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Treatment of myocarditis is often limited to symptomatic treatment due to unknown pathomechanisms. In order to identify new therapeutic approaches, the contribution of locked nucleic acid antisense oligonucleotides (LNA ASOs) in autoimmune myocarditis was investigated. Hence, A/J mice were immunized with cardiac troponin I (TnI) to induce experimental autoimmune myocarditis (EAM) and treated with LNA ASOs. The results showed an unexpected anti-inflammatory effect for one administered LNA ASO MB_1114 by reducing cardiac inflammation and fibrosis. The target sequence of MB_1114 was identified as lactate dehydrogenase B (mLDHB). For further analysis, mice received mLdhb-specific GapmeR during induction of EAM. Here, mice receiving the mLdhb-specific GapmeR showed increased protein levels of cardiac mLDHB and a reduced cardiac inflammation and fibrosis. The effect of increased cardiac mLDHB protein level was associated with a downregulation of genes of reactive oxygen species (ROS)-associated proteins, indicating a reduction in ROS. Here, the suppression of murine pro-apoptotic Bcl-2-associated X protein (mBax) was also observed. In our study, an unexpected anti-inflammatory effect of LNA ASO MB_1114 and mLdhb-specific GapmeR during induction of EAM could be demonstrated in vivo. This effect was associated with increased protein levels of cardiac mLDHB, mBax suppression and reduced ROS activation. Thus, LDHB and LNA ASOs may be considered as a promising target for directed therapy of myocarditis. Nevertheless, further investigations are necessary to clarify the mechanism of action of anti-inflammatory LDHB-triggered effects.

BACKGROUND: Application of the 4th version of Universal Definition of Myocardial Infarction (UDMI) to characterize rates and prognostic relevance of myocardial injury in COVID-19 disease. METHODS: This retrospective, single-centre observational study enrolled 104 patients hospitalized with SARS-CoV-2 infection. Kaplan-Meier analysis and multivariate Cox regression were used to identify influence of acute or chronic myocardial injury on a composite primary (mortality, incident acute respiratory distress syndrome, incident mechanical ventilation) and secondary endpoint (mortality, incident acute myocardial injury during hospitalization, incident venous thrombosis, pulmonary embolism or stroke). RESULTS: A total of 27 (26.0%) patients presented with chronic myocardial injury, and 19 (18.3%) with acute myocardial injury. 42 patients(40.4%) developed an incident myocardial injury during hospitalization. The presence of acute or chronic myocardial injury on admission and incident myocardial injury during hospitalization were associated with higher rates of endpoints. Independent predictors for the primary endpoint were higher severity stages according to Siddiqi et al. classification system and history of dyslipidaemia. Maximal hs-cTnT and D-dimer concentrations during hospitalization showed an association (r = 0.61). CONCLUSIONS: Objective description of myocardial injury according to the 4th UDMI in the current COVID-19 pandemic is crucial in order to discriminate patients with acute myocardial infarction and acute, chronic or incident myocardial injury.

Background To evaluate the prognostic value of eleven microRNAs (miRNAs) compared to high-sensitivity Troponin T (hs-cTnT) in patients presenting with suspected acute coronary syndrome (ACS) to the emergency department (ED). Methods 1,042 patients presenting between August 2014 and April 2017 were included. Expression levels of eleven microRNAs (miR-21-5p, miR-22-3p, miR-29a-3p, miR-92a-3p, miR-122-5p, miR-126-3p, miR-132-3p, miR-133a-3p, miR-134-5p, miR-191-3p, and miR-423-5p) were determined using RT-qPCR. All-cause mortality (ACM) and a composite of ACM, acute myocardial infarction (AMI) and stroke were defined as endpoints. Results During a median follow-up of 399 (P25-P75: 381–525) days 58 patients (5.6%) died. The composite endpoint occurred in 86 patients (8.3%). Different expression levels of miR-21-5p (median, P25-P75: 5.28 [5.14–5.51] vs. 5.16 [4.97–5.35], p = 0.0033) and miR-122-5p (median, P25-P75: 5.17 [4.81–5.49] vs. 5.35 [5.01–5.69], p = 0.0184) were observed in patients who died compared to survivors. ROC-optimized cutoff of miR-21-5p (HR, P25-P75: 3.3 [1.2–9.4], p = 0.0239), but not miR-122-5p (HR, P25-P75: 0.4 [0.2–0.8], p = 0.0116), was predictive for all-cause mortality, even after adjustment in a multivariate model. Nevertheless, addition of miR-21-5p and miR-122-5p decreased prognostic accuracy of hs-cTnT for all-cause mortality (△AUC: 0.112, p = 0.0159). Hs-cTnT admission values had a high prognostic value for ACM (AUC [95%CI] = 0.794 [0.751–0.837]) and the composite of ACM, AMI and stroke (AUC [95%CI] = 0.745 [0.695–0.794]). Conclusions Despite a different expression depending on outcomes miR-21-5p and miR-122-5p do not add prognostic information to hs-cTnT in patients presenting with suspected ACS to the ED.

Background An established objective and standardized reporting of clinical severity and disease progression in COVID-19 is still not established. We validated and compared the usefulness of two classification systems reported earlier–a severity grading proposed by Siddiqi and a system from the National Australian COVID-19 guideline. Both had not been validated externally and were now tested for their ability to predict complications. Methods In this retrospective, single-centre observational study, patients hospitalized with confirmed COVID-19 across all severity stages were enrolled. The clinical severity was graded at admission and during hospitalization. Multivariate Cox regression was used to identify independent risk factors for mortality, a composite primary (mortality, incident acute respiratory distress syndrome, incident mechanical ventilation), a secondary endpoint (mortality, incident acute myocardial injury, incident venous thrombosis, pulmonary embolism or stroke) and progression of severity grades. Results Of 109 patients 17 died, 31 and 48 developed the primary and secondary endpoint, respectively. Worsening of the severity grade by at least one stage occurred in 27 and 28 patients, respectively. Siddiqi and Australian classification were identified as independent predictors for the primary endpoint (adjusted hazard ratio (aHR) 2.30, p Conclusions Standardized and objective severity grading is useful to unequivocally stratify patients presenting with COVID-19 for their individual risk of complications.

Background: Immune checkpoint inhibitor (ICI) therapy is often accompanied by immune-related pathology, with an increasing occurrence of high-risk ICI-related myocarditis. Understanding the mechanisms involved in this side effect could enable the development of management strategies. In mouse models, immune checkpoints, such as PD-1 (programmed cell death protein 1), control the threshold of self-antigen responses directed against cardiac TnI (troponin I). We aimed to identify how the immunoproteasome, the main proteolytic machinery in immune cells harboring 3 distinct protease activities in the LMP2 (low-molecular-weight protein 2), LMP7 (low-molecular-weight protein 7), and MECL1 (multicatalytic endopeptidase complex subunit 1) subunit, affects TnI-directed autoimmune pathology of the heart. Methods: TnI-directed autoimmune myocarditis (TnI-AM), a CD4 + T-cell–mediated disease, was induced in mice lacking all 3 immunoproteasome subunits (triple-ip −/− ) or lacking either the gene encoding LMP2 and LMP7 by immunization with a cardiac TnI peptide. Alternatively, before induction of TnI-AM or after establishment of autoimmune myocarditis, mice were treated with the immunoproteasome inhibitor ONX 0914. Immune parameters defining heart-specific autoimmunity were investigated in experimental TnI-AM and in 2 cases of ICI-related myocarditis. Results: All immunoproteasome-deficient strains showed mitigated autoimmune-related cardiac pathology with less inflammation, lower proinflammatory and chemotactic cytokines, less interleukin-17 production, and reduced fibrosis formation. Protection from TnI-directed autoimmune heart pathology with improved cardiac function in LMP7 −/− mice involved a changed balance between effector and regulatory CD4 + T cells in the spleen, with CD4 + T cells from LMP7 − /− mice showing a higher expression of inhibitory PD-1 molecules. Blocked immunoproteasome proteolysis, by treatment of TLR2 (Toll-like receptor 2)–engaged and TLR7 (Toll-like receptor 7)/TLR8 (Toll-like receptor 8)–engaged CD14 + monocytes with ONX 0914, diminished proinflammatory cytokine responses, thereby reducing the boost for the expansion of self-reactive CD4 + T cells. Correspondingly, in mice, ONX 0914 treatment reversed cardiac autoimmune pathology, preventing the induction and progression of TnI-AM when self-reactive CD4 + T cells were primed. The autoimmune signature during experimental TnI-AM, with high immunoproteasome expression, immunoglobulin G deposition, interleukin-17 production in heart tissue, and TnI-directed humoral autoimmune responses, was also present in 2 cases of ICI-related myocarditis, demonstrating the activation of heart-specific autoimmune reactions by ICI therapy. Conclusions: By reversing heart-specific autoimmune responses, immunoproteasome inhibitors applied to a mouse model demonstrate their potential to aid in the management of autoimmune myocarditis in humans, possibly including patients with ICI-related heart-specific autoimmunity.

