Dapagliflozin Alleviates Myocardial Inflammation by Regulating the Macrophage Polarization and Stat3-related Pathways in Coxsackie Virus B3-induced Acute Viral Myocarditis

Viral myocarditis (VMC), which is most prevalently caused by Coxsackievirus B3 (CVB3) infection, is a serious clinical condition characterized by cardiac inflammation. Dapagliflozin, a kind of sodium glucose co-transporters 2(SGLT-2) inhibitor, exhibited protective effects on plenty of inflammatory diseases, while its effect on viral myocarditis has not been studied. Recently we found the protective effect of dapagliflozin on VMC. After CVB3 infection, dapagliflozin were given orally to Balb/c male mice for 8 days and then the severity of myocarditis was assessed. Our results indicated that dapagliflozin significantly alleviated the severity of viral myocarditis, elevated the survival rate, and ameliorated cardiac function. Besides, dapagliflozin can decrease the level of proinflammatory cytokines included IL-1β, IL-6, TNF-α. Furthermore, dapagliflozin can inhibit macrophages differentiate to classically activated macrophages (M1) in cardiac tissue and activate the Stat3 signal pathway which is reported to promote polarization of the alternatively activated macrophage (M2). In conclusion, our study demonstrates that dapagliflozin alleviates myocardial inflammation by regulating the macrophage polarization and Stat3-related pathways in coxsackie virus B3-induced acute viral myocarditis.

Peripheral Blood MicroRNAs as Potential Biomarkers of Myocardial Damage in Acute Viral Myocarditis

Background: microRNAs (miRs) have emerged as important modulators of cardiovascular development and disease. Our aim was to determine whether cardiac-related miRs such as miR-21-5p and miR-1-3p were differentially expressed in acute viral myocarditis and whether any of them was related with the extent of myocardial damage and left ventricular dysfunction. Methods: We enrolled 40 patients with acute viral myocarditis. Blood samples were taken on admission and miRs expression levels in peripheral blood mononuclear cells were quantified by real-time reverse transcription polymerase chain reaction. Results: miR-21-5p, miR-1-3p were significantly elevated in acute myocarditis. miR-21-5p levels showed a strong correlation with global longitudinal strain (r = 0.71, p < 0.01), while miR-1-3p had significant correlations with troponin I (r = 0.79, p < 0.01). Conclusions: The expression of miR-21-5p and miR-1-3p in peripheral blood is increased in acute viral myocarditis, and this increase is correlated with myocardial damage and indicative of left ventricular systolic dysfunction in these patients.

Secondary Prevention of Potentially Life-Threatening Arrhythmia Using Implantable Cardioverter Defibrillators in Patients with Biopsy-Proven Viral Myocarditis and Preserved Ejection Fraction

<b><i>Background:</i></b> Arrhythmia and sudden cardiac death (SCD) are known complications of acute viral myocarditis, regardless of ejection fraction (EF) at presentation. Whether such complications confer long-term risk is unknown, especially in those who present with preserved left ventricular (LV) function. No guidelines exist to the long-term reduction of arrhythmic death in such patients. <b><i>Method:</i></b> In this retrospective study, we analyzed the long-term results of implantable cardioverter defibrillator (ICD) treatment in patients after an acute phase of myocarditis with life-threatening arrhythmia. <b><i>Results:</i></b> We identified 51 patients who had ICDs implanted following life-threatening arrhythmia presentation of confirmed acute viral myocarditis, despite preserved LVEF. Overall, 72.5% of patients had a clinical history of chest pain and viral infection with fever. Viral myocarditis was confirmed by cardiac magnetic resonance imaging (all had late enhancement) plus endomyocardial biopsies (most frequent were Epstein-Barr virus 29.4%, adenovirus 17.6%, and Coxsackie 17.6%), and 88.2% were discharged on anti-arrhythmic drugs. Overall, 12 patients (23.5%) required ICD intervention within the first 3 months, a further 7 patients (37.3% overall) between 3 and 12 months, and a further 12 patients (60.8% overall) until 58 months. During the follow-up, 3 of 51 patients (5.9%) died—deaths were due to cardiac events (<i>n</i> = 1), fatal infection (<i>n</i> = 1), and car accidents (<i>n</i> = 1). Of the 31 patients who had ventricular tachycardias after the acute phase of myocarditis, 11 needed radiofrequency ablation due to a high number of events or electrical storm. No baseline variables were identified that would serve as a basis for risk stratification. <b><i>Conclusion:</i></b> Malignant arrhythmic events due to viral myocarditis are potential predictors of future SCD in patients not only with a reduced but also with a preserved EF.

Modern critical approach to the diagnosis of acute viral myocarditis and inflammatory cardiomyopathies in clinical practice: Focus on the roles of echocardiography and antivirus antibodies

SIGNIFICANCE OF THE PROBLEM: The diagnosis of acute viral myocarditis is one of the diagnoses most difficult to make in cardiology and medicine in general. Echocardiography and cardiomagnetic resonance play a crucial role in the clinical diagnosis and the serum titer of antiviral antibodies to cardiotropic viruses is still unjustifiably used for the diagnosis of myocarditis in everyday practice. RESEARCH OBJECTIVES: To analyze the frequency and significance of echocardiographic parameters in the diagnosis of clinically suspected acute viral myocarditis, to determine the role of antiviral antibody titer (AVA) dynamics for the diagnosis of myocarditis and to compare viral serology and echocardiographic function versus echocardiographic function. METHODOLOGY: A retrograde transverse study was performed in the ten-year period from 2006. to 2015, where 126 consecutive patients from the database of the Office of Internal medicine ''Dr. Bastać'' were analyzed, with a working diagnosis of clinically suspected viral myocarditis. They were clinically, ECG, echocardiographically and serologically monitored for 4 to 8 weeks due to the dynamics of AVA titer. The examined group (A) was divided into subgroups: A1 with elevated AVA class IgM titer in 43 (32%) subjects and subgroup A2 without elevated IgM titer in 83 (68%) patients. The control group of healthy (B) of 103 subjects was comparable.Statistical processing was done in the EXCELL database via descriptive statistics, Student's-T test and Chi2 test. RESULTS: 126 patients had clinically suspected myocarditis (≥2 ESC criteria). Diastolic left ventricular dysfunction in 39/126 (31%) patients was the dominant echocardiographic criterion for clinically suspected myocarditis. Reduced ejection fraction (EF <50%) was measured at 19/126 (15%), followed by left ventricular dilatation. Regional systolic dysfunction was found in 21/126 (17%) and changes in myocardial texture in 17 (13%) subjects. The clinical probability of viral etiology was diagnostically supported by elevated titer of IgM antibodies in 43 (32%) subjects (subgroup A1) where IgM antibodies to Parvo B 19 virus predominate in 36/43 patients (84%). Most were without elevated titer of IgM antibodysubgroup A2 83 (68%). Clear dynamics of IgM antibody titer was observed in 23 persons, a decrease in IgM titer with an increase in IgG titer (seroconversion) in 13 patients. Determination of anti-heart autoantibodies (AHA) was done in 17 severe cases, of which 9 had positive AHA. A comparison of subgroups A1 and A2 did not reveal a statistically significant difference in echocardiographic parameters. The whole group A of clinically suspected myocarditis compared to control group B has statistically highly significantly lower parameters of global systolic (EF=8,7±4,6 vs. 63±7,9; p<0,001), longitudinal systolic (S'=6,9±1,3 vs. 9,9±2,1) and diastolic function (E/e'11,9±4,8 vs. 8,7±4,6; p<0,001), and a highly statistically significant increase in left ventricular telediastolic dimension, myocardial mass index, and left atrial size. CONCLUSION: The diagnosis of acute viral myocarditis in clinical practice is made on the basis of the clinical picture, ECG and echocardiography that indicate myocarditis with the exclusion of cardiac comorbidities, based on the ESC criteria for suspected clinical myocarditis. The whole group A had highly statistically significantly lower parameters of systolic and diastolic function compared to control group B. Normal ECG and echocardiography cannot serve to exclude the diagnosis of myocarditis. Comparison of subgroups A1 and A2 did not reveal a statistically significant difference in echocardiographic parameters.