Aims COVID‐19, a respiratory viral disease causing severe pneumonia, also affects the heart and other organs. Whether its cardiac involvement is a specific feature consisting of myocarditis, or simply due to microvascular injury and systemic inflammation, is yet unclear and presently debated. Because myocardial injury is also common in other kinds of pneumonias, we investigated and compared such occurrence in severe pneumonias due to COVID‐19 and other causes. Methods and results We analysed data from 156 critically ill patients requiring mechanical ventilation in four European tertiary hospitals, including all n = 76 COVID‐19 patients with severe disease course requiring at least ventilatory support, matched to n = 76 from a retrospective consecutive patient cohort of severe pneumonias of other origin (matched for age, gender, and type of ventilator therapy). When compared to the non‐COVID‐19, mortality (COVID‐19 = 38.2% vs. non‐COVID‐19 = 51.3%, P = 0.142) and impairment of systolic function were not significantly different. Surprisingly, myocardial injury was even more frequent in non‐COVID‐19 (96.4% vs. 78.1% P = 0.004). Although inflammatory activity [C‐reactive protein (CRP) and interleukin‐6] was indifferent, d‐dimer and thromboembolic incidence (COVID‐19 = 23.7% vs. non‐COVID‐19 = 5.3%, P = 0.002) driven by pulmonary embolism rates (COVID‐19 = 17.1% vs. non‐COVID‐19 = 2.6%, P = 0.005) were higher. Conclusions Myocardial injury was frequent in severe COVID‐19 requiring mechanical ventilation, but still less frequent than in similarly severe pneumonias of other origin, indicating that cardiac involvement may not be a specific feature of COVID‐19. While mortality was also similar, COVID‐19 is characterized with increased thrombogenicity and high pulmonary embolism rates.

Sudden cardiac death (SCD), most often induced by ventricular arrhythmias, is one of the main reasons for cardiovascular-related mortality. While coronary artery disease remains the leading cause of SCD, other pathologies like cardiomyopathies and, especially in the younger population, genetic disorders, are linked to arrhythmia-related mortality. Despite many efforts to enhance the efficiency of risk-stratification strategies, effective tools for risk assessment are still missing. Biomarkers have a major impact on clinical practice in various cardiac pathologies. While classic biomarkers like brain natriuretic peptide (BNP) and troponins are integrated into daily clinical practice, inflammatory biomarkers may also be helpful for risk assessment. Indeed, several trials investigated their application for the prediction of arrhythmic events indicating promising results. Furthermore, in recent years, active research efforts have brought forward an increasingly large number of “novel and alternative” candidate markers of various pathophysiological origins. Investigations of these promising biological compounds have revealed encouraging results when evaluating the prediction of arrhythmic events. To elucidate this issue, we review current literature dealing with this topic. We highlight the potential of “classic” but also “novel” biomarkers as promising tools for arrhythmia prediction, which in the future might be integrated into clinical practice.

Myocarditis is associated with formidable symptoms and increased risk of adverse outcomes. Current approaches mostly rely on symptomatic treatments, warranting novel concepts for clinical practice. The aim of this study was to investigate the microRNA (miRNA) expression profile of Balb/c mice with experimental autoimmune myocarditis (EAM), choose a representative miRNA to antagonize after review of available literature and test its effects on myocardial inflammation in vitro and in vivo. Phase 1: EAM was induced in 12 male Balb/c mice, 10 animals served as controls. After sacrifice, next-generation sequencing (NGS) of the miRNA expression profile was performed. Based on these results, H9C2 cells and human ventricular cardiac fibroblasts exposed to lipopolysaccharide (LPS) were treated with the selected candidate antagomiR-21a-5p. Phase 2: EAM was induced in 48 animals. Thereof, 24 animals were either treated with antagomiR-21a-5p or negative control oligonucleotide in a nanoparticle formulation. Transthoracic echocardiography (TTE) was performed on Days 0, 7, 14, and 21. Histopathological examination was performed after sacrifice. Phase 1: EAM resulted in a significant up-regulation of 27 miRNAs, including miR-21a-5p (log2FC: 2.23, adj. P = 0.0026). Transfection with antagomiR-21a-5p resulted in a significant reduction of TNFα, IL-6, and collagen I in vitro. Phase 2: Treatment with antagomiR-21a-5p, formulated in polymeric nanoparticles for systemic injection, significantly attenuated myocardial inflammation (P = 0.001) and fibrosis (P = 0.013), as well as myocardial ‘hypertrophy’ on TTE. Silencing of miR-21a-5p results in a significant reduction of the expression of pro-inflammatory cytokines in vitro, as well as a significant attenuation of inflammation, fibrosis and echocardiographic effects of EAM in vivo.

Background: Heart failure with preserved ejection fraction (HFpEF) remains an ongoing therapeutic and diagnostic challenge to date. In this study we aimed for an analysis of the diagnostic potential of four novel cardiovascular biomarkers, GDF-15, H-FABP, sST2, and suPAR in HFpEF patients compared to controls as well as ICM, and DCM. Methods: In total, we included 252 stable outpatients and controls (77 DCM, 62 ICM, 18 HFpEF, and 95 controls) in the present study. All patients were in a non-decompensated state and on a stable treatment regimen. Serum samples were obtained and analyzed for GDF-15 (inflammation, remodeling), H-FABP (ischemia and subclinical ischemia), sST2 (inflammation, remodeling) and suPAR (inflammation, remodeling) by means of ELISA. Results: A significant elevation of GDF-15 was found for all heart failure entities compared to controls (p < 0.005). Similarly, H-FABP evidenced a significant elevation in all heart failure entities compared to the control group (p < 0.0001). Levels of sST2 were significantly elevated in ICM and DCM patients compared to the control group and HFpEF patients (p < 0.0001). Regarding suPAR, a significant elevation in ICM and DCM patients compared to the control group (p < 0.0001) and HFpEF patients (p < 0.01) was observed. An AUC analysis identified H-FABP (0.792, 95% CI 0.713–0.870) and GDF-15 (0.787, 95% CI 0.696–0.878) as paramount diagnostic biomarkers for HFpEF patients. Conclusion: Based on their differences in secretion patterns, novel cardiovascular biomarkers might represent a promising diagnostic tool for HFpEF in the future.

Aims Dendritic cells (DCs) are central mediators of adaptive immunity, and there is growing evidence of their role in myocardial inflammatory disease. We hypothesized that plasmacytoid and myeloid DCs are involved in the mechanisms of myocarditis and analysed these two main subtypes in human myocarditis subjects, as well as in a murine model of experimental autoimmune myocarditis (EAM). Methods and results Circulating DCs were analysed by flow cytometry in patients with acute myocarditis, dilated cardiomyopathy, and controls. Myocardial biopsies were immunostained for the presence of DCs and compared with non‐diseased controls. In a mouse model of acute myocarditis induced through synthetic cardiac myosine peptide injection, effects of immunomodulation including DC inhibition through MCS‐18 versus placebo treatment were tested at the peak of inflammation (Day 21), as well as 1 week later (partial recovery). Circulatory pDCs and mDCs were significantly reduced in myocarditis patients compared with controls (P < 0.01 for both) and remained so even after 6 months of follow‐up. Human myocarditis biopsies showed accumulation of pDCs (two‐fold CD304+/three‐fold CD123+, all P < 0.05) compared with controls. Myocardial pDCs and mDCs accumulated in EAM (P for both <0.0001). MCS‐18 treatment reduced pDC levels (P = 0.009), reduced myocardial inflammation (myocarditis score reduction from 2.6 to 1.8, P = 0.026), and improved ejection fraction (P = 0.03) in EAM at Day 21 (peak of inflammation). This effect was not observed during the partial recovery of inflammation on Day 28. Conclusions Circulating DCs are reduced in human myocarditis and accumulate in the inflamed myocardium. MCS‐18 treatment reduces DCs in EAM, leading to amelioration of inflammation and left ventricular remodelling during the acute phase of myocarditis. Our data further elucidate the role of DCs and their specific subsets in acute inflammatory cardiomyopathies.

Background. Following COVID-19, patients often present with ongoing symptoms comparable to chronic fatigue and subjective deterioration of exercise capacity (EC), which has been recently described as postacute COVID-19 syndrome. Objective. To objectify the reduced EC after COVID-19 and to evaluate for pathologic limitations. Methods. Thirty patients with subjective limitation of EC performed cardiopulmonary exercise testing (CPET). If objectively limited in EC or deteriorated in oxygen pulse, we offered cardiac stress magnetic resonance imaging (MRI) and a follow-up CPET. Results. Eighteen male and 12 female patients were included. Limited relative EC was detected in 11/30 (36.7%) patients. Limitation correlated with reduced body weight-indexed peak oxygen (O₂) uptake (peakV̇O₂/kg) (mean 74.7 (±7.1) % vs. 103.6 (±14.9) %, ). Reduced peakV̇O₂/kg was found in 18/30 (60.0%) patients with limited EC. Patients with reduced EC widely presented an impaired maximum O₂ pulse (75.7% (±5.6) vs. 106.8% (±13.9), ). Abnormal gas exchange was absent in all limited EC patients. Moreover, no patient showed signs of reduced pulmonary perfusion. Using cardiac MRI, diminished biventricular ejection fraction was ruled out in 16 patients as a possible cause for reduced O₂ pulse. Despite noncontrolled training exercises, follow-up CPET did not reveal any exercise improvements. Conclusions. Deterioration of EC was not associated with ventilatory or pulmonary vascular limitation. Exercise limitation was related to both reduced O₂ pulse and peakV̇O₂/kg, which, however, did not correlate with the initial severity of COVID-19. We hypothesize that impaired microcirculation or limited peripheral O₂ utilization might be causative for prolonged deterioration of EC following acute COVID-19 infection.