11 and 15 patient samples respectively; CMV DNA/RNA in additional 5 and 4 samples respectively; EBV DNA/RNA in additional 5 and 1 samples respectively; and HHV-6 DNA/RNA in additional 3 and 1 samples respectively. Furthermore, viral reads of adenovirus type 2, adenovirus-associated virus type 2 (AAV-2), herpes viruses 7 and 8, and human parvovirus 4 were also found among the cohort. Thus, targeted NGS was able to identify 82 viral infections in a cohort of 33 DCMi patients, while only 22 were found using routine PCR tests. For routinely tested B19V, the use of the new NGS diagnostic approach improved sensitivity by 42% and specificity by 72%. Conclusions The presented NGS method represents a powerful new tool for the diagnosis of viral and inflammatory heart disease. The sensitivity is significantly higher than with conventional PCR approaches and the taxonomic classification is more specific. This enables the detection of previously false-negative routine viruses as well as potentially new cardiotropic pathogens from limited bioptic patient material – thus significantly increasing the diagnostic yield of EMB. In addition, our study demonstrates a high prevalence of non-enteroviral cardiotropic viruses in DCMi patients, shedding new light on the etiology of this heterogenous diseases and paving the way for more specific future treatments.

Ringlike late gadolinium enhancement: prevalence, association with cardiac phenotype, and patient outcome in an unselected cohort referred for cardiovascular magnetic resonance imaging

Abstract Background The identification of a non-ischemic ringlike enhancement in the left ventricular (LV) myocardium by cardiac magnetic resonance imaging (CMR) has emerged as a significant biomarker associated with arrhythmogenic cardiomyopathy (CMP) and adverse patient outcomes. Recently, the term "scarring CMP" has been also proposed to encompass various conditions characterized by a high burden of non-ischemic, often ring-like, myocardial scarring, including both genetic and acquired etiologies. Purpose To systematically evaluate CMR phenotypic traits and etiologic backgrounds in patients with ringlike enhancement and to assess the burden of adverse outcomes during follow-up (FU). Methods This is a single-center, retrospective analysis of prospectively enrolled patients undergoing CMR (from 2002 to 2024). Ringlike late gadolinium enhancement (LGE) was defined as continuous enhancement in three or more adjacent segments based on the AHA 17 segment model. Patients records were reviewed for etiologic classification and FU assessment. Results Among 23.472 patients, 19.696 (84%) underwent LGE assessment. In 152 patients (0.77%; 73% male; mean age 48.5 ± 17 years) a ringlike LGE was identified. The mean number of LV segments with LGE was 10 ± 3. Right ventricular (RV) LGE was present in 23% of subjects. LV fatty metaplasia was detected in 22%. Infero-lateral segments were most frequently affected. CMR showed the following morpho-functional features: LV dilatation (53%), LV hypokinesia (69%), LV hypertrophy (10.5%), LV non-compaction (11%), RV dilation (26%), and RV ejection fraction < 40% (21%). Phenotypic classification according to 2023 ESC guidelines identified dilated CMP phenotype (43%), non-dilated LV CMP phenotype (39%), predominant arrhythmogenic right ventricular phenotype (6%), hypertrophic phenotype (7%). 5% of cases remained unclassified, all of them showing LV dilated non-hypokinetic phenotype. Genetic analysis was performed in 101 patients (66%). Etiologic classification revealed non-desmosomal gene related CMP (24%), desmosomal gene related CMP (8%), inflammatory CMP (16%), genetic neuromuscular diseases (5%), congenital metabolic errors (3%), familiar gene elusive CMP (2%) and unknown etiology (45%). Notably, only 17% of patients classified as having inflammatory CMP and 66% of those with unknown etiology underwent genetic testing, with negative results. The median follow-up duration was 3 (IQR: 1-7) years. All-cause mortality occurred in 10.5% of patients, while 17% experienced sustained ventricular tachycardia, appropriate implantable cardioverter-defibrillator therapies, or sudden cardiac death. Heart transplantation or left ventricular assist device implantation was required in 8% of cases. Conclusion Ringlike LGE is a rare, non-disease-specific feature that can be found in different morpho-functional CMP phenotypes. It is associated with frequent genetic-determined etiology and high burden of arrhythmic and non-arrhythmic outcomes.