Current pandemic caused by SARS-CoV-2 inducing viral COVID-19 pneumonia, is categorized in 3 stages. Some biomarkers could be assigned to one of these stages, showing a correlation to mortality in COVID-19 patients. Laboratory findings in COVID-19, especially when serially evaluated, may represent individual disease severity and prognosis. These may help planning and controlling therapeutic interventions. Biomarkers for myocardial injury (high sensitive cardiac troponin, hsTn) or hemodynamic stress (NTproBNP) may occur in COVID-19 pneumonia such as in other pneumonias, correlating with severity and prognosis of the underlying disease. In hospitalized COVID-19 patients' mild increases of hsTn or NTproBNP may be explained by cardiovascular comorbidities and direct or indirect cardiac damage or stress caused by or during COVID-19 pneumonia. In case of suspected NSTE-ACS and COVID-19, indications for echocardiography or reperfusion strategy should be carefully considered against the risk of contamination.PHäNOTYPISIERUNG UND RISIKOSTRATIFIZIERUNG BEI COVID-19: Die aktuelle COVID-19-Erkrankung verläuft in 3 Stadien. Einige Serum-Biomarker können einem der 3 Stadien zugeordnet werden und es besteht ein Zusammenhang mit der Mortalität. Laborwerte können insbesondere bei serieller Erfassung helfen, Aussagen zur Schwere der Erkrankung und Prognose zu liefern. In Zukunft könnten diese dann ggf. zur Steuerung der Therapie genutzt werden. COVID-19-KARDIOVASKULäRE ERKRANKUNGEN UND MYOKARDSCHADEN: Biomarker von Myokardschaden (high-sensitives kardiales Troponin, hs-cTn) oder hämodynamischem Stress (NT-proBNP) können bei COVID-19, wie bei anderen Pneumonien, auftreten und korrelieren mit der Schwere und Prognose der Grunderkrankung. Bei hospitalisierten Patienten mit COVID-19 erklären sich milde Erhöhungen von hs-cTn oder NT-proBNP durch deren kardiovaskuläre Komorbidität und durch die direkte oder indirekte akute Herzschädigung bzw. den Stress durch und während der COVID-19-Pneumonie. Bei gegebenem Verdacht auf einen Nicht-ST-Hebungsinfarkt und COVID-19 sollte eine sorgfältige Abwägung der Indikation für eine Echokardiografie und invasive Diagnostik gegen das Risiko der Kontamination abgewogen werden.

Was ist neu Phänotypisierung und Risikostratifizierung bei COVID-19 Die aktuelle COVID-19-Erkrankung verläuft in 3 Stadien. Einige Serum-Biomarker können einem der 3 Stadien zugeordnet werden und es besteht ein Zusammenhang mit der Mortalität. Laborwerte können insbesondere bei serieller Erfassung helfen, Aussagen zur Schwere der Erkrankung und Prognose zu liefern. In Zukunft könnten diese dann ggf. zur Steuerung der Therapie genutzt werden. COVID-19-kardiovaskuläre Erkrankungen und Myokardschaden Biomarker von Myokardschaden (high-sensitives kardiales Troponin, hs-cTn) oder hämodynamischem Stress (NT-proBNP) können bei COVID-19, wie bei anderen Pneumonien, auftreten und korrelieren mit der Schwere und Prognose der Grunderkrankung. Bei hospitalisierten Patienten mit COVID-19 erklären sich milde Erhöhungen von hs-cTn oder NT-proBNP durch deren kardiovaskuläre Komorbidität und durch die direkte oder indirekte akute Herzschädigung bzw. den Stress durch und während der COVID-19-Pneumonie. Bei gegebenem Verdacht auf einen Nicht-ST-Hebungsinfarkt und COVID-19 sollte eine sorgfältige Abwägung der Indikation für eine Echokardiografie und invasive Diagnostik gegen das Risiko der Kontamination abgewogen werden.