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(1) Background: Heart failure with reduced ejection fraction (HFrEF) remains a major health burden. Angiotensin-Receptor-Neprilysin-Inhibitors (ARNIs) are an established HFrEF therapy which increases natriuretic peptide levels by inhibiting neprilysin. Leptin is a lipid metabolism parameter, which is also involved in glucose metabolism and is suggested to correlate with HF burden. While the hormone also seems to interact with neprilysin, potential associations with ARNI therapy have not been investigated yet. (2) Methods: To study this issue, we measured levels of leptin and fructosamine in consecutive 72 HFrEF patients before initiation of ARNI therapy and 3–6 months after initiation of therapy in two European centers. Biomarker levels were correlated with clinical parameters including ejection fraction, LVEF, and NYHA class. (3) Results: During a follow-up of up to 6 months, clinical parameters improved significantly (LVEF: 30.2 ± 7.8% to 37.6 ± 10.0%, (p < 0.001) and a significant improvement of the mean NYHA class with initial 32 patients in NYHA III or IV and 8 patients in NYHA class III/IV during the follow up (p < 0.001). The initial NT-proBNP levels of 2251.5 ± 2566.8 pg/mL significantly improved to 1416.7 ± 2145 pg/mL, p = 0.008) during follow up. ARNI therapy was also associated with an increase in leptin levels (17.5 ± 23.4 µg/L to 22.9 ± 29.3, p < 0.001) and furthermore, affected glucose metabolism indicated by elevation of fructosamine values (333.9 ± 156.8 µmol/L to 454.8 ± 197.8 µmol/L, p = 0.013). (4) Conclusion: while in the early phase of therapy, ARNI promotes clinical improvement of HFrEF, and it also seems to affect fat and glucose parameters, indicating significant metabolic implications of this therapy regime.

MicroRNAs (miRNAs) are small, non-coding RNA molecules that are post-transcriptional regulators of gene expression. miRNAs have been shown to be key regulators of complicated pathological processes and hence great biomarkers for the early prediction of diseases, such as cardiovascular diseases and radiation-associated alteration after spaceflight. In this study, we present possible antagomir treatments targeting three different miRNAs, miR-16-5p, miR-125b-5p, and let-7a-5p, to mitigate the activity of the spaceflight environment in cardiovascular diseases. We focus on three proteins of interest associated with fibrotic remodeling, TGF-β1, SMAD3, and COL1, analyzing the molecular outcomes of antagomir treatment when exposed to Galactic Cosmic Radiation (GCR), Solar Particle Events (SPE) radiation, and microgravity. These proteins have been shown to play different fibrotic and antifibrotic roles and show molecular changes associated with exposure to the space environment. Furthermore, our results demonstrate the therapeutic potential of antagomirs as a countermeasure for future spaceflight missions.

Echocardiography is currently the noninvasive method of choice to screen patients with severe aortic valve stenosis (AS) for pulmonary hypertension (PH) by estimating systolic pulmonary artery pressure (sPAP). However, radiological options are also available by determining the main pulmonary artery (MPA) diameter in the setting of CT angiography. The aim of the present study was to compare cardiovascular biomarkