Search Results (301)

Although the SARS-CoV-2 pandemic no longer poses a global emergency, the virus continues to diversify and acquire immunoevasive properties. Understanding the molecular pathways that shape SARS-CoV-2 pathogenesis has become essential. In this paper, we summarize the most recent current evidence on how the spike protein structurally evolves, on changes in key non-structural proteins, such as nsp14, and on host factors, such as TMPRSS2 and neuropilin-1. These changes, together, shape viral entry, replication fidelity and interferon antagonism. Given the emerging Omicron variants of SARS-CoV-2, recent articles in the literature, cryo-EM analyses, and artificial intelligence-assisted mutational modeling were analyzed to infer and contextualize mutation-driven mechanisms. It is through these changes that the virus adapts and evolves, such as optimizing angiotensin-converting enzyme binding, modifying antigenic surfaces, and accumulating mutations that affect CD8⁺ T-cell recognition. Multi-omics data studies further support SARS-CoV-2 pathogenesis through convergent evidence linking viral adaptation to host immune and metabolic reprogramming, as occurs in myocarditis, liver injury, and acute kidney injury. By integrating proteomic, transcriptomic, and structural findings, this work presents how the virus persists and dictates disease severity through interferon antagonism (ORF6, ORF9b, and nsp1), adaptive immune evasion, and metabolic rewiring. All these insights underscore the need for next-generation interventions that provide a multidimensional framework for understanding the evolution of SARS-CoV-2 and guiding future antiviral strategies. Full article

(1) Background: The clinical course of acute myocarditis in adolescents is heterogeneous, and reliable predictors of early functional changes remain limited, particularly in patients without severe systolic dysfunction. Routine hematologic parameters may reflect the early inflammatory response, but their prognostic relevance in pediatric non-fulminant myocarditis is poorly defined. This exploratory study aimed to assess whether admission inflammatory blood indices are associated with short-term changes in left ventricular systolic function in adolescents with acute myocarditis. (2) Methods: We retrospectively analyzed 44 adolescents (median age 16 years, 84% male) hospitalized with suspected acute non-fulminant myocarditis between 2020 and 2023. All patients had preserved or mildly reduced left ventricular ejection fraction (LVEF) at presentation. Clinical, laboratory, electrocardiographic, and echocardiographic data obtained at admission were analyzed. Changes in LVEF between the acute and post-acute phases during hospitalization were assessed using transthoracic echocardiography. Cardiac magnetic resonance imaging was performed in a subset of patients to support diagnosis but was not uniformly available for quantitative analysis. (3) Results: No in-hospital deaths occurred. A modest positive correlation was observed between neutrophil count at admission and improvement in LVEF during hospitalization (r = 0.348, p = 0.028). No significant associations were found between LVEF change and white blood cell count, lymphocyte count, monocyte count, neutrophil-to-lymphocyte ratio (NLR), troponin I, or NT-proBNP. (4) Conclusions: In adolescents with non-fulminant acute myocarditis and preserved or mildly reduced systolic function, admission neutrophil count was associated with short-term improvement in left ventricular ejection fraction. Given the retrospective design, limited sample size, and absence of mechanistic data, these findings should be interpreted as hypothesis-generating. Further prospective studies incorporating standardized cardiac magnetic resonance imaging and immunologic profiling are needed to clarify the clinical significance of this association. Full article

Chagas disease is caused by the protozoan Trypanosoma cruzi, and its current treatment is limited to the use of two nitroderivatives, benznidazole (Bz) and nifurtimox; however, their toxicity often leads to discontinuation, justifying the search for new therapeutic options. The biological activity of quinones has long shown efficacy towards pathogenic microorganisms. In our previous investigations, two naphthoquinones combining ortho- and para-quinoidal moieties exhibited remarkable trypanocidal activity and presented low toxicity to host cells. Here, these two active compounds were further assessed. On trypomastigotes and epimastigotes, brominated (NQ1) and chlorinated (NQ2) nor-beta-lapachone-derived 1,2,3-triazoles were more active than Bz, presenting IC₅₀/24 h values in the range of 0.8 to 3.1 µM. NQ1-treated epimastigotes showed a mitochondrial impairment and reactive oxygen species (ROS) production under electron microscopy and flow cytometry. The in vitro evaluation of both combinations of compounds with Bz indicated an additive interaction. In vivo, oral treatment with NQ1 reduced parasitemia in an acute model, with no evidence of toxicity. The treatment also led to a reduction in myocarditis, decreasing the PR interval in electrocardiographic analysis and reversing the sinus bradycardia caused by infection. These data suggest that T. cruzi mitochondrion are part of the NQ1 mechanism of action. In vivo, this compound presented moderate trypanocidal and promising anti-inflammatory activity. Its combination with Bz could enhance current therapeutic protocols and should be better explored in the future. Full article

Cardiovascular magnetic resonance (CMR) imaging is a key component of current diagnostic pathways in subjects with acute myocarditis. The 2020 ESC Guidelines on Sports Cardiology recommend athletes with acute myocarditis to abstain from sports during the recovery phase from inflammation and to undergo comprehensive evaluation—including CMR—before safely returning to play. This retrospective study analyzed 95 non-competitive athletes presenting with acute myocarditis and evaluated by initial and repeated CMRs. CMR exams assessed myocardial inflammation, edema, and scarring as defined based on the updated Lake Louise criteria. As per 2020 ESC Guidelines, eligibility was granted by excluding extensive myocardial damage. Initial CMR showed 84% positive STIR (edema) and 79% with LGE ≥ 3 segments. After 3–6 months, STIR positivity dropped to 12%, LGE extent remained globally stable, but with some reduction in 42%. Few experienced recurrent myocarditis or LVEF decline; 24% met return-to-play criteria by repeated CMR. Our study shows that few non-competitive athletes recovering from acute myocarditis meet ESC CMR criteria to resume competitive sports at prescribed follow-up evaluation. The long-term prognostic value of CMR markers like LGE and edema remains unclear, highlighting the need for further research to refine return-to-play guidelines and ensure athlete safety. Full article

Despite substantial progress in medical care, acute myocarditis remains a life-threatening disorder with a sudden onset, often unexpectedly complicating a simple and common upper respiratory tract infection. In most cases, myocarditis is triggered by viral infections (over 80%), with an estimated incidence of 10–106 per 100,000 annually. The clinical course may worsen in cases of mixed etiology, where a primary viral infection is complicated by secondary bacterial pathogens, leading to prolonged inflammation and an increased risk of progression to chronic active myocarditis or dilated cardiomyopathy. We present a case report illustrating the clinical problem of acute myocarditis progression into a chronic active form. A central element of host defense is the inflammasome—an intracellular complex that activates pyroptosis and cytokine release (IL-1β, IL-18). While these processes help combat pathogens, their persistent activation may sustain inflammation and trigger heart failure and cardiac fibrosis, eventually leading to dilated cardiomyopathy. In this review, we summarize the current understanding of inflammasome pathways and their dual clinical role in myocarditis: they are essential for controlling acute infection but may become harmful when overactivated, contributing to chronic myocardial injury. Additionally, we discuss both novel and established therapeutic strategies targeting inflammatory and anti-fibrotic mechanisms, including IL-1 receptor blockers (anakinra, canakinumab), NOD-like receptor protein 3 (NLRP3) inhibitors (colchicine, MCC950, dapansutrile, INF200), NF-κB inhibitors, and angiotensin receptor-neprilysin inhibitors (ARNI), as well as microRNAs. Our aim is to emphasize the clinical importance of early identification of patients at risk of transitioning from acute to chronic inflammation, elucidate the role of inflammasomes, and present emerging therapies that may improve outcomes by balancing effective pathogen clearance with limitation of chronic cardiac damage. Full article

Background: Acute myocarditis is defined as an inflammatory process consisting of multiple complex physiopathological processes. Due to its variability, the management of this condition has been a topic of debate. Our study aimed to evaluate the efficacy and safety of intravenous immunoglobulin (IVIg). Methods: We retrospectively collected data from patients admitted to a paediatric cardiology department from 2015 to 2020. Following the inclusion and exclusion criteria, a total of 68 patients diagnosed with acute myocarditis were selected and divided into two groups: treated with IVIg and untreated. We determined clinical and paraclinical parameters, such as symptom remission, normalisation of the ejection fraction at discharge, and cardiac marker evolution. Mixed-design analysis of variance and McNemar tests were performed to determine the statistical differences between groups. Results: In the treated group, 88.2% of the patients developed symptom remission at discharge vs. 50% in the untreated group, and 61.8% of the treated patients presented normalisation of the ejection fraction (EF) vs. 8.8% in the untreated group (p < 0.05). The evolution of cardiac markers did not statistically differ between the treated and untreated groups. Regarding safety, three treated patients presented mild, temporary side effects. Conclusions: Having found a statistically significant improvement in symptomatology and left ventricular EF, our study suggests the efficacy of IVIg in the treatment of acute myocarditis. Treatment with immunoglobulins was relatively safe, with only mild adverse reactions (fever and mild chest pain). Full article

Background: Differentiating between immune checkpoint inhibitor (ICI) myocarditis and non-ICI myocarditis is clinically important. Cardiovascular magnetic resonance (CMR) is a well-established method for diagnosing acute myocarditis. The value of CMR for distinguishing ICI myocarditis from non-ICI myocarditis remains unclear, which this study sought to determine. Methods: A total of 54 patients (n = 26 ICI myocarditis; n = 28 non-ICI myocarditis) underwent clinical CMR for the assessment of cardiac function (cines), myocardial fibrosis (native T1-mapping, extracellular volume [ECV] fraction, late gadolinium enhancement [LGE]) and myocardial oedema (native T2-mapping). Results: ICI myocarditis patients were older than non-ICI myocarditis patients (75 years [71–78] vs. 39 years [30–64]; p < 0.001). Both groups had similar left ventricular (LV) ejection fraction (58 ± 11% vs. 58 ± 6%; p = 0.970). ICI myocarditis and non-ICI myocarditis patients also had similar native myocardial T1 values (1041 ± 84 ms vs. 1063 ± 60 ms; p = 0.281), native myocardial T2 values (59 ± 6 ms vs. 59 ± 6 ms; p = 0.943) and ECV (0.32 ± 0.07 vs. 0.31 ± 0.04; p = 0.403). Native myocardial T1 values (Rho = −0.553) and ECV (Rho = −0.502) were significantly associated with LVEF in non-ICI myocarditis patients (both p < 0.05). There was no significant association between myocardial T1 values, T2 values or ECV, with LVEF, in ICI myocarditis patients (all p < 0.05). Non-ICI myocarditis patients had a greater frequency of LGE in the LV compared to ICI myocarditis patients (89% vs. 52% p = 0.005). However, the pattern of LGE was similar between the two patient groups (mostly subepicardial and/or mid-wall). Conclusions: In this single centre retrospective cohort, the findings suggest that quantitative parametric mapping methods by CMR may not differentiate between ICI vs. non-ICI myocarditis. Further work is needed to assess the value of CMR for diagnosing standalone ICI myocarditis. Full article

Acute myocarditis (AM) is an inflammatory cardiac condition resulting from infections, toxic exposures, or immune-mediated mechanisms, with clinical presentations ranging from mild symptoms to heart failure (HF) or cardiogenic shock. Although viral infections remain the predominant cause, both the absolute prevalence and the relative distribution of different etiologies may change over time and across regions depending on endemic diseases. Immune checkpoint inhibitor (ICI)-associated myocarditis has emerged as a newly recognized entity, with diagnostic rates increasing in parallel with growing awareness and the expanding population of cancer patients eligible for ICI therapy. Additionally, genetic predisposition—particularly mutations linked to arrhythmogenic cardiomyopathy—is also being increasingly acknowledged as a susceptibility factor. Recent advances have markedly improved the diagnostic approach to AM. The availability of high-sensitivity cardiac troponins and the widespread use of cardiac magnetic resonance imaging (CMRI) have enhanced early detection and tissue characterization. CMRI, especially following the updated Lake Louise Criteria (2018), which incorporate T1 and T2 mapping, enables accurate assessment of myocardial inflammation and fibrosis. Endomyocardial biopsy (EMB) remains essential in complicated cases, particularly to identify histologic subtypes that may benefit from immunosuppressive therapy. Early EMB (within 48 h) has been associated with better outcomes in fulminant presentations. The use of immunohistochemistry with leukocyte-specific markers has further increased the sensitivity of EMB. Therapeutic strategies now integrate etiology-specific approaches. Immunosuppressive therapy is indicated for distinct histological forms such as eosinophilic (EM) and giant cell myocarditis (GCM) or cases associated with systemic autoimmune disease. Conversely, in most patients with acute myocarditis complicated by acute HF or cardiogenic shock, no specific treatment is currently recommended beyond evidence-based management of acute HF and general supportive therapy. Full article

Background/Objectives: Myocarditis can occur in patients with coronavirus disease 2019 (COVID-19) as part of the systemic involvement of this infectious syndrome. The persistence of this non-ischemic late gadolinium enhancement (LGE) pattern can be considered an indicator of ongoing myocardial involvement or a sequela of myocarditis. We aimed to assess the effects of LGE on cardiac function and morphology in patients with COVID-19 admitted in intensive care unit for acute respiratory distress syndrome. Methods: Fifty patients (age 59 ± 11, female n = 15) were enrolled. Results: The prevalence of LGE was 33.3%. LGE was present in the lateral wall in all patients except for one, with LGE positivity at the interventricular septum. In general, patients with and without LGE had similar CMR variables values. In one case, LGE was associated with regional wall motion abnormality. The factor associated with LGE was the duration of hospitalization (7.97 ± 3.8 and 12.5 ± 6.7 days in patients without and with LGE, p = 0.007). Conclusions: LGE non-ischemic pattern was not associated with left ventricular dilatation or dysfunction or remodeling in patients with severe clinical manifestation of COVID-19. LGE is mainly present in patients with more prolonged duration of hospitalization. LGE may represent a residual scar with limited prognostic impact that larger multicenter studies could confirm. Full article

Myocarditis is an inflammatory disease of the heart characterized by a complex interplay between innate and adaptive immune responses. The innate immune system provides first-line defense and includes soluble molecules, including macrophages, neutrophils, dendritic cells, and molecular mediators, but lacks immunological memory. In contrast, the adaptive immune system, via T and B lymphocytes, offers high specificity and long-term memory, which can sometimes target myocardial tissue, causing autoimmune injury. Particularly, acute myocarditis is characterized by dysregulated immune signaling, with cytokines (IL-2, IFN-γ, IL-12, IL-4, IL-10) and chemokines (MCP-1, CXCL4, CXCL10) driving disease progression, while adhesion molecules (ICAM-1, VCAM-1, VAP-1) promote leukocyte trafficking and cardiac inflammation. The balance between pro-inflammatory and regulatory responses determines disease outcomes, ranging from resolution with recovery to fulminant myocarditis or progression to dilated cardiomyopathy. Emerging therapeutic approaches targeting cytokines, chemokines, and adhesion molecules, along with established immunosuppressive treatments, underline the potential for modulating immune responses in myocarditis and, thereby, improving patient outcomes. Full article

Coxsackievirus B3 (CVB3) is a primary causative agent of viral myocarditis (VMC), which can lead to both acute and chronic cardiac inflammation accompanied by progressive heart failure and arrhythmias. Although CVB3 has been implicated in various forms of programmed cell death, whether it triggers necroptosis and the underlying mechanisms remains unclear. This study aimed to investigate the role and mechanism of CVB3-induced necroptosis and its effect on viral replication. Using both in vitro and in vivo models, we demonstrated that CVB3 infection significantly upregulates the expression of key necroptotic markers RIP1 and RIP3 in HeLa cells and mouse myocardial tissues. This upregulation was accompanied by elevated intracellular reactive oxygen species (ROS) levels and suppression of the Nrf2/HO-1 antioxidant pathway. Intervention with the necroptosis inhibitor Necrostatin-1 (Nec-1) or the ROS scavenger N-acetylcysteine (NAC) markedly attenuated cell death, suppressed viral replication, and ameliorated myocardial injury and inflammatory responses in infected mice. Mechanistically, CVB3 inhibits the Nrf2/HO-1 pathway, thereby inducing substantial ROS accumulation that promotes necroptosis. This effect can be reversed by NAC treatment. Our study reveals a novel mechanism through which CVB3 induces ROS-dependent necroptosis via the suppression of the Nrf2/HO-1 pathway, providing new insights into the pathogenesis of viral myocarditis and suggesting potential therapeutic strategies. Full article

Background: Myocarditis is a recognized complication of COVID-19, but prevalence estimates vary by disease phase and diagnostic method. Methods: We conducted a systematic review and meta-analysis of 54 studies including 32,500 patients, stratified by acute COVID-19, post-COVID, and MIS-C phases. Results: The pooled prevalence of myocarditis was 1.2% (95% CI: 0.8–1.6) in acute COVID-19, 7.4% (95% CI: 5.1–9.8) in post-COVID, and 39.8% (95% CI: 32.4–47.2) in MIS-C. CMR-based diagnosis yielded higher prevalence than clinical criteria (8.1% vs. 0.9%). Major cardiac outcomes included reduced LVEF in 22% and ventricular arrhythmias in 15% of cases. Heterogeneity across studies remained high (I² = 98%). Conclusions: Myocarditis prevalence in COVID-19 varies widely across phases and diagnostic methods. Findings suggest a need for cautious screening approaches, particularly in MIS-C and selected post-COVID or athlete populations, while emphasizing the importance of standardized reporting and long-term follow-up data. Full article

Background/Objectives: Eosinophilic myocarditis (EM) is a rare, life-threatening inflammatory cardiomyopathy driven by eosinophil cytotoxicity and extracellular trap formation. Interleukin-5 (IL-5) inhibition may disrupt this pathogenic cascade. We reviewed contemporary evidence on IL-5 blockade in EM and contextualized it with an illustrative case. Methods: We searched PubMed through May 2025 for reports of EM treated with mepolizumab or benralizumab. Inclusion criteria were consistent with prior cohorts: acute cardiac symptoms with biomarker elevation plus abnormalities on transthoracic echocardiography and/or cardiac magnetic resonance imaging (CMR), along with documented IL-5-targeted therapy. We extracted clinical, imaging, biopsy, treatment-timing, and outcome data and included one institutional case. Results: Twenty-one episodes were analyzed (median age, 45 years; 10 men). Underlying conditions included eosinophilic granulomatosis with polyangiitis (10 cases; 48%), hypereosinophilic syndrome (5 cases; 24%), drug reaction with eosinophilia and systemic symptoms (DRESS, 3 cases; 14%), and eosinophilic asthma (3 cases; 14%). Treatments involved mepolizumab in 17 cases (81%) and benralizumab in 4 (19%); 4 patients received “early-start” therapy within 14 days of EM diagnosis. Among the 11 episodes with reported left ventricular ejection fraction (LVEF) at baseline and follow-up, the median baseline LVEF was 40% (range, 30–62), with 10 of 11 (91%) <50%. On follow-up, all 11 patients improved: 4 normalized (≥50%) and 7 improved to 40–49%. CMR (n = 18) demonstrated late gadolinium enhancement in 14 cases (78%), edema in 9 (50%), and intracardiac thrombus in 4 (22%). Endomyocardial biopsy confirmed eosinophilic infiltration in 13 of 15 cases (87%). Outcomes included one death (fulminant DRESS), one recovery following veno-arterial extracorporeal membrane oxygenation, and one successful heart transplantation. Illustrative case: A 24-year-old man on a steroid taper received mepolizumab 300 mg on Day 4. His LVEF improved from 47% to 59% by Day 15, accompanied by biomarker decline and successful steroid tapering. Conclusions: Across published cases and our institutional experience, IL-5–targeted therapy appears safe, steroid-sparing, and associated with rapid ventricular recovery, particularly when initiated early. Although limited, these findings support the need for prospective trials to define the optimal agent, dosing, timing, and integration with standard immunosuppression and anticoagulation. Full article

Background/Objectives: Myocarditis is a recognized complication of COVID-19 infection, with potential long-term cardiac sequelae. While acute cardiac involvement has been frequently reported, late-stage myocardial effects remain less well characterized. Cardiac magnetic resonance (CMR) imaging, particularly T1 and T2 mapping, offers non-invasive tissue characterization for myocardial inflammation and fibrosis. This study aimed to evaluate segmental myocardial tissue changes in patients with late-stage COVID-19–related myocarditis using CMR and compare findings with patients with non-COVID-19 myocarditis and healthy controls. Methods: This retrospective, single-center study included 25 patients with clinically suspected COVID-19 myocarditis who underwent CMR between 36 and 565 days post-infection. T1 and T2 mapping values and late gadolinium enhancement (LGE) patterns were assessed and compared with 14 non-COVID-19 myocarditis patients and 19 healthy controls. Subgroup analyses were performed according to vaccination status and left ventricular ejection fraction (LVEF). Results: Patients with reduced LVEF had significantly higher T1 and T2 values in several myocardial segments. Compared to controls, the COVID-19 myocarditis group showed significantly elevated T1 values in all segments except 2 and 3. No significant difference in T2 values was observed. LGE was present in 61% of COVID-19 myocarditis patients, predominantly with a subepicardial pattern. No significant differences were observed between vaccinated and unvaccinated patients. Conclusions: Late-stage COVID-19 myocarditis is associated with persistent segmental myocardial tissue abnormalities, particularly elevated T1 values and subepicardial LGE. Segmental CMR mapping may provide additional diagnostic value in identifying residual myocardial injury in patients with ongoing cardiac symptoms after COVID-19 infection. Full article

Encephalomyocarditis virus (EMCV) is an important zoonotic pathogen that infects many animals with mild symptoms. However, swine is the most receptive host and causes acute and lethal myocarditis and/or encephalitis, and induces sudden death in piglets. There are currently no approved antivirals against EMCV. In recent years, antiviral therapies based on small interfering RNA (siRNA) have been rapidly developed as effective alternative therapies. In this study, we designed siRNAs targeting highly conserved regions in the EMCV genome coinciding with VP2 and 3C genes. We show that these siRNAs were non-immunostimulatory and significantly inhibited EMCV replication in vitro. The siRNAs were then complexed in liposomes before testing in a lethal EMCV mouse model in vivo. Both prophylactic and therapeutic intravenous delivery of siRNAs ameliorated viral infection in multiple organs and improved animal survival. This is the first demonstration of the use of a liposomal delivery platform to deliver highly conserved anti-EMCV siRNAs for EMCV antiviral therapy in vivo. Full article