Targeting NLRP3 signaling reduces myocarditis-induced arrhythmogenesis and cardiac remodeling.

BACKGROUND: Myocarditis substantially increases the risk of ventricular arrhythmia. Approximately 30% of all ventricular arrhythmia cases in patients with myocarditis originate from the right ventricular outflow tract (RVOT). However, the role of NLRP3 signaling in RVOT arrhythmogenesis remains unclear. METHODS: Rats with myosin peptide-induced myocarditis (experimental group) were treated with an NLRP3 inhibitor (MCC950; 10 mg/kg, daily for 14 days) or left untreated. Then, they were subjected to electrocardiography and echocardiography. Ventricular tissue samples were collected from each rat's RVOT, right ventricular apex (RVA), and left ventricle (LV) and examined through conventional microelectrode and histopathologic analyses. In addition, whole-cell patch-clamp recording, confocal fluorescence microscopy, and Western blotting were performed to evaluate ionic currents, intracellular Ca2+ transients, and Ca2+-modulated protein expression in individual myocytes isolated from the RVOTs. RESULTS: The LV ejection fraction was lower and premature ventricular contraction frequency was higher in the experimental group than in the control group (rats not exposed to myosin peptide). Myocarditis increased the infiltration of inflammatory cells into cardiac tissue and upregulated the expression of NLRP3; these observations were more prominent in the RVOT and RVA than in the LV. Furthermore, experimental rats treated with MCC950 (treatment group) improved their LV ejection fraction and reduced the frequency of premature ventricular contraction. Histopathological analysis revealed higher incidence of abnormal automaticity and pacing-induced ventricular tachycardia in the RVOTs of the experimental group than in those of the control and treatment groups. However, the incidences of these conditions in the RVA and LV were similar across the groups. The RVOT myocytes of the experimental group exhibited lower Ca2+ levels in the sarcoplasmic reticulum, smaller intracellular Ca2+ transients, lower L-type Ca2+ currents, larger late Na+ currents, larger Na+-Ca2+ exchanger currents, higher reactive oxygen species levels, and higher Ca2+/calmodulin-dependent protein kinase II levels than did those of the control and treatment groups. CONCLUSION: Myocarditis may increase the rate of RVOT arrhythmogenesis, possibly through electrical and structural remodeling. These changes may be mitigated by inhibiting NLRP3 signaling.

Prognostic value of visual and quantitative CMR regional myocardial function in patients with suspected myocarditis.

According to updated Lake-Louise Criteria, impaired regional myocardial function serves as a supportive criterion in diagnosing myocarditis. This study aimed to assess visual regional wall motional abnormalities (RWMA) and novel quantitative regional longitudinal peak strain (RLS) for risk stratification in the clinical setting of myocarditis. In patients undergoing CMR and meeting clinical criteria for suspected myocarditis global longitudinal strain (GLS), late gadolinium enhancement (LGE), RWMA and RLS were assessed in the anterior, septal, inferior, and lateral regions and correlated to the occurrence of major adverse cardiac events (MACE), including heart failure hospitalization, sustained ventricular tachycardia, recurrent myocarditis, and all-cause death. In 690 consecutive patients (age: 48.0 ± 16.0 years; 37.7% female) with suspected myocarditis impaired RLS was correlated with RWMA and LV-GLS but not with the presence of LGE. At median follow up of 3.8 years, MACE occurred in 116 (16.8%) patients. Both, RWMA and RLS in anterior-, septal-, inferior-, and lateral- locations were univariately associated with outcomes (all p < 0.001), but not after adjusting for clinical characteristics and LV-GLS. In the subgroup of patients with normal LV function, RWMA were not predictive of outcomes, whereas septal RLS had incremental and independent prognostic value over clinical characteristics (HRadjusted = 1.132, 95% CI 1.020-1.256; p = 0.020). RWMA and RLS can be used to assess regional impairment of myocardial function in myocarditis but are of limited prognostic value in the overall population. However, in the subgroup of patients with normal LV function, septal RLS represents a distinctive marker of regional LV dysfunction, offering potential for risk-stratification.

The Spontaneous Course of Human Herpesvirus 6 DNA-Associated Myocarditis and the Effect of Immunosuppressive Intervention.

INTRODUCTION: This study investigated the spontaneous clinical course of patients with endomyocardial biopsy (EMB)-proven lymphocytic myocarditis and cardiac human herpesvirus 6 (HHV6) DNA presence, and the effectiveness of steroid-based intervention in HHV6-positive patients. RESULTS: 756 heart failure (HF) patients underwent an EMB procedure to determine the underlying cause of unexplained HF. Low levels of HHV6 DNA, detectable by nested PCR only, were found in 10.4% of the cases (n = 79) of which 62% (n = 49) showed myocardial inflammation. The spontaneous course of patients with EMB-proven HHV6 DNA-associated lymphocytic myocarditis (n = 26) showed significant improvements in the left ventricular ejection fraction (LVEF) and clinical symptoms, respectively, in 15/26 (60%) patients, 3-12 months after disease onset. EMB mRNA expression of components of the NLRP3 inflammasome pathway and protein analysis of cardiac remodeling markers, analyzed by real-time PCR and MALDI mass spectrometry, respectively, did not differ between HHV6-positive and -negative patients. In another cohort of patients with ongoing symptoms related to lymphocytic myocarditis associated with cardiac levels of HHV6-DNA copy numbers <500 copies/µg cardiac DNA, quantified by real-time PCR, the efficacy and safety of steroid-based immunosuppression for six months was investigated. Steroid-based immunosuppression improved the LVEF (≥5%) in 8/10 patients and reduced cardiac inflammation in 7/10 patients, without an increase in cardiac HHV6 DNA levels in follow-up EMBs. CONCLUSION: Low HHV6 DNA levels are frequently detected in the myocardium, independent of inflammation. In patients with lymphocytic myocarditis with low levels of HHV6 DNA, the spontaneous clinical improvement is nearby 60%. In selected symptomatic patients with cardiac HHV6 DNA copy numbers less than 500 copies/µg cardiac DNA and without signs of an active systemic HHV6 infection, steroid-based therapy was found to be effective and safe. This finding needs to be further confirmed in large, randomized trials.

Self-limiting COVID-19-associated Kikuchi-Fujimoto disease with heart involvement: case-based review.

BACKGROUND: The association between COVID-19 infection and the development of autoimmune diseases is currently unknown, but there are already reports presenting induction of different autoantibodies by SARS-CoV-2 infection. Kikuchi-Fuimoto disease (KFD) as a form of histiocytic necrotizing lymphadenitis of unknown origin. OBJECTIVE: Here we present a rare case of KFD with heart involvement after COVID-19 infection. To our best knowledge only a few cases of COVID-19-associated KFD were published so far. Based on presented case, we summarize the clinical course of KFD and its association with autoimmune diseases, as well we discuss the potential causes of perimyocarditis in this case. METHODS: We reviewed the literature regarding cases of "Kikuchi-Fujimoto disease (KFD)" and "COVID-19" and then "KFD" and "heart" or "myocarditis" by searching medical journal databases written in English in PubMed and Google Scholar. RESULTS: Only two cases of KFD after COVID infection have been described so far. CONCLUSION: SARS-CoV-2 infection can also be a new, potential causative agent of developing KFD.

Clinically Suspected Myocarditis Temporally Related to COVID-19 Vaccination in Adolescents and Young Adults: Suspected Myocarditis After COVID-19 Vaccination.

BACKGROUND: Understanding the clinical course and short-term outcomes of suspected myocarditis after the coronavirus disease 2019 (COVID-19) vaccination has important public health implications in the decision to vaccinate youth. METHODS: We retrospectively collected data on patients <21 years old presenting before July 4, 2021, with suspected myocarditis within 30 days of COVID-19 vaccination. Lake Louise criteria were used for cardiac MRI findings. Myocarditis cases were classified as confirmed or probable on the basis of the Centers for Disease Control and Prevention definitions. RESULTS: We report on 139 adolescents and young adults with 140 episodes of suspected myocarditis (49 confirmed, 91 probable) at 26 centers. Most patients were male (n=126, 90.6%) and White (n=92, 66.2%); 29 (20.9%) were Hispanic; and the median age was 15.8 years (range, 12.1-20.3; interquartile range [IQR], 14.5-17.0). Suspected myocarditis occurred in 136 patients (97.8%) after the mRNA vaccine, with 131 (94.2%) after the Pfizer-BioNTech vaccine; 128 (91.4%) occurred after the second dose. Symptoms started at a median of 2 days (range, 0-22; IQR, 1-3) after vaccination. The most common symptom was chest pain (99.3%). Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%), or no anti-inflammatory therapies (8.6%). Twenty-six patients (18.7%) were in the intensive care unit, 2 were treated with inotropic/vasoactive support, and none required extracorporeal membrane oxygenation or died. Median hospital stay was 2 days (range, 0-10; IQR, 2-3). All patients had elevated troponin I (n=111, 8.12 ng/mL; IQR, 3.50-15.90) or T (n=28, 0.61 ng/mL; IQR, 0.25-1.30); 69.8% had abnormal ECGs and arrhythmias (7 with nonsustained ventricular tachycardia); and 18.7% had left ventricular ejection fraction <55% on echocardiogram. Of 97 patients who underwent cardiac MRI at a median 5 days (range, 0-88; IQR, 3-17) from symptom onset, 75 (77.3%) had abnormal findings: 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria. Among 26 patients with left ventricular ejection fraction <55% on echocardiogram, all with follow-up had normalized function (n=25). CONCLUSIONS: Most cases of suspected COVID-19 vaccine myocarditis occurring in persons <21 years have a mild clinical course with rapid resolution of symptoms. Abnormal findings on cardiac MRI were frequent. Future studies should evaluate risk factors, mechanisms, and long-term outcomes.

P2Y12 Inhibition in Murine Myocarditis Results in Reduced Platelet Infiltration and Preserved Ejection Fraction.

Previous mouse studies have shown the increased presence of platelets in the myocardium during early stages of myocarditis and their selective detection by MRI. Here, we aimed to depict early myocarditis using molecular contrast-enhanced ultrasound of activated platelets, and to evaluate the impact of a P2Y12 receptor platelet inhibition. Experimental autoimmune myocarditis was induced in BALB/c mice by subcutaneous injection of porcine cardiac myosin and complete Freund adjuvant (CFA). Activated platelets were targeted with microbubbles (MB) coupled to a single-chain antibody that binds to the "ligand-induced binding sites" of the GPIIb/IIIa-receptor (=LIBS-MB). Alongside myocarditis induction, a group of mice received a daily dose of 100 g prasugrel for 1 month. Mice injected with myosin and CFA had a significantly deteriorated ejection fraction and histological inflammation on day 28 compared to mice only injected with myosin. Platelets infiltrated the myocardium before reduction in ejection fraction could be detected by echocardiography. No selective binding of the LIBS-MB contrast agent could be detected by either ultrasound or histology. Prasugrel therapy preserved ejection fraction and significantly reduced platelet aggregates in the myocardium compared to mice without prasugrel therapy. Therefore, P2Y12 inhibition could be a promising early therapeutic target in myocarditis, requiring further investigation.

Relationships between Circulating Matrix Metalloproteinases, Tissue Inhibitor TIMP-2, and Renal Function in Patients with Myocarditis.

INTRODUCTION: Under physiological conditions, the myocardial extracellular matrix (ECM) is maintained by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). However, changes in the balance between MMPs and TIMPs can lead to pathological remodeling of the ECM, which contributes to cardiovascular and kidney diseases. The aim of our study was to assess levels of MMPs and TIMP-2 in patients with myocarditis and their relationship to renal function. MATERIALS AND METHODS: Forty five patients with myocarditis who underwent CMR were included, comprising 11 with concurrent chronic kidney disease (CKD). Blood samples were obtained to assess serum levels of MMP-2, MMP-3, MMP-9, and TIMP-2. RESULTS: Serum MMP-2, MMP-3, and TIMP-2 levels negatively correlated with the ejection fraction in patients with myocarditis, while MMP-3 levels correlated with longitudinal deformation (p < 0.05). Serum MMP-2, MMP-3, and TIMP-2 levels also negatively correlated with renal function, as assessed by the estimated glomerular filtration rate (eGFR) (p < 0.05). Patients with myocarditis and concurrent CKD had higher levels of MMP-2 and TIMP-2 than those without kidney damage. CONCLUSIONS: (1) We demonstrated that MMP-2, MMP-3, and TIMP-2 concentrations were related to left-ventricular ejection fraction, and MMP-3 levels correlated with longitudinal deformation, indicating MMPs play an important role in the post-inflammatory remodeling of the myocardium. (2) A negative correlation between the eGFR and MMP-2, MMP-3, and TIMP-2 and a positive correlation between creatinine and MMP-3 levels indicate the role of MMPs and TIMP-2 in renal dysfunction.

Cardiovascular magnetic resonance findings in young adult patients with acute myocarditis following mRNA COVID-19 vaccination: a case series.

BACKGROUND: Messenger RNA (mRNA) coronavirus disease of 2019 (COVID-19) vaccine are known to cause minor side effects at the injection site and mild global systemic symptoms in first 24-48 h. Recently published case series have reported a possible association between acute myocarditis and COVID-19 vaccination, predominantly in young males. METHODS: We report a case series of 5 young male patients with cardiovascular magnetic resonance (CMR)-confirmed acute myocarditis within 72 h after receiving a dose of an mRNA-based COVID-19 vaccine. RESULTS: Our case series suggests that myocarditis in this setting is characterized by myocardial edema and late gadolinium enhancement in the lateral wall of the left ventricular (LV) myocardium, reduced global LV longitudinal strain, and preserved LV ejection fraction. All patients in our series remained clinically stable during a relatively short inpatient hospital stay. CONCLUSIONS: In conjunction with other recently published case series and national vaccine safety surveillance data, this case series suggests a possible association between acute myocarditis and COVID-19 vaccination in young males and highlights a potential pattern in accompanying CMR abnormalities.

[Research Progress of Immune Checkpoint Inhibitor-associated Myocarditis].

Immune checkpoint inhibitors (ICIs) is a negative regulatory factor antibody, which activates T cells to play an anti-tumor effect in immunotherapy, and can also cause immune-related adverse responses, thereby inducing a series of immune related adverse events (irAEs). Among these irAEs, although the incidence of ICIs-related myocarditis is very low, the fatality rate is significantly higher than other adverse reactions, close to 50%. Clinicians should be vigilant when applying ICIs, but the pathogenesis of ICIs-related myocarditis is still unclear. This article combines the recent research results of ICIs to summarize the mechanism and clinical manifestations of ICIs-related myocarditis, so as to improve clinicians' understanding of the adverse reactions.
.

Cardiac MRI in Patients with Prolonged Cardiorespiratory Symptoms after Mild to Moderate COVID-19.

Background Myocardial injury and inflammation at cardiac MRI in patients with COVID-19 have been described in recent publications. Concurrently, a chronic COVID-19 syndrome (CCS) after SARS-CoV-2 infection has been observed and manifests with symptoms such as fatigue and exertional dyspnea. Purpose To explore the relationship between CCS and myocardial injury and inflammation as an underlying cause of the persistent complaints in previously healthy individuals. Materials and Methods In this prospective study from January 2021 to April 2021, study participants without known cardiac or pulmonary diseases prior to SARS-CoV-2 infection who had persistent CCS symptoms such as fatigue or exertional dyspnea after convalescence and healthy control participants underwent cardiac MRI. The cardiac MRI protocol included evaluating the T1 and T2 relaxation times, extracellular volume, T2 signal intensity ratio, and late gadolinium enhancement (LGE). Student t tests, Mann-Whitney U tests, and χ2 tests were used for statistical analysis. Results Forty-one participants with CCS (mean age, 39 years ± 13 [standard deviation]; 18 men) and 42 control participants (mean age, 39 years ± 16; 26 men) were evaluated. The median time between the initial incidence of mild to moderate COVID-19 not requiring hospitalization and undergoing cardiac MRI was 103 days (interquartile range, 88-158 days). Troponin T levels were normal. Parameters indicating myocardial inflammation and edema were comparable between participants with CCS and control participants (T1 relaxation times: 978 msec ± 23 vs 971 msec ± 25 [P = .17]; T2 relaxation times: 53 msec ± 2 vs 52 msec ± 2 [P = .47]; T2 signal intensity ratios: 1.6 ± 0.2 vs 1.6 ± 0.3 [P = .10]). Visible myocardial edema was present in none of the participants. Three of 41 (7%) participants with CCS demonstrated nonischemic LGE, whereas no participants in the control group demonstrated nonischemic LGE (0 of 42 [0%]; P = .07). None of the participants fulfilled the 2018 Lake Louise criteria for the diagnosis of myocarditis. Conclusion Individuals with chronic COVID-19 syndrome who did not undergo hospitalization for COVID-19 did not demonstrate signs of active myocardial injury or inflammation at cardiac MRI. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Lima and Bluemke in this issue.

Perimyocarditis following first dose of the mRNA-1273 SARS-CoV-2 (Moderna) vaccine in a healthy young male: a case report.

BACKGROUND: Half of U.S. adults have received at least one dose of the COVID-19 vaccines produced by either Pfizer, Moderna, or Johnson and Johnson, which represents a major milestone in the ongoing pandemic. Given the emergency use authorizations for these vaccines, their side effects and safety were assessed over a compressed time period. Hence, ongoing monitoring for vaccine-related adverse events is imperative for a full understanding and delineation of their safety profile. CASE PRESENTATION: An 22-year-old Caucasian male presented to our hospital center complaining of pleuritic chest pain. Six months prior he had a mild case of COVID-19, but was otherwise healthy. He had received his first dose of the Moderna vaccine three days prior to developing symptoms. Laboratory analysis revealed a markedly elevated troponin and multiple imaging modalities during his hospitalization found evidence of wall motion abnormalities consistent with a diagnosis of perimyocarditis. He was started on aspirin and colchicine with marked improvement of his symptoms prior to discharge. CONCLUSIONS: We present a case of perimyocarditis that was temporally related to COVID-19 mRNA vaccination in an young male with prior COVID-19 infection but otherwise healthy. Our case report highlights an albeit rare but important adverse event for clinicians to be aware of. It also suggests a possible mechanism for the development of myocardial injury in our patient.

Comparison of the Limb-lead Electrocardiogram to the 12-Lead Electrocardiogram for Identifying Conditions Associated with Sudden Cardiac Death in Youth Athletes.

The optimal screening strategy to prevent sudden cardiac death (SCD) in athletes remains unknown. Pre-participation screening with electrocardiogram (ECG) remains controversial. The utility and accuracy of limb-lead (LL) ECG alone in identifying cardiac abnormalities associated with SCD has not been studied. This study was a comparative secondary data analysis, comparing the interpretation accuracy of 4 physicians evaluating publicly available ECGs of the most common cardiac conditions associated with SCD in athletes. Each physician interpreted a total of 100 ECGs: 50 normal ECGs (25 LL and 25 standard 12L) and 50 abnormal ECGs (25 LL and 25 standard 12L). The agreement between LL ECGs and 12L ECGs was assessed by Cohen's kappa coefficient and the accuracy of identifying an abnormal ECG was compared across LL and 12L ECGs using a chi-squared test. Inter-rater reliability was assessed by estimating the Fleiss's kappa coefficient. The sensitivity of LL ECG and 12L ECG was identical at 86%. The specificity of LL ECG was 75% (95% CI = 65% to 83%) and 12L ECG was 82% (95% CI = 73% to 89%). Substantial agreement was seen between LL ECG and 12L ECG interpretation across all readers (k = 0.63; 95% CI = 0.49 to 0.77). Interpretation accuracy was 81% (95% CI = 74% to 86%) and 84% (95% CI 78% to 89%) using LL ECG and 12L ECG, respectively (p = 0.43). In conclusion, the accuracy, sensitivity, and specificity were high and comparable for both LL ECG and 12L ECG in identifying cardiovascular conditions associated with SCD. Agreement between LL ECG and 12L ECG was substantial.

Electrocardiographic changes are strongly correlated with the extent of cardiac inflammation in mice with Coxsackievirus B3-induced viral myocarditis.

OBJECTIVE: Viral myocarditis (VM) can induce changes in myocardial electrical conduction and arrhythmia. However, their relationship with myocarditis-associated arrhythmic substrates in the heart such as inflammation and fibrosis is relatively unknown. This we have analyzed in the present study. METHODS: C3H mice were infected with 1×105 plaque-forming units Coxsackievirus B3 (CVB3, n=68) and were compared with uninfected control mice (n=10). Electrocardiograms (ECGs) were recorded in all conscious mice shortly before sacrifice and included heart rate; P-R interval; QRS duration; QTc interval and R-peak amplitude of lead II and aVF. Mice were sacrificed at 4, 7, 10, 21, 35 or 49 days post-infection. Cardiac lesion size, calcification, fibrosis and cellular infiltration of CD45+ lymphocytes, MAC3+ macrophages, Ly6G+ neutrophils and mast cells were quantitatively determined in cross-sections of the ventricles. Putative relations between ECG changes and lesion size and/or cardiac inflammation were then analyzed. RESULTS: Significant transient reductions in QRS duration and R-peak amplitude occurred between 4 and 14 days post-infection and returned to baseline values thereafter. The magnitude of these ECG changes strongly correlated to the extent of lymphocyte (days 7 and 14), macrophage (days 7 and 10) and neutrophil (days 7) infiltration. The ECG changes did not significantly correlate with lesion size and fibrosis. CONCLUSION: VM induces transient changes in myocardial electrical conduction that are strongly related to cellular inflammation of the heart. These data show that even in mild VM, with relatively little cardiac damage, the inflammatory infiltrate can form an important arrhythmogenic substrate.

Usefulness of Left Ventricular Myocardial Deformation in Children Hospitalized for Acute Myocarditis who Develop Arrhythmias.

Cardiac arrhythmias occur in 3-40% of patients with acute myocarditis and cause significant morbidity and mortality. Myocardial injury also results in abnormal myocardial deformation. The relationship between left ventricular (LV) deformation, measured by two-dimensional speckle tracking echocardiography (2D-STE), and arrhythmia in pediatric myocarditis is unknown. We evaluated the association between 2D-STE and arrhythmias in children hospitalized with acute myocarditis. We reviewed patients ≤ 18 years hospitalized for acute myocarditis from 2008 to 2018. Arrhythmias were defined as 1) non-sustained or sustained ventricular tachycardia or ventricular fibrillation, 2) sustained supraventricular tachycardia (SVT), 3) high-grade or complete heart block, and 4) any arrhythmia treated with an antiarrhythmic medication. Systolic LV strain values (including LV global longitudinal strain (GLS), global circumferential strain (GCS), and six segments of LV regional long axis strain) were obtained from initial echocardiograms during hospitalization. Of 66 patients hospitalized, 23 (35%) had arrhythmias. SVT was the predominant arrhythmia (74%). Global and regional strain indices were reduced in the arrhythmia group: LV GLS [-8.9 (IQR -13.6, -6.1) vs. -13.7 (IQR -16.9, -9.7), p = 0.038]; basal inferior/septal [-10.7 (IQR -15.5, -7.8) vs. -16.4 (IQR -18, -11.8), p = 0.009]; basal anterior/lateral [-7.1 (IQR -12.8, -4.7) vs. -9.4 (IQR -16.7, -7.4), p = 0.025]; and mid inferior/septal segments [-9 (IQR -13, -7.7) vs. -14.1 (IQR -22.5, -10.7), p = 0.007]. After controlling for age, reductions in GLS and segmental strain in the two basal and two mid-segments were associated with increased arrhythmia occurrence (p <0.05). Our findings suggest that echocardiographic LV deformation by 2D-STE may be useful in identifying pediatric patients with acute myocarditis at risk for arrhythmias.