Immune system plays a crucial role in the physiological and pathological regulation of the cardiovascular system. The exploration history and milestones of immune system in cardiovascular diseases (CVDs) have evolved from the initial discovery of chronic inflammation in atherosclerosis to large-scale clinical studies confirming the importance of anti-inflammatory therapy in treating CVDs. This progress has been facilitated by advancements in various technological approaches, including multi-omics analysis (single-cell sequencing, spatial transcriptome et al.) and significant improvements in immunotherapy techniques such as chimeric antigen receptor (CAR)-T cell therapy. Both innate and adaptive immunity holds a pivotal role in CVDs, involving Toll-like receptor (TLR) signaling pathway, nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1/2) signaling pathway, inflammasome signaling pathway, RNA and DNA sensing signaling pathway, as well as antibody-mediated and complement-dependent systems. Meanwhile, immune responses are simultaneously regulated by multi-level regulations in CVDs, including epigenetics (DNA, RNA, protein) and other key signaling pathways in CVDs, interactions among immune cells, and interactions between immune and cardiac or vascular cells. Remarkably, based on the progress in basic research on immune responses in the cardiovascular system, significant advancements have also been made in pre-clinical and clinical studies of immunotherapy. This review provides an overview of the role of immune system in the cardiovascular system, providing in-depth insights into the physiological and pathological regulation of immune responses in various CVDs, highlighting the impact of multi-level regulation of immune responses in CVDs. Finally, we also discuss pre-clinical and clinical strategies targeting the immune system and translational implications in CVDs.

Eosinophilic myocarditis (EM) is a rare cardiac condition that is often difficult to diagnose. Although endocardial myocardial biopsy is considered the gold standard for diagnosis, sampling errors can lead to false-negative results. This case report discusses the diagnosis and treatment of dilated cardiomyopathy in a patient with EM.

In this article, we report a case of a 32-year-old female patient diagnosed with dilated cardiomyopathy. EM was strongly suspected based on a progressive increase in eosinophil count, the absence of known allergens or common etiological factors, elevated eosinophil levels in alveolar lavage fluid, and a diagnosis of eosinophilic pneumonia. However, endocardial myocardial biopsy results failed to show definite evidence of myocarditis. Despite the implementation of various therapeutic interventions including pharmacological treatments, electrical defibrillation, endotracheal intubation, and ventilator-assisted breathing, the patient's condition showed minimal improvement. Subsequent initiation of extracorporeal membrane oxygenation and intra-aortic balloon pump support also failed to achieve the anticipated recovery. The patient subsequently underwent heart transplantation, and cardiac tissue samples were sent for pathology examination. The diagnostic report revealed a large number of eosinophils, confirming the diagnosis of EM. After heart transplantation, the patient's vital signs gradually stabilized, and she was discharged in good condition.

Endocardial myocardial biopsy plays an important role in diagnosing EM but may yield false-negative results. In this case, heart transplantation provided critical diagnostic information, with the pathology report confirming the presence of eosinophils and supporting the diagnosis of EM.

This study aims to investigate the expression of Pentraxin 3 (PTX3) and Nod-like receptor family pyrin domain-containing 3 (NLRP3) in myocarditis and to elucidate their roles and potential interplay in the pathogenesis of myocarditis.

Immunofluorescence staining was performed on myocardial autopsy specimens from deceased patients with severe myocarditis or severe trauma. H9C2 cardiomyocytes were divided into five groups: Control, Lipopolysaccharide (LPS), LPS + PTX3 overexpression, LPS + small interfering RNA targeting PTX3 (si-PTX3), and LPS + PTX3 overexpression + si-NLRP3. The expression levels of PTX3 and NLRP3 at the RNA level were quantified using quantitative real-time polymerase chain reaction (qPCR), while protein expression was assessed via western blot. The concentrations of interleukin-1β (IL-1β) and IL-18 were determined by enzyme-linked immunosorbent assay (ELISA). Macrophages migration was evaluated using Transwell assays.

Immunofluorescence staining revealed co-localization and increased expression of PTX3 and NLRP3 in the myocardium of patients with severe myocarditis. In vitro experiments demonstrated that PTX3 enhanced the expression of NLRP3, IL-1β, and IL-18 in LPS-stimulated cardiomyocytes. Furthermore, PTX3 was shown to promote macrophage migration by regulating NLRP3 expression, as assessed by Transwell assays.

Our findings suggest that PTX3-mediated NLRP3 activation contributes to inflammatory responses and promotes macrophage migration in myocarditis. This study provides a foundation for future investigations into PTX3-targeted therapies for myocarditis.

(1) To derive a prediction rule for pediatric myocarditis that distinguishes low-risk patients for whom additional work-up, including venipuncture or cardiac imaging, may be avoided, (2) to assess the test characteristics of troponin in our study population.

This retrospective case-control study included all patients who presented to a pediatric emergency department between 2010 and 2021 and underwent troponin testing for suspected myocarditis. Myocarditis cases (identified using American Heart Association criteria) and controls were to approximate a 1:2 ratio. Logistic regression with forward selection was used to derive a prediction rule for myocarditis. As the goal was to derive a rule for low-risk children, in whom venipuncture would be unnecessary, laboratory results were analyzed separately.

We identified 93 case patients and 202 control patients. The final prediction rule included chest pain [adjusted odds ratio (aOR): 3.5, 95% CI: 1.8 to 7.0], reported or measured fever (aOR: 1.7, 95% CI: 1.0 to 3.1,) and atrioventricular conduction delays or ST segment changes (aOR: 2.6, 95% CI: 1.4 to 4.7). Sensitivity, calculated as the proportion of cases with at least one of the 3 predictors was 99% (95% CI: 0.94 to 0.99), and specificity was 14% (95% CI: 0.09 to 0.20). With at least 2 predictors, sensitivity was 60% (95% CI: 0.50 to 0.71) and specificity was 72% (95% CI: 0.65 to 0.78).

The prediction rule developed can help identify children at low risk for myocarditis and, therefore, avoid troponin testing and/or further evaluation including cardiology consult or cardiac imaging. Specificity was insufficient to rule in myocarditis without additional investigation.

Comprehending the current epidemiological trends and risk factors of myocarditis is crucial for guiding future targeted prevention and treatment strategies.

Utilizing data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021, we conducted a secondary analysis of the incidence, prevalence, death, and disability-adjusted life years (DALYs) of myocarditis by sex, age group and socio-demographic index (SDI) across 204 countries and territories from 1990 to 2021. And non-optimal temperatures, defined as same-day exposure to ambient temperatures deviating from the minimum death risk threshold, were identified as risk-factors for myocarditis-related death and DALYs.

From 1990 to 2021, the global prevalence of myocarditis increased from 320,623 (95% uncertainty interval: 268,557 to 371,912) to 505,030 (432,295 to 587,819). Concurrently, the age-standardized prevalence rate (ASPR) per 100,000 people also saw a slight increase (no statistical significance) from 6.35 (5.37 to 7.36) to 6.41 (5.48 to 7.44). However, the age-standardized incidence rate (ASIR), age-standardized death rate (ASDR) and age-standardized DALY rate (ASYR) exhibited declines, with estimated annual percentage changes of -0.20 (-0.23 to -0.17), -1.37 (-1.81 to -0.92) and -1.71 (-1.95 to -1.46), respectively. SDI quintile analysis showed that the high SDI quintile had the highest ASIR and ASPR, while the middle and high-middle SDI quintiles exhibited the highest ASDR and ASYR. Furthermore, the burden of myocarditis was notably high among males and older adult populations. Non-optimal temperature, particularly low temperature, emerged as a key risk factor for myocarditis-related ASDR and ASYR.

Although the ASIR, ASDR and ASYR for myocarditis exhibited decreasing trends from 1990 to 2019, further efforts are needed to develop targeted public health strategies, especially for low SDI regions, males, and older adult populations.

Myocarditis, an inflammatory disease of the heart muscle, is often triggered by viral infections. This inflammation, which can lead to severe cardiac dysfunction and adverse outcomes, is mediated by various CC and CXC chemokines that interact with receptors in a "one-to-many" fashion. Ticks have evolved chemokine-binding salivary proteins known as Evasins, which efficiently suppress inflammation. This study explores a tailored Evasin-derived CC chemokine-targeting strategy using a 17-mer synthetic dimeric peptide, BK1.3. This peptide inhibits the inflammatory chemokines CCL2, CCL3, CCL7, and CCL8 in murine Coxsackievirus B3 (CVB3) infection, a viral trigger of myocarditis. Administered at a dose of 5 mg/kg twice daily, BK1.3 effectively maintains virus control without exacerbating CVB3-induced morbidity markers, such as hemodynamic compromise, multiorgan failure with hepatitis and pancreatitis, hypothermia, hypoglycemia, and weight loss. Metabolic profiling combined with proteomics reveals preserved reprogramming of lipid storage and gluconeogenesis capacity in the liver, alongside sustained energy production in the injured heart muscle. In survivors of acute CVB3 infection exhibiting manifestations of the subacute phase, BK1.3 enhances virus control, reduces myeloid cell infiltration in the heart and liver, improves markers of liver injury, and alleviates cardiac dysfunction, as evidenced by echocardiographic global longitudinal strain analysis. These findings affirm the safety profile of BK1.3 peptide therapeutics in a preclinical mouse model of acute CVB3 infection and emphasize its potential for therapeutic advancement in addressing virus-induced inflammation in the heart.

Fulminant myocarditis (FM) is a progressive and severe form of acute myocarditis, complicated by cardiogenic shock. The clinical presentation and aetiologies of FM are often heterogeneous, making it difficult to diagnose. Irrespective of how FM presents, it rapidly evolves to haemodynamic deterioration and requires prompt treatment to stabilize. As such, the use of mechanical circulatory support (MCS) devices has emerged as a critical intervention to achieve haemodynamic support, early unloading, and systemic perfusion and to prevent multiorgan dysfunction in patients with FM. Although scientific societies have proposed recommendations and management pathways, due to the heterogeneity in FM, there remains a lack of clarity in the diagnostic pathway and selection of MCS device for this young patient population. This review provides an updated and integrated overview of the diagnostic flow and important clinical considerations when managing patients with FM.

Early identification of fulminant myocarditis (FM) is the key to reducing mortality, but there is still a lack of effective biomarkers for diagnosis. The aim of this study was to investigate the value of soluble ST2 (sST2) in identifying FM in children.

This was a single-center clinical observational study. We consecutively enrolled 144 children younger than 14 years of age diagnosed with viral myocarditis between January 2018 and November 2023, of whom 63 were diagnosed with FM.

The sST2 level in the FM group was significantly higher than that in the non-FM group [104.40 (68.80, 150.10) vs. 38.30 (19.85, 55.05), p < 0.001]. ROC curves showed that the optimal cut-off values of sST2, TNI, NT-proBNP and CRP for FM were 63.8 ng/ml, 13.3 ng/ml, 3182 pg/ml and 26.5 mg/L, respectively. The sensitivity and specificity of sST2 were 84.13% and 88.9%, indicating the highest early diagnosis efficiency. Multifactorial correction showed that sST2 ≥ 63.8 ng/ml and NT-proBNP ≥ 3182 pg/ml were independent diagnostic predictors of FM (OR = 22.374, 95% CI: 8.140 ∼ 61.499, P < 0.001), and (OR = 3.208, 95% CI: 1.163 ∼ 8.846, P = 0.024).

With high sensitivity and specificity, sST2 may serve as a strong predictor of pediatric FM.

Cardiovascular disease (CVD) is the leading cause of morbidity globally, with chronic inflammation as a key modifiable risk factor. Toll-like receptors (TLRs), pivotal components of the innate immune system, including TLR-3, -7, -8, and -9 within endosomes, trigger intracellular cascades, leading to inflammatory cytokine production by various cell types, contributing to systemic inflammation and atherosclerosis. Recent research highlights the role of endosomal TLRs in recognizing self-derived nucleic acids during sterile inflammation, implicated in autoimmune conditions like myocarditis.

This review explores the impact of endosomal TLRs on viral infections, autoimmunity, and inflammatory responses, shedding light on their intricate involvement in cardiovascular health and disease by examining literature on TLR-mediated mechanisms and their roles in CVD pathophysiology.

Removal of endosomal TLRs mitigates myocardial damage and immune reactions, applicable in myocardial injury. Targeting TLRs with agonists enhances innate immunity against fatal viruses, lowering viral loads and mortality. Prophylactic TLR agonist administration upregulates TLRs, protecting against fatal viruses and improving survival. TLRs play a complex role in CVDs like atherosclerosis and myocarditis, with therapeutic potential in modulating TLR reactions for cardiovascular health.

Acute myocarditis is a rare but potentially life-threatening condition in infants and children. While immunosuppressive agents have shown limited effectiveness, intravenous immunoglobulin (IVIg) holds promise as a treatment option.

To study the efficacy and safety of intravenous immunoglobulin (IVIg) in treating acute viral myocarditis in children.

We searched five databases including PubMed, EMBASE, the Cochrane Library, Scopus, and Web of Science; and four trial registries for published studies on the topic. Grey literature was searched through ProQuest and Open Grey databases. The studies eligible for this review were randomized controlled trials in children (< 18 years) with acute viral myocarditis (Population), comparing IVIg (Intervention), versus no IVIg i.e., any other treatment or placebo (Comparator), for efficacy and safety (Outcomes).

The literature search identified a total of 9,524 records. Two reviewers independently screened these records. A total of 73 citations were deemed potentially eligible, all of which were non-RCTs or review articles on full text examination. There were no RCTs identified to address the review question.

There are no RCTs in children comparing the efficacy and safety of IVIg treatment in acute viral myocarditis. Prospective randomized trials are urgently required.

This review aims to assess the current landscape of animal models used in myocarditis research, with a focus on understanding their utility in uncovering the pathophysiology of the disease. The goal is to evaluate these models' strengths and weaknesses and propose optimizations to make them more relevant and reliable for both mechanistic studies and therapeutic interventions in myocarditis.

Recent studies have primarily utilized animal models, particularly viral and autoimmune myocarditis models, to study disease mechanisms. Coxsackievirus remains the most common virus used in viral myocarditis models, offering high success rates but limited applicability to human cases due to differences in infection patterns. Autoimmune myocarditis models, often involving humanized mice, have made strides in mimicking human immune responses but still face challenges in accuracy and clinical relevance. COVID-19 has introduced new avenues for research, especially concerning vaccine-induced myocarditis, although findings remain preliminary. Animal models remain crucial for myocarditis research, but each comes with distinct challenges. Viral models excel in success rate but suffer from partial relevance to human conditions. Autoimmune models are useful in immunological studies, though costly and less replicable. Vaccine-associated models are closely related to modern clinical conditions, but lack theoretical support and therefore lack reliability. Optimizing these models could improve our understanding of myocarditis and lead to more effective treatments. Future research should aim to refine these models to better simulate human conditions and enhance their clinical applicability, ultimately advancing the diagnosis and treatment of myocarditis.

A previously healthy, 28-year-old man presented with a two-day history of diarrhea and chest pain, suggestive of infectious myocarditis. Initial workup revealed elevated troponin-I levels and diffuse ST-segment elevations on electrocardiogram (ECG). Transthoracic echocardiography showed a reduced left ventricular ejection fraction (40-45%), posteroinferior wall akinesis, and a small pericardial effusion. Stool studies were positive for rotavirus antigen via enzyme immunoassay (EIA). Cardiac magnetic resonance imaging (MRI) and endomyocardial biopsy (EMB) were not performed due to facility limitations; however, clinical findings, troponin-I trends, and echocardiographic abnormalities supported the diagnosis of rotavirus-associated myocarditis. The patient was treated with oral rehydration, colchicine, and metoprolol, leading to symptom resolution and a decline in troponin-I levels. This case underscores the importance of considering rotavirus as a potential etiologic agent in myocarditis, even in immunocompetent adults without significant comorbidities, and highlights the need for clinicians to recognize gastrointestinal viruses as possible causes of cardiac inflammation.

Eosinophilic myocarditis (EM) is a rare, potentially life-threatening, form of inflammatory heart disease characterized by eosinophilic infiltration of the myocardium. Different diseases are involved in its etiopathogeneses, such as eosinophilic granulomatosis with polyangiitis (or Churg-Strauss Syndrome), hypereosinophilic syndromes, parasitic infections, drug reactions, paraneoplastic syndromes and primary immunodeficiencies (e.g. Omenn Syndrome). There is a wide spectrum of clinical pictures at presentation ranging from chronic restrictive cardiomyopathy (Loeffler cardiomyopathy) to acute necrotizing myocarditis with cardiogenic shock. The genetic contribution and the environmental interplay, such as SARS-CoV-2 infection and related vaccines, are fields not well studied yet. Many non-invasive tools, mainly echocardiography and cardiac magnetic resonance imaging, along with invasive procedures, such as endomyocardial biopsy, are the crucial steps in the diagnostic workup. The correct diagnosis is a challenge but mandatory for timely and appropriate immunosuppressive therapy.

Nanomedicine coated with cell membranes has attracted increasing attention for its enhanced targeting capability and biocompatibility. Based on previous research, we identified interferon regulatory factor 1 (IRF1)-mediated macrophage pyroptosis as a potential therapeutic target for myocarditis. Herein, we fabricated an innovative immune cell membrane-coated zeolitic imidazolate framework-8 (ZIF-8) nano-delivery platform and explored its effects on myocarditis.

ZIF-8 nanoparticles loaded with siRNA targeting IRF1 (siIRF1) were coated with a T lymphocyte-macrophage hybrid membrane (siIRF1@ZIF@HM NPs) via sonication and extrusion. The morphological and biological characteristics of the nanoparticles were evaluated using transmission electron microscopy (TEM) and dynamic light scattering (DLS). Cellular cytotoxicity was assessed by a cell counting kit-8 assay. Cellular uptake and endo-lysosomal escape in M1-differentiated macrophages were visualized via fluorescence microscopy. The targeting specificity and anti-myocarditis effects were evaluated in an experimental autoimmune myocarditis (EAM) mouse model. The anti-pyroptosis effects were assessed by Western blot analysis both in vivo and in vitro.

Transcriptional sequencing identified T lymphocytes and macrophages as suitable membrane sources. The ZIF-8 nanoparticles exhibited high siRNA loading capacity and pH responsiveness, enabling an efficient release of siIRF1 from endo-lysosomes to the cytoplasm in macrophages. The hybrid membrane coating enabled specific targeting of M1 macrophages both in vivo and in vitro. Furthermore, delivery of siIRF1 effectively suppressed IRF1 expression and inhibited pyroptosis in IFN-γ-stimulated macrophages. Intravenous injection of siIRF1@ZIF@HM NPs significantly alleviated myocarditis progression without evident side effects.

The siIRF1 nanotherapeutic approach shows potential for attenuating myocardial inflammation and mitigating myocarditis progression. Our study highlights the promise of this customized biomimetic nano-delivery system for treating inflammatory diseases.

Myocarditis, marked by heart muscle inflammation, poses significant clinical challenges. This study, guided by PRISMA guidelines, explores the expanding role of artificial intelligence (AI) in myocarditis, aiming to consolidate current knowledge and guide future research. Following PRISMA guidelines, a systematic review was conducted across PubMed, Cochrane Reviews, Scopus, Embase, and Web of Science databases. MeSH terms including artificial intelligence, deep learning, machine learning, myocarditis, and inflammatory cardiomyopathy were used. Inclusion criteria involved original articles utilizing AI for myocarditis, while exclusion criteria eliminated reviews, editorials, and non-AI-focused studies. The search yielded 616 articles, with 42 meeting inclusion criteria after screening. The identified articles, spanning diagnostic, survival prediction, and molecular analysis aspects, were analyzed in each subsection. Diagnostic studies showcased the versatility of AI algorithms, achieving high accuracies in myocarditis detection. Survival prediction models exhibited robust discriminatory power, particularly in emergency settings and pediatric populations. Molecular analyses demonstrated AI's potential in deciphering complex immune interactions. This systematic review provides a comprehensive overview of AI applications in myocarditis, highlighting transformative potential in diagnostics, survival prediction, and molecular understanding. Collaborative efforts are crucial for overcoming limitations and realizing AI's full potential in improving myocarditis care.

Myocarditis in children is more common in clinical practice, which can cause different degrees of cardiac function damage. We investigated the effects of creatine phosphate in the treatment of myocarditis in children. Children in the control group were treated with sodium fructose diphosphate, and children in the observation group were treated with creatine phosphate on the basis of the control group. After treatment, the myocardial enzyme profile and cardiac function of children in the observation group were better than the control group. The total effective rate of treatment for children in the observation group was higher than that in the control group. In conclusion, creatine phosphate could significantly improve myocardial function, improve myocardial enzyme profile and reduce myocardial damage in children with pediatric myocarditis and had a high safety of use, which was worthy of clinical promotion.

Myocarditis is an inflammatory disease of the myocardium and remains to this day a challenging diagnosis. A promising novel imaging method uses the expression of somatostatin receptors (SSTRs) on inflammatory cells to visualize myocardial inflammation. However, little is known about the histopathological correlate of SSTR imaging in different forms of myocarditis.

In the present retrospective histopathological study, we systematically analysed the expression of SSTR subtype 2 (SSTR2) on inflammatory cells of 33 patients with biopsy- or explant-proven myocarditis (lymphocytic myocarditis (n = 5), giant-cell myocarditis (n = 11), and cardiac sarcoidosis (n = 17)), and in eight controls (multi-organ donors) without signs of myocardial inflammation and/or scars.

In all patients, immunohistochemical staining for SSTR2 was positive in areas with CD68-positive macrophages and multinucleated giant cells. Staining for SSTR2 was most prominent in the presence of multinucleated giant cells. The colocalization of both SSTR2 and CD68 on the same cell could be confirmed using immunofluorescence microscopy. Western blotting confirmed the upregulated expression of SSTR2 in cases of granulomatous inflammation (sarcoidosis) of the skeletal and heart muscle, in comparison with controls.

In conclusion, our findings demonstrate the expression of SSTR2 on the protein level on CD68-positive macrophages and multinucleated giant cells in various forms of myocarditis, which provides a clear rationale for the diagnostic use of SSTR imaging in this patient group.

The European Society of Cardiology (ESC), the American College of Cardiology, the American Heart Association, and expert consensus documents provide different diagnostic criteria for myocarditis. Their overlap and prognostic value have never been compared.

This study aims to assess and compare the predictive value of ESC criteria for clinically suspected myocarditis, updated Lake-Louise criteria (LLC), American Heart Association criteria for probable acute myocarditis (pAM), and expert consensus criteria for acute myocarditis (AM) and complicated myocarditis (CM).

Patients with a clinical suspicion of myocarditis referred for cardiac magnetic resonance were enrolled at 2 centers. Those with any prior cardiomyopathy were excluded. The association of composite outcome events (heart failure hospitalization, recurrent myocarditis, sustained ventricular tachycardia, or death) with ESC diagnostic criteria, LLC, pAM, AM, and CM were compared.

Among 1,557 consecutive patients referred for cardiac magnetic resonance with possible myocarditis, 1,050 (62.6% male; 48.9 ± 16.8 years of age) were without an alternative diagnosis. Of those, 938 (89.3%) met ESC criteria for clinically suspected myocarditis, 299 (28.5%) LLC, and 356 (33.9%), 216 (20.6%), and 77 (7.3%) pAM, AM, and CM, respectively. Adverse events occurred in 161 patients (15.3%) during a median follow-up of 3.4 years. The highest annualized event rates (6.6%) were observed in patients meeting LLC, whereas negative ESC criteria indicated excellent prognosis (0.7% annualized event rate). Among all myocarditis definitions, ESC criteria and LLC were the strongest multivariable outcome predictors and had independent and incremental prognostic value (HRadjusted: 3.87; 95% CI: 1.22-12.2; P = 0.021, and HRadjusted: 2.53; 95% CI: 1.83-3.49; P < 0.001, respectively) when adjusted for clinical characteristics.

In a real-world cohort of patients with possible myocarditis, diagnosis was reached in most patients using ESC criteria whereas only approximately one-quarter of patients reached a diagnosis with LLC. The independent prognostic value of ESC-criteria and LLC highlights the complementary role of clinical and CMR-based findings in the diagnosis and risk stratification of myocarditis.

Myocarditis is a type of cardiovascular disease related to inflammation of cardiac muscle which can be even fatal to some extent. Early and simple diagnosis is crucial for this complication; however, complex or machine-based methods, such as histological tests, x-rays, electrocardiograms, etc., are usually used for its detection. C-reactive protein (CRP) is a biomarker that naturally elevates during inflammation. Therefore, we tried to understand the correlation between CRP and myocarditis. We primarily identified 451 studies from PubMed, Google Scholar, and ScienceDirect and ultimately selected four studies as eligible. We identified the mean difference (MD) in CRP levels between the myocarditis patients and healthy controls. The study quality, outliers, sensitivity, significance, and heterogeneity were also checked. The MD (6.03 (95%CI: 2.41-9.64), p<0.00001) corresponds to a higher and significant CRP level in myocarditis as compared to the control group. The study quality was found to be high with no bias or outliers and the heterogeneity was also determined to be high (I2=99%). Using the fixed effect model, the forest plot determined a similar result as the main outcome (MD: 5.08 (95%CI: 4.85-5.32)) proving higher sensitivity and reproducibility. These findings indicated the possibility of CRP being an established biomarker for an accurate diagnosis and prognosis of myocarditis.

A 10-year-old child with stabilised idiopathic dilated cardiomyopathy was admitted to the hospital with sudden worsening of heart failure. Further analysis showed increased NT-proBNP and positive for COVID-19. Myocarditis secondary to COVID-19 was assumed. Recurrent hospitalizations with inotropic support were required due to the progressive worsening of cardiac function. Seven months after SARS-CoV-2 myocarditis, she underwent heart transplantation.

Coxsackievirus group B3 (CVB3) belongs to the genus Enteroviruses of the family Picornaviridae and is the main pathogen underlying viral myocarditis (VMC). No specific therapeutic is available for this condition. Argininosuccinate synthase 1 (ASS1) is a key enzyme in the urea cycle that converts citrulline and aspartic acid to argininosuccinate. Here, we found that CVB3 and its capsid protein VP2 inhibit the autophagic degradation of ASS1 and that CVB3 consumes citrulline to upregulate ASS1, triggers urea cycle metabolic reprogramming, and then activates macrophages to develop pro-inflammatory polarization, thereby promoting the occurrence and development of VMC. Conversely, citrulline supplementation to prevent depletion can downregulate ASS1, rescue macrophage polarization, and alleviate the pathogenicity of VMC. These findings provide a new perspective on the occurrence and development of VMC, revealing ASS1 as a potential new target for treating this disease.

Viral myocarditis (VMC) is a common and potentially life-threatening myocardial inflammatory disease, most commonly caused by CVB3 infection. So far, the pathogenesis of VMC caused by CVB3 is mainly focused on two aspects: one is the direct myocardial injury caused by a large number of viral replication in the early stage of infection, and the other is the local immune cell infiltration and inflammatory damage of the myocardium in the adaptive immune response stage. There are few studies on the early innate immunity of CVB3 infection in myocardial tissue, but the appearance of macrophages in the early stage of CVB3 infection suggests that they can play a regulatory role as early innate immune response cells in myocardial tissue. Here, we discovered a possible new mechanism of VMC caused by CVB3, revealed new drug targets for anti-CVB3, and discovered the therapeutic potential of citrulline for VMC.

Pacemakers are frequently essential in managing conduction disorders. Recently, the advancement of leadless pacemakers (LPs) has emerged, offering an alternative without the need for an upper shoulder incision or pacing leads. Despite the advantages, including reduced infection risk and improved durability, the novel nature of LPs means that some complications are still being identified. This report presents a unique case of pericarditis occurring after the implantation of a Micra leadless pacemaker (MLP) (Medtronic, Minneapolis, MN). It demonstrates the critical need for careful post-procedural monitoring to promptly detect and address potential complications associated with this emerging technology.

Myocarditis is a rare cardiomyocyte inflammatory process, typically caused by viruses, with potentially devastating cardiac sequalae in both competitive athletes and in the general population. Investigation into myocarditis prevalence in the Coronavirus disease 2019 (COVID-19) era suggests that infection with Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an independent risk factor for myocarditis, which is confirmed mainly through cardiovascular magnetic resonance imaging. Recent studies indicated that athletes have a decreased risk of myocarditis after recent COVID-19 infection compared to the general population. However, given the unique nature of competitive athletics with their frequent participation in high-intensity exercise, athletes possess distinct factors of susceptibility for the development of myocarditis and its subsequent severe cardiac complications (e.g., sudden cardiac death, fulminant heart failure, etc.). Under this context, this review focuses on comparing myocarditis in athletes versus non-athletes, owing special attention to the distinct clinical presentations and outcomes of myocarditis caused by different viral pathogens such as cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, human immunodeficiency virus, and Parvovirus B19, both before and after the COVID-19 pandemic, as compared with SARS-CoV-2. By illustrating distinct clinical presentations and outcomes of myocarditis in athletes versus non-athletes, we also highlight the critical importance of early detection, vigilant monitoring, and effective management of viral and non-viral myocarditis in athletes and the necessity for further optimization of the return-to-play guidelines for athletes in the COVID-19 era, in order to minimize the risks for the rare but devastating cardiac fatality.

The study aimed to explore clinical indicators that can predict the prognosis of children with acute fulminant myocarditis (AFM) through a retrospective analysis.

A retrospective analysis was conducted on the clinical indices of 79 children diagnosed with AFM and hospitalized from March 2013 to March 2023. Relevant demographic and clinical data, including symptoms at admission, laboratory results, and outcomes were extracted to identify factors associated with in-hospital mortality.

A total of 79 children with AFM were analyzed. The survival group (n = 61) had a longer median hospital stay and higher medical expenses compared to the death group (n = 18). Significant differences in the levels of left ventricular ejection fraction (LVEF)(P < 0.001), myoglobin (MYO)(P < 0.001), aspartate aminotransferase (AST)(P < 0.001), lactate dehydrogenase (LDH)(P = 0.004), B-type natriuretic peptide (BNP)(P = 0.005), arterial potential hydrogen (PH)(P < 0.001), bicarbonate (HCO3-)(P = 0.003), serum lactate (Lac)(P = 0.001), peripheral oxygen saturation (SpO2)(P = 0.008), and white blood cell count (WBC)(P = 0.007) were observed between the two groups. Additionally, there were significant differences in the incidences of multi-organ failure (P = 0.003) and respiratory failure (P = 0.001) between the two groups.

Severe myocardial injury (AST > 194.00 U/L, LDH > 637.50 U/L, MYO > 265.75 µg/L, BNP > 1738.50 ng/L), acidosis (PH < 7.29, HCO3- <18.45 mmol/L, Lac > 12.30 mmol/L), hypoxia (SpO2 < 97.50%), inflammatory response (WBC > 9.69*109/L), left ventricular systolic dysfunction (LVEF < 28.25%), multi-organ failure, and respiratory failure are significantly associated with higher mortality rates. These factors can accurately identify AFM children at an increased risk of death.

Myocardial inflammation is increasingly detected noninvasively by tissue mapping with cardiovascular magnetic resonance (CMR). Intraindividual agreement with endomyocardial biopsy (EMB) or markers of myocardial injury, high-sensitive cardiac troponin (hs-cTnT) in patients with clinically suspected viral myocarditis is incompletely understood.

Prospective multicenter study of consecutive patients with clinically suspected myocarditis who underwent blood testing for hs-cTnT, CMR, and EMB as a part of diagnostic workup. EMB was considered positive based on immunohistological criteria in line with the European Society of Cardiology (ESC) definitions. CMR diagnoses employed tissue mapping using sequence-specific cut-off for native T1 and T2 mapping; active inflammation was defined as T1 ≥2 standard deviation (SD) and T2 ≥2 SD above the mean of normal range. Hs-cTnT of greater than 13.9 ng/L was considered significant.

A total of 114 patients (age (mean ± SD) 54 ± 16, 65% males) were included, of which 79 (69%) had positive EMB criteria, 64 (56%) CMR criteria, and a total of 58 (51%) positive troponin. Agreement between EMB and CMR diagnostic criteria was poor (CMR vs ESC: area under the curve (AUC): 0.51 (0.39-0.62)). The agreement between a significant hs-cTnT rise and CMR-based diagnosis of myocarditis was good (AUC: 0.84 (0.68-0.92); p < 0.001), but poor for EMB (0.50 (0.40-0.61). Hs-cTnT was significantly associated with native T1 and T2, high-sensitive C-reactive protein, and N-terminal pro-hormone brain natriuretic peptide (r = 0.37, r = 0.35, r = 0.30, r = 0.25; p < 0.001), but not immunohistochemical criteria or viral presence.

In clinically suspected viral myocarditis, all diagnostic approaches reflect the pathophysiological elements of myocardial inflammation; however, the differing underlying drivers only partially overlap. The EMB and CMR diagnostic algorithms are neither interchangeable in terms of interpretation of myocardial inflammation nor in their relationship with myocardial injury.

Chest pain is a common presenting complaint in adolescent patients. Myocarditis is an important and potentially serious etiology of chest pain for clinicians who care for these patients to recognize. Myocarditis is commonly virally mediated, while extra-intestinal cardiac manifestations of bacterial enteritis, such as Campylobacter infections,are rare. Awareness of this uncommon, but potentially life-threatening pathophysiology is important for clinicians to understand.  In our case, a 17-year-old male presented with chest discomfort, chest pain on inspiration, headache, myalgias, vomiting, and diarrhea. He denied recent viral illnesses or immunizations. He lived in rural Ohio, swam recently in a freshwater lake, and had eaten home-prepared deer meat. His father had diarrhea as well. Presenting vital signs were within normal limits for age. The patient was obese (BMI 48.5), with an otherwise normal physical exam, including a thorough cardiopulmonary assessment. Laboratory workup revealed leukocytosis (16.1 x 109/L) and elevated high-sensitivity troponin (15,857 ng/L, >22,000 ng/L three hours later, ref range <20). Gastrointestinal polymerase chain reaction (PCR) panel detected Campylobacter spp., and stool culture was positive for Campylobacter jejuni. ECG, echocardiography, chest X-ray, and CT angiography were normal. Cardiac MRI revealed an increased T2 signal consistent with myocarditis. The patient was treated with non-steroidal anti-inflammatory drugs (NSAIDs) and azithromycin and had complete resolution in symptoms. He was exercise-restricted for six months.  Myocarditis is a potentially fatal pathology, representing a significant cause of sudden death in young adults. Myocarditis can present with a broad spectrum of signs and symptoms as well as variable clinical severity. Bacterial causes of myocarditis are uncommon, with Campylobacter among the least common. Campylobacter gastroenteritis, however, is quite common worldwide. Extra-intestinal and cardiac manifestations are rare; thus, it is important to maintain a high index of suspicion. Due in part to its rarity, treatment for Campylobacter-associated myocarditis is not well established. Treatment for myocarditis, regardless of etiology, is largely supportive in nature. Campylobacter-directed antibiotics, such as azithromycin, have been used successfully in adolescents with Campylobacter-associated myocarditis. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used for symptom control, though their use remains controversial. Activity restriction is recommended for six months to reduce the risk of sudden cardiac death.  Myocarditis is an important cause of sudden death in young adults and is a rare extra-intestinal manifestation of Campylobacter bacterial gastroenteritis. Pediatric and adult providers should be aware of this presentation and its pathophysiology. They should also utilize a multi-modal workup, aggressive supportive care, appropriate subspecialty consultation, and appropriate antibiotics for patients with diarrheal illness and a high clinical suspicion for extra-intestinal involvement, such as myocarditis.

Neutrophilic myocarditis often stems from bacterial or fungal infections, and it is typically detectable through blood cultures or analyses of the primary infection site. However, research specifically addressing the morphological features of acute myocarditis in complex sepsis cases is scarce, with existing studies primarily dating back to the pre-antibiotic era.

This study constitutes a retrospective and descriptive analysis encompassing 22 forensic cases. We collected data from forensic reports emphasising clinical details, disease history, gross observations, and histopathological findings.

The results show that using positive-air-pressure ventilation could be related to cardiac inflammation (45.45%, 10/22). Despite large-spectrum antibiotic therapy, the blood samples were positive for Staphylococcus aureus (MRSA strain), Klebsiella pneumoniae (ESBL strain), Acinetobacter baumannii, and Pseudomonas aeruginosa. Colonies developed in the myocardium of 36% of the patients (8/22), where 4 of them had septic emboli. Fungal myocarditis accompanied bacterial infections (2/8) and were unsuspected clinically. Background changes, such as interstitial fibrosis and arteriosclerosis, were associated with a greater degree of inflammation and septic embolism.

Neutrophilic myocarditis in patients with emerging sepsis is linked to fatal virulent infections, where bacteria and/or fungi contaminate and impair the myocardium syncytium. Prolonged hospitalisation and positive-air-pressure ventilation may be a risk factor for this condition and needs further research.

Immune checkpoint inhibitors (ICIs) are the current standard of care for non-small-cell lung cancer (NSCLC). Myocarditis is a rare but serious immune-related adverse event (irAE) associated with ICI therapy. We present a patient who received a single dose of pembrolizumab for NSCLC and developed ICI-associated pneumonia. Although pneumonia improved with corticosteroid therapy, the patient subsequently developed ICI-associated fulminant myocarditis. Despite high-dose corticosteroid therapy, the patient died on day 30 after pembrolizumab initiation. Even if an observed irAE was effectively treated, clinicians should remain vigilant for other irAEs, especially those that are difficult to control with low-dose corticosteroids.

Myocarditis is an inflammatory condition affecting the heart muscle, if left unaddressed, may lead to severe complications such as heart failure, arrhythmias, and sudden cardiac death. Current subtyping methods lack sufficient pathological analysis to guide healthcare. Here, we present a clustering analysis using pathological features of H&E stained whole-slide images of from 39 patients with myocarditis who have gone through heart transplantation. Totally, 3,791 pathological features were extracted using each nucleus segmented from StarDist segmentation network. After feature dimensionality reduction, 181 features were selected for clustering with K-Modes method. Two groups of patients with significant differences in time from heart failure to transplantation and time from onset to transplantation were identified. This study demonstrates the feasibility of using pathohistological images to enhance the progression assessment of patients with myocarditis, which may help improve diagnostic accuracy and facilitating targeted therapeutic interventions for cardiac-related diseases.

Autoimmunity significantly contributes to the pathogenesis of myocarditis, underscored by its increased frequency in autoimmune diseases such as systemic lupus erythematosus and polymyositis. Even in cases of myocarditis caused by viral infections, dysregulated immune responses contribute to pathogenesis. However, whether triggered by existing autoimmune conditions or viral infections, the precise antigens and immunologic pathways driving myocarditis remain incompletely understood. The emergence of myocarditis associated with immune checkpoint inhibitor therapy, commonly used for treating cancer, has afforded an opportunity to understand autoimmune mechanisms in myocarditis, with autoreactive T cells specific for cardiac myosin playing a pivotal role. Despite their self-antigen recognition, cardiac myosin-specific T cells can be present in healthy individuals due to bypassing the thymic selection stage. In recent studies, novel modalities in suppressing the activity of pathogenic T cells including cardiac myosin-specific T cells have proven effective in treating autoimmune myocarditis. This review offers an overview of the current understanding of heart antigens, autoantibodies, and immune cells as the autoimmune mechanisms underlying various forms of myocarditis, along with the latest updates on clinical management and prospects for future research.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection often leads to pulmonary complications. Cardiovascular sequelae, including myocarditis and heart failure, have also been reported. Here, the study presents two fulminant myocarditis cases infected by SARS-CoV-2 exhibiting remarkable elevation of cardiac biomarkers without significant pulmonary injury, as determined by imaging examinations. Immunohistochemical staining reveals the viral antigen within cardiomyocytes, indicating that SARS-CoV-2 could directly infect the myocardium. The full viral genomes from respiratory, anal, and myocardial specimens are obtained via next-generation sequencing. Phylogenetic analyses of the whole genome and spike gene indicate that viruses in the myocardium/pericardial effusion and anal swabs are closely related and cluster together yet diverge from those in the respiratory samples. In addition, unique mutations are found in the anal/myocardial strains compared to the respiratory strains, suggesting tissue-specific virus mutation and adaptation. These findings indicate genetically distinct SARS-CoV-2 variants have infiltrated and disseminated within myocardial tissues, independent of pulmonary injury, and point to different infection routes between the myocardium and respiratory tract, with myocardial infections potentially arising from intestinal infection. These findings highlight the potential for systemic SARS-CoV-2 infection and the importance of a thorough multi-organ assessment in patients for a comprehensive understanding of the pathogenesis of COVID-19.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2n first appeared in Wuhan, China in 2019. Soon after, it was declared a pandemic by the World Health Organization. The health crisis imposed by a new virus and its rapid spread worldwide prompted the fast development of vaccines. For the first time in human history, two vaccines based on recombinant genetic material technology were approved for human use. These mRNA vaccines were applied in massive immunization programs around the world, followed by other vaccines based on more traditional approaches. Even though all vaccines were tested in clinical trials prior to their general administration, serious adverse events, usually of very low incidence, were mostly identified after application of millions of doses. Establishing a direct correlation (the cause-effect paradigm) between vaccination and the appearance of adverse effects has proven challenging. This review focuses on the main adverse effects observed after vaccination, including anaphylaxis, myocarditis, vaccine-induced thrombotic thrombocytopenia, Guillain-Barré syndrome, and transverse myelitis reported in the context of COVID-19 vaccination. We highlight the symptoms, laboratory tests required for an adequate diagnosis, and briefly outline the recommended treatments for these adverse effects. The aim of this work is to increase awareness among healthcare personnel about the serious adverse events that may arise post-vaccination. Regardless of the ongoing discussion about the safety of COVID-19 vaccination, these adverse effects must be identified promptly and treated effectively to reduce the risk of complications.

Cardiac discomfort has been reported periodically in COVID-19-vaccinated individuals. Thus, this study aimed to evaluate the role of myocardial strains in the early assessment of the clinical presentations after COVID-19 vaccination. Totally, 121 subjects who received at least one dose of vaccine within 6 weeks underwent laboratory tests, electrocardiogram (ECG), and echocardiogram. Two-dimensional speckle tracking echocardiography (2D-STE) was implemented to analyze changes in the left ventricular myocardium. After vaccination, 66 individuals (55.4 ± 17.4 years) developed cardiac discomforts, such as chest tightness, palpitations, dyspnea, and chest pain. The ECG readings exhibited both premature ventricular contractions and premature atrial contractions (n = 24, 36.4%), while none of the individuals in the control group manifested signs of cardiac arrhythmia. All had normal serum levels of creatine phosphokinase, creatine kinase myocardial band, troponin, N-terminal pro b-type natriuretic peptide, platelets, and D-dimer. Left ventricular ejection fraction in the symptomatic group (71.41% ± 7.12%) and the control group (72.18% ± 5.11%) (p = 0.492) were normal. Use of 2D-STE presented global longitudinal strain (GLS) and global circumferential strain (GCS) was reduced in the symptomatic group (17.86% ± 3.22% and 18.37% ± 5.22%) compared to the control group (19.54% ± 2.18% and 20.73% ± 4.09%) (p = 0.001 and p = 0.028). COVID-19 vaccine-related cardiac adverse effects can be assessed early by 2D-STE. The prognostic implications of GLS and GCS enable the evaluation of subtle changes in myocardial function after vaccination.

Transient left ventricular dysfunction (TLVD), a temporary condition marked by reversible impairment of ventricular function, remains an underdiagnosed yet significant contributor to morbidity and mortality in clinical practice. Unlike the well-explored atherosclerotic disease of the epicardial coronary arteries, the diverse etiologies of TLVD require greater attention for proper diagnosis and management. The spectrum of disorders associated with TLVD includes stress-induced cardiomyopathy, central nervous system injuries, histaminergic syndromes, various inflammatory diseases, pregnancy-related conditions, and genetically determined syndromes. Furthermore, myocardial infarction with non-obstructive coronary arteries (MINOCA) origins such as coronary artery spasm, coronary thromboembolism, and spontaneous coronary artery dissection (SCAD) may also manifest as TLVD, eventually showing recovery. This review highlights the range of ischemic and non-ischemic clinical situations that lead to TLVD, gathering conditions like Tako-Tsubo Syndrome (TTS), Kounis syndrome (KS), Myocarditis, Peripartum Cardiomyopathy (PPCM), and Tachycardia-induced cardiomyopathy (TIC). Differentiation amongst these causes is crucial, as they involve distinct clinical, instrumental, and genetic predictors that bode different outcomes and recovery potential for left ventricular function. The purpose of this review is to improve everyday clinical approaches to treating these diseases by providing an extensive survey of conditions linked with TLVD and the elements impacting prognosis and outcomes.

Viral myocarditis, an inflammatory disease of the myocardium, is a significant cause of sudden death in children and young adults. The current coronavirus disease 19 pandemic emphasizes the need to understand the pathogenesis mechanisms and potential treatment strategies for viral myocarditis. Here, we found that TRIM29 was highly induced by cardiotropic viruses and promoted protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses that promote viral replication in cardiomyocytes in vitro. TRIM29 deficiency protected mice from viral myocarditis by promoting cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive monocytic myeloid-derived suppressor cells (mMDSC) in vivo. Mechanistically, TRIM29 interacted with PERK to promote SUMOylation of PERK to maintain its stability, thereby promoting PERK-mediated signaling pathways. Finally, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK connection, thereby bolstering cardiac function, enhancing cardiac antiviral responses, and curbing inflammation and immunosuppressive mMDSC in vivo. Our findings offer insight into how cardiotropic viruses exploit TRIM29-regulated PERK signaling pathways to instigate viral myocarditis, suggesting that targeting the TRIM29-PERK axis could mitigate disease severity.

In forensic medicine, myocarditis is a complicated topic in the context of sudden death and medical malpractice. A good knowledge of the etiopathology, histopathology, and available literature are both indispensable and essential for the correct management and evaluation of the causal link. Some agents, which are rarely lethal for humans, are not necessarily related to death from myocarditis, even if an infection in other organs such as the gastrointestinal tract is documented. The diagnosis of the causes of death is often difficult and confusing. In some cases, the hypothetical diagnosis of myocarditis as the cause of death is formulated by deduction, causing error and misleading the correct temporal evaluation of pathological events. We reviewed the literature realizing that histomorphological data are scarce and often poorly documented. Only after COVID-19 have the histomorphological aspects of myocarditis been better documented. This is due to poor autopsy practice and poor accuracy in identifying the specific histotype of myocarditis with identification of the responsible agent. We believe that four points are essential for a better understanding and complete diagnosis of the disease: (1) clinical classification of myocarditis; (2) etiological classification of myocarditis; (3) pathophysiology of viral and bacterial infections with host response; and (4) histopathological diagnosis with precise identification of the histotype and pathogen. In the review we provide histological images from authoritative scientific references with the aim of providing useful information and food for thought to readers.

Although most cases of myocarditis are self-limiting with a gradual improvement in cardiac function, the involvement of myocarditis in sudden cardiac death among children and young adults remains substantial, with rates of 3-17 % and 8.6-12 %, respectively. Moreover, the risk of developing chronic dilated cardiomyopathy ranges from 21 % to 30 % in all cases confirmed by biopsy. Current therapeutic strategies for myocarditis and its complications range from standard supportive care for heart failure and arrhythmias to etiologically oriented, case-based therapeutic options. For example, immunosuppression is indicated only in certain forms of acute myocarditis with clinical or endomyocardial biopsy evidence of immune checkpoint inhibitor-induced myocarditis and autoimmune diseases, including giant cell myocarditis, eosinophilic myocarditis, vasculitis, or cardiac sarcoidosis. However, our views on myocarditis treatment have changed considerably over the past two decades, thanks to the emergence of regenerative cells/tissues as well as drug and gene delivery systems. Cell-based therapies are now growing in popularity in any field of medicine. Studies evaluating the therapeutic efficacy of different stem cells in the treatment of acute myocarditis and its chronic complications have shown that although the experimental characteristics varied from study to study, in general, these strategies reduced inflammation and myocardial fibrosis while preventing myocarditis-induced systolic dysfunction and adverse remodeling in animal models.

Respiratory syncytial virus (RSV) causes a substantial disease burden among infants. In older children and adults, incidence is underestimated due to nonspecific symptoms and limited standard-of-care testing. We aimed to estimate RSV-attributable hospitalizations and deaths in Spain during 2016-2019.

Nationally representative hospitalization and mortality databases were obtained from the Ministry of Health and the National Statistical Office. A quasi-Poisson regression model was fitted to estimate the number of hospitalizations and deaths attributable to RSV as a function of periodic and aperiodic time trends and viral activity, while allowing for potential overdispersion.

In children, the RSV-attributable respiratory hospitalization incidence was highest among infants aged 0-5 months (3998-5453 cases/100,000 person-years, representing 72% of all respiratory hospitalizations) and decreased with age. In 2019, estimated rates in children 0-5, 6-11, 12-23 months and 6-17 years were approximately 1.3, 1.4, 1.5, and 6.5 times higher than those based on standard-of-care RSV-specific codes. In adults, the RSV-attributable cardiorespiratory hospitalization rate increased with age and was highest among persons ≥ 80 years (1325-1506 cases/100,000, 6.5% of all cardiorespiratory hospitalizations). In 2019, for persons aged 18-49, 50-59, 60-79, and ≥ 80 years, estimated rates were approximately 8, 6, 8, and 16 times higher than those based on standard-of-care RSV-specific codes. The RSV-attributable cardiorespiratory mortality rate was highest among ≥ 80 age group (126-150 deaths/100,000, 3.5-4.1% of all cardiorespiratory deaths), when reported mortality rate ranged between 0 and 0.5/100,000.

When accounting for under-ascertainment, estimated RSV-attributable hospitalizations were higher than those reported based on standard-of-care RSV-specific codes in all age groups but particularly among older children and older adults. Like other respiratory viruses, RSV contributes to both respiratory and cardiovascular complications. Efficacious RSV vaccines could have a high public health impact in these age and risk groups.