The diagnostic value of endomyocardial biopsy in the era of precision medicine: data from over 8,000 patients with comprehensive biopsy diagnostics

Abstract Background Endomyocardial biopsy (EMB) is an important diagnostic tool for evaluating various cardiac diseases such as myocarditis and storage disorders as well as for the monitoring heart transplant patients. Despite advances in non-invasive imaging techniques to characterize myocardial tissue, EMB remains the gold standard for definitive diagnosis and initiation of specific therapy. Here we report EMB laboratory results from over 8,000 patients and demonstrate the diagnostic utility of EMB. Methods and results We retrospectively reviewed EMB analyses performed at our institution. EMBs for monitoring graft rejection were not included in this study. Clinical data, suspected clinical diagnoses and EMB-based laboratory results were collected. Histopathological, immunohistochemical and molecular biology biopsy findings were recorded and reviewed for degree of concordance with clinical diagnosis. In total, EMBs from N=8,085 consecutive patients with unexplained heart failure were analyzed. The comprehensive EMB analysis revealed that N=616 (7.6%) patients had cardiac storage disease, most of whom had cardiac amyloidosis (N=606). N=357 (4.4%) patients were diagnosed with acute forms of myocarditis, including N=95 cases with active myocarditis, N=148 cases with giant cell myocarditis, N=95 cases with sarcoidosis and N=19 cases with eosinophilic myocarditis. A total of N=3,392 (42%) patients were found to have inflammatory heart disease such as inflammatory cardiomyopathy and borderline myocarditis, whereby a differentiation of the inflammatory infiltrates revealed considerable differences in the quality of inflammation. Viral genomes were found in the myocardium of N=6,072 (75%) patients, with treatment-relevant viral infections detected in N=2,015 (25%) cases. The remaining N=1,705 (21%) patients were diagnosed with other cardiomyopathies, including dilated cardiomyopathy (N=1,252), heart failure with preserved ejection fraction (N=325), hypertrophic cardiomyopathy (N=117) and arrhythmogenic right ventricular cardiomyopathy (N=11). Conclusions This retrospective study of over 8,000 patients with heart failure clearly shows that a definitive diagnosis is only possible with a comprehensive EMB diagnosis and leads to specific therapy in 79% of the cases. In the remaining 21% of patients, infectious and inflammatory causes could be excluded in order to initiate standard heart failure therapy. It is important to emphasize here that the quality of the inflammation and therapy-relevant viral infections cannot be detected with imaging techniques, which underlines the clinical-therapeutic importance of endomyocardial biopsy.

Neutrophil extracellular traps are an important component of chronic myocardial inflammation in patients with heart failure

Abstract Background and aim We have previously shown that heart failure (HF) is characterized by chronic inflammation. However, the role of neutrophils (N) and extracellular neutrophil traps (NETs) in the myocardium of patients with HF is largely unknown. The present study investigated the number of neutrophils (N) and their proportion that develop NETs in HF. Methods We used quantitative confocal microscopy and NETs markers in the left ventricular biopsies obtained from 5 controls and from patients with HF due to dilated (DCM, n=7), ischemic (ICM, n=7) and inflammatory (infCMP, n=7) cardiomyopathy. We used immunolabeling for CD45 (N) and for NETs (citrullinated histone 3 (CitH3), peptidylarginine deiminase-4 (PAD-4), neutrophil elastase (NE) and myeoloperoxidase (MPO). Results Compared to the control, the number of N was 4.3-5.7 times higher in HF. Using single labeling for NETs marker revealed that 41.1±4.6% of N in DCM, 42.9±4.1% in ICM and 47.6±2.9% in infCMP developed NETs. The use of dual labeling (MPO with CitH3, MPO with PAD-4 and CitH3 with NE) resulted in 54.5±4.7% of N-developing NETs in DCM, 59.5±4.1% in ICM and 77.6%±4.2 in infCMP. The difference between N-undergoing NETs was statistically different in infCMP than in DCM.and ICM. The proportion of N-forming NETs in control tissue was less than 5% and was significantly different from that in HF patients regardless of etiology. Conclusions This is the first study to show the presence of NETs in human hearts in situ and demonstrates that NETs are an important component of chronic inflammation in HF due to cardiomyopathies.

The Desmoplakin Phenotype Spectrum: Is the Inflammation the "Fil Rouge" Linking Myocarditis, Arrhythmogenic Cardiomyopathy, and Uncommon Autoinflammatory Systemic Disease?

Myocarditis is an inflammatory condition of cardiac tissue presenting significant variability in clinical manifestations and outcomes. Its etiology is diverse, encompassing infectious agents (primarily viruses, but also bacteria, protozoa, and helminths) and non-infectious factors (autoimmune responses, toxins, and drugs), though often the specific cause remains unidentified. Recent research has highlighted the potential role of genetic susceptibility in the development of myocarditis (and in some cases the development of inflammatory dilated cardiomyopathy, i.e., the condition in which there is chronic inflammation (>3 months) and left ventricular dysfunction\dilatation), with several studies indicating a correlation between myocarditis and genetic backgrounds. Notably, pathogenic genetic variants linked to dilated or arrhythmic cardiomyopathy are found in 8-16% of myocarditis patients. Genetic predispositions can lead to recurrent myocarditis and a higher incidence of ventricular arrhythmias and heart failure. Moreover, the presence of DSP mutations has been associated with distinct pathological patterns and clinical outcomes in arrhythmogenic cardiomyopathy (hot phases). The interplay between genetic factors and environmental triggers, such as viral infections and physical stress, is crucial in understanding the pathogenesis of myocarditis. Identifying these genetic markers can improve the diagnosis, risk stratification, and management of patients with myocarditis, potentially guiding tailored therapeutic interventions. This review aims to synthesize current knowledge on the genetic underpinnings of myocarditis, with an emphasis on desmoplakin-related arrhythmogenic cardiomyopathy, to enhance clinical understanding and inform future research directions.

Identification of potential therapeutic targets for nonischemic cardiomyopathy in European ancestry: an integrated multiomics analysis

BackgroundNonischemic cardiomyopathy (NISCM) is a clinical challenge with limited therapeutic targets. This study aims to identify promising drug targets for NISCM.MethodsWe utilized cis-pQTLs from the deCODE study, which includes data from 35,559 Icelanders, and SNPs from the FinnGen study, which includes data from 1,754 NISCM cases and 340,815 controls of Finnish ancestry. Mendelian randomization (MR) analysis was performed to estimate the causal relationship between circulating plasma protein levels and NISCM risk. Proteins with significant associations underwent false discovery rate (FDR) correction, followed by Bayesian colocalization analysis. The expression of top two proteins, LILRA5 and NELL1, was further analyzed using various NISCM datasets. Descriptions from the Human Protein Atlas (HPA) validated protein expression. The impact of environmental exposures on LILRA5 was assessed using the Comparative Toxicogenomics Database (CTD), and molecular docking identified the potential small molecule interactions.ResultsMR analysis identified 255 circulating plasma proteins associated with NISCM, with 16 remaining significant after FDR correction. Bayesian colocalization analysis identified LILRA5 and NELL1 as significant, with PP.H4 > 0.8. LILRA5 has a protective effect (OR = 0.758, 95% CI, 0.670–0.857) while NELL1 displays the risk effect (OR = 1.290, 95% CI, 1.199–1.387) in NISCM. Decreased LILRA5 expression was found in NISCM such as diabetic, hypertrophic, dilated, and inflammatory cardiomyopathy, while NELL1 expression increased in hypertrophic cardiomyopathy. HPA data indicated high LILRA5 expression in neutrophils, macrophages and endothelial cells within normal heart and limited NELL1 expression. Immune infiltration analysis revealed decreased neutrophil in diabetic cardiomyopathy. CTD analysis identified several small molecules that affect LILRA5 mRNA expression. Among these, Estradiol, Estradiol-3-benzoate, Gadodiamide, Topotecan, and Testosterone were found to stably bind to the LILRA5 protein at the conserved VAL-15 or THR-133 residues in the Ig-like C2 domain.ConclusionBased on European Ancestry Cohort, this study reveals that LILRA5 and NELL1 are potential therapeutic targets for NISCM, with LILRA5 showing particularly promising prospects in diabetic cardiomyopathy. Several small molecules interact with LILRA5, implying potential clinical implication.

AIM2 Deficiency Alleviates Cardiac Inflammation and Hypertrophy in HFD/STZ-Induced Diabetic Mice by Inhibiting the NLRC4/IRF1 Signaling Pathway.

Absent in melanoma 2(AIM2) exacerbates atherosclerosis by inflammasome assembly. However, AIM2-mediated inflammation in diabetic cardiomyopathy remains incompletely understood. Here we investigate the role of AIM2 in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. By RNA-seq, we found that AIM2 were significantly upregulated in HG-induced macrophages, upregulation of AIM2 in cardiac infiltrating macrophages was confirmed in a high-fat diet (HFD)/streptozotocin (STZ)-induceddiabetic mouse model . Therefore, AIM2 knockout mice were constructed. Compared to WT mice, HFD/STZ-induced cardiac hypertrophy and dysfunction were significantly improved in AIM2-/- mice, despite no changes in blood glucose and body weight. Further, AIM2 deficiency inhibited cardiac recruitment of M1-macrophages and cytokine production. Mechanistically, AIM2-deficient macrophgaes reduced IL-1β and TNF-α secretion, which impaired the NLRC4/IRF1 signaling in cardiomyocytes, and reduced further recruitment of macrophages, attenuated cardiac inflammation and hypertrophy, these effects were confirmed by silencing IRF1 in WT mice, and significantly reversed by overexpression of IRF1 in AIM2-/- mice. Taken together, our findings suggest that AIM2 serves as a novel target for the treatment of diabetic cardiomyopathy.

Lab-on-a-chip models of cardiac inflammation.

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide with numerous inflammatory cell etiologies associated with impaired cardiac function and heart failure. Inflammatory cardiomyopathy, also known as myocarditis, is an acquired cardiomyopathy characterized by inflammatory cell infiltration into the myocardium with a high risk of progression to deteriorated cardiac function. Recently, amidst the ongoing COVID-19 pandemic, the emergence of acute myocarditis as a complication of SARS-CoV-2 has garnered significant concern. Given its mechanisms remain elusive in conjunction with the recent withdrawal of previously FDA-approved antiviral therapeutics and prophylactics due to unexpected cardiotoxicity, there is a pressing need for human-mimetic platforms to investigate disease pathogenesis, model dysfunctional features, and support pre-clinical drug screening. Traditional in vitro models for studying cardiovascular diseases have inherent limitations in recapitulating the complexity of the in vivo microenvironment. Heart-on-a-chip technologies, combining microfabrication, microfluidics, and tissue engineering techniques, have emerged as a promising approach for modeling inflammatory cardiac diseases like myocarditis. This review outlines the established and emerging conditions of inflamed myocardium, identifying key features essential for recapitulating inflamed myocardial structure and functions in heart-on-a-chip models, highlighting recent advancements, including the integration of anisotropic contractile geometry, cardiomyocyte maturity, electromechanical functions, vascularization, circulating immunity, and patient/sex specificity. Finally, we discuss the limitations and future perspectives necessary for the clinical translation of these advanced technologies.

Role of Cardiac Magnetic Resonance in Inflammatory and Infiltrative Cardiomyopathies: A Narrative Review.

Cardiac magnetic resonance (CMR) has acquired a pivotal role in modern cardiology. It represents the gold standard for biventricular volume and systolic function assessment. Moreover, CMR allows for non-invasive myocardial tissue evaluation, highlighting tissue edema, fibrosis, fibro-fatty infiltration and iron overload. This manuscript aims to review the impact of CMR in the main inflammatory and infiltrative cardiomyopathies, providing details on specific imaging patterns and insights regarding the most relevant trials in the setting.

Determinants of possible inflammatory myocardial damage in acute intestinal infections in children

BACKGROUND: Non-coronary cardiomyopathies, including inflammatory cardiomyopathies, are one of the leading causes of disability and mortality in children and adults. Inflammatory cardiomyopathy in most cases is an outcome of myocarditis as a result of direct agent-dependent myocardial damage or autoimmune reactions in the absence of genetic predisposition. AIM: On the basis of clinical assessment of cardiovascular system changes, to develop a discriminant model to predict the possibility of myocardial damage of inflammatory genesis in acute intestinal infections (AII) in children. MATERIALS AND METHODS: In the Intestinal Infections Department of the Children’s Research and Clinical Center for Infectious Diseases of FMBA of Russia in the period 2020-2022, 33 children aged from 1 month to 13 years with AII of different etiology were consecutively observed, in whom, according to clinical, laboratory and instrumental examination data, for the first time in their lives, changes in cardiovascular system were detected. The sample was formed using an algorithm for diagnosing inflammatory myocardial lesions in points, the sum of which concluded that there were no or presence of such, which allowed us to identify group 1 (n = 24) and group 2 (n = 9), respectively. Etiological diagnosis of acute intestinal infections was performed in all children, clinical and laboratory data, results of a 12-channel electrocardiogram (ECG), transthoracic echocardiography (EchoCG) were evaluated. The differences in the groups were revealed using the Pearson chi-squared test and the Mann–Whitney test, which were considered reliable at p 0.05. The method of discriminant analysis was used. RESULTS: Functional systolic noise and increased cardiospecific enzymes were observed less frequently in group 1 than in group 2 (4.2%; 22.2% and 67%; 100%). Of the pathological ECG changes, violations of the repolarization process were observed (16.7%; 33.3%). No significant changes in the Echo-KG were detected. The viral etiology of acute intestinal infections dominated (79.2%; 88.9%). Changes in the hemogram were characterized by a high frequency of leukocytosis in group 1 (29.2%; 0%) and leukopenia in group 2 (4.2%; 22.2%). In group 1, there was a higher frequency of neutrophilosis (79.2%; 44.4%), rod-shaped shift (62.5%; 22.2%), thrombocytosis (29.2%; 0%), lymphocytopenia (95.8%; 55.6%; p 0.05), monocytosis (8.3%; 0%); increased C-reactive protein (41.7%; 33.3%), ALT (29.2%; 11.1%), urea (29.2%; 11.1%), leukocyturia (16.7%; 0%). CONCLUSIONS: Clinical evaluation of cardiovascular system changes in children with acute intestinal infections using a discriminant model allows to exclude myocardial damage of inflammatory genesis with high probability (95.7%), which is of practical importance.

Abstract Or114: Inhibiting IL-1 Signaling to Cardiac Fibroblasts Protects Against Acute Viral Myocarditis

Background: Understanding what factors perpetuate cardiac inflammation in patients with unremitting inflammatory dilated cardiomyopathy (iDCM) is critical for developing curative therapies. We have previously demonstrated that inflammatory fibroblasts (IFs), a subset of cardiac fibroblasts (CFs) that promote inflammation, depend on IL-17A signaling to drive iDCM progression in experimental autoimmune myocarditis. Here, we demonstrate that IL-1 signaling more potently activates IFs than IL-17A. IL-1 signaling has been implicated in the pathogenesis of viral myocarditis, the most common etiology of myocarditis, though the mechanism is unclear. Hypothesis: We hypothesize that IL-1 signaling to CFs induces their differentiation into IFs, which drive pathogenic inflammation during viral myocarditis. Methods: Primary murine CF cultures were used to characterize IF activation by various cytokines. Next, we both performed qPCR on sorted CFs and used a CCL2-mCherry reporter mouse line to phenotype IF activation during Coxsackievirus B3 (CVB3) myocarditis. Finally, in-vivo fibroblast-specific IL-1 signaling was genetically ablated using PDGFRα cre IL1r1 fl/fl mice. We infected PDGFRα cre and PDGFRα cre IL1r1 fl/fl mice with CVB3 and assessed myocarditis severity during the peak of inflammation using histological scoring and flow cytometry. Results: Innate, Th1, Th2, and Th17 related cytokines such as IL-1β, IFNγ, IL-13, and IL-17A induced unique IF gene expression signatures. IL-1β most potently activated IFs with a pro-myeloid cytokine inflammatory profile. During CVB3 myocarditis, IF activation peaked on day 3 post infection and was sustained until day 10. Ablating IL-1 signaling to CFs reduced the magnitude of cardiac inflammation by 45% ± 14% (p=0.002) during the peak of CVB3 myocarditis with a reduction in monocyte, CD4+ T cells, CD8+ T cells, and NK cell recruitment. Gene expression analysis of sorted CFs from mutant and control mice revealed reduced expression of pro-myeloid chemokines such as CXCL1 and CCL2 on day 3 of CVB3 myocarditis. Conclusions: Cardiac fibroblasts exhibit remarkable plasticity allowing them to respond to a changing micro-environment. Blocking IL-1 signaling to IFs during CVB3 myocarditis inhibited production of pro-inflammatory chemokines resulting in attenuation of myocardial inflammation. Therefore, early IF activity acts as a rheostat to modulate the magnitude of cardiac inflammation during myocarditis.

Viral Myocarditis as a Factor Leading to the Development of Heart Failure Symptoms, Including the Role of Parvovirus B19 Infection-Systematic Review.

Myocarditis (MC) is defined as an immunological inflammatory reaction with various etiologies, clinical presentations and prognoses within the myocardium. Currently, parvovirus B19 (PVB19) has become the main factor leading to this disease, replacing the previously dominant viruses A and B. In the case of chronic heart failure with subsequent dilated cardiomyopathy, approximately 67% have a viral etiology, and most of them are the result of PVB19 infection. However, the analysis showed a correlation between PVB19 infection and the risk of developing inflammatory dilated cardiomyopathy (DCMi). PVB19 is detected in 23% of patients with DCMi. Chronic infection may also contribute to progressive left ventricular failure in patients with a history of MC. The above effect suggests the active replication of PVB19 only in heart biopsies with inflammation due to MC or DCMi. Moreover, the supply of IFN-β to suppress the active transcription of PVB19 accompanied by DCMi over a period of 6 months results in the normalization of NT-proBNP and an improvement in LVEF along with NYHA performance. The small number of reports on this topic and inaccuracies resulting from constantly conducted research and ongoing changes make it impossible to clearly answer the question of whether PVB19 is a factor inducing de novo MC and DCM or only accompanies the above conditions. However, large clinical cohort studies lead to the perception of PVB19 as a viral etiological agent capable of causing de novo MC together with DCMi.

Immunomodulating and Immunosuppressive Therapy for Virus-Negative Immune-Mediated Myocarditis.

Myocarditis is an inflammatory disease of the myocardium caused by infectious and noninfectious agents. Clinical manifestations range from mildly symptomatic forms to acute heart failure, cardiogenic shock, life-threatening arrhythmias and sudden death. Myocarditis is still a challenging diagnosis because of its wide variability in clinical presentation and unpredictable course. Moreover, a standardized, specific treatment in not yet available. Immunosuppressive treatment for virus-negative lymphocytic myocarditis is still controversial. Conversely, immunosuppression is well established in sarcoidosis, eosinophilic, giant-cell, drug hypersensitivity, and trauma-related myocarditis as well as lymphocytic myocarditis associated with connective tissue diseases or with the rejection of a transplanted heart. Recently, immunosuppressive therapy has been also recognized as an effective treatment in virus-negative inflammatory cardiomyopathy. The aim of this review is to underline the role of immunomodulating and immunosuppressive therapies in patients with immune-mediated myocarditis and illustrate the different treatment strategies depending on the etiology. An endomyocardial biopsy remains the gold standard for the diagnosis of myocarditis as well as for a tailored treatment.

The emerging role of cardiovascular magnetic resonance in the evaluation of cardiac involvement in systemic sclerosis

Abstract Systemic sclerosis (SSc) is an autoimmune rheumatic disease, characterized by vascular, inflammatory and fibrotic alterations. Cardiac involvement is the « fatal tip of the iceberg» in SSc, as it leads to high morbidity/mortality. Cardiovascular imaging modalities play an important role in the early diagnosis and treatment assessment of cardiac involvement. Echocardiography is the corner stone for evaluation of cardiac involvement, providing information about function, wall motion, pulmonary pressure, pericardium and valvular disease. It is a low-cost modality, widely available, without radiation and with great experience among cardiologists. However, it is a window and operator dependent modality and cannot provide tissue characterization information, absolutely necessary for diagnosis and treatment of cardiac involvement in SSc. Cardiovascular magnetic resonance (CMR) can perform myocardial function and tissue characterization in the same examination without radiation, has excellent reproducibility and is window and operator independent. The great advantage of CMR is the capability to assess peri- myo-vascular inflammation, myocardial ischemia and presence of replacement and diffuse myocardial fibrosis in parallel with ventricular function assessment. The modified Lake Louise criteria including T2, native T1 mapping and extracellular volume fraction (ECV) has been recently used to diagnose inflammatory cardiomyopathy. According to expert recommendations, myocardial inflammation should be considered if at least 2 indices, one T2 and one T1 parameter are positive, whereas native T1 mapping and ECV assess diffuse fibrosis or oedema, even in the absence of late gadolinium enhancement (LGE). Moreover, transmural/subendocardial LGE following the distribution of coronary arteries and diffuse subendocardial fibrosis not related with epicardial coronary arteries are indicative of epicardial and micro-vascular coronary artery disease, respectively. To conclude, CMR can overcome the limitations of echocardiography by identifying acute/active or chronic myocardial inflammation/fibrosis, ischemia and myocardial infarction using classic and parametric indices in parallel with biventricular function assessment

Inflammatory Myocardial Disease Case Report Following COVID-19 Infection: Giant Cell Myocarditis versus Cardiac Sarcoidosis: To Be or Not to Be

Abstract COVID-19 can induce cardiac involvement, which can include myocardial infarction, various types of arrhythmia, atrioventricular block, myocarditis, acute heart failure, and sudden cardiac death, in approximately 30% of infected patients. There are some reports on the triggering of sarcoid-like reactions and inflammatory myocardial processes by various types of infections. However, little is known about the relationship between COVID-19 and inflammatory cardiomyopathies such as cardiac sarcoidosis (CS) and giant cell myocarditis (GCM). Herein, we describe the clinical course, management, and follow-up of an unmasked inflammatory cardiomyopathy in a 57-year-old Iranian woman, who presented with ventricular arrhythmia 4 months after mild COVID-19 infection. The onset of symptomatic inflammatory myocardial disorders such as CS or GCM may be triggered by COVID-19 infection. The best approach to the management of myocardial inflammatory COVID-19 should probably be individualized based on the patient’s clinical presentation and severity of cardiac involvement.

A case of biopsy‐proven inflammatory dilated cardiomyopathy following heterologous mRNA‐1273 third‐dose immunization

A case of biopsy‐proven inflammatory dilated cardiomyopathy following heterologous mRNA‐1273 third‐dose immunization

Management of cardiac sarcoidosis.

Cardiac sarcoidosis (CS) is a form of inflammatory cardiomyopathy associated with significant clinical complications such as high-degree atrioventricular block, ventricular tachycardia, and heart failure as well as sudden cardiac death. It is therefore important to provide an expert consensus statement summarizing the role of different available diagnostic tools and emphasizing the importance of a multidisciplinary approach. By integrating clinical information and the results of diagnostic tests, an accurate, validated, and timely diagnosis can be made, while alternative diagnoses can be reasonably excluded. This clinical expert consensus statement reviews the evidence on the management of different CS manifestations and provides advice to practicing clinicians in the field on the role of immunosuppression and the treatment of cardiac complications based on limited published data and the experience of international CS experts. The monitoring and risk stratification of patients with CS is also covered, while controversies and future research needs are explored.

Differential Deep RNA Sequencing for Diagnostic Detection of Microbial Infections in Inflammatory Cardiomyopathy.

Inflammatory heart disease can be triggered by a variety of causes, both infectious and noninfectious in nature. We hypothesized that inflammatory cardiomyopathy is potentially related to microbial infection. In this retrospective study, we used deep RNA sequencing on formalin-fixed paraffin-embedded heart tissue specimens to detect pathogenic agents. We first investigated 4 single-sample cases to test the feasibility of this diagnostic protocol and further 3 control-sample paired cases to improve the protocol with differential metatranscriptomics next-generation sequencing (mtNGS) analysis. We demonstrate that differential mtNGS allows identification of various microbials as potentially pathogenic, for example, Cutibacterium acnes, Corynebacterium aurimucosum, and Pseudomonas denitrificans, which are usually commensal in healthy individuals. Differential mtNGS also allows characterization of human host response in each individual by profiling alterations of gene expression, networked pathways, and inferred immune cell compositions, information of which is beneficial for us to understand different etiologies and immunity roles in each case. Additionally, differential mtNGS allows the identification of genetic variants in patients that may contribute to their susceptibility to particular microbial infections. The demonstrated power of differential mtNGS in simultaneous capture of both the infectious microbial(s) and the status of human host immune response could help us better understand the pathogenesis of complex inflammatory cardiomyopathy, if conducted on a larger scale of the population. The developed differential mtNGS method could also shed light on its translation and adoption of such a laboratory test in clinic practice, allowing for a more effective diagnosis to guide therapeutic treatment of the disease.

New insights gained from cellular landscape changes in myocarditis and inflammatory cardiomyopathy.

Advances in the etiological classification of myocarditis and inflammatory cardiomyopathy (ICM) have reached a consensus. However, the mechanism of myocarditis/ICM remains unclear, which affects the development of treatment and the improvement of outcome. Cellular transcription and metabolic reprogramming, and the interactions between cardiomyocytes and non-cardiomyocytes, such as the immune cells, contribute to the process of myocarditis/ICM. Recent efforts have been made by multi-omics techniques, particularly in single-cell RNA sequencing, to gain a better understanding of the cellular landscape alteration occurring in disease during the progression. This article aims to provide a comprehensive overview of the latest studies in myocarditis/ICM, particularly as revealed by single-cell sequencing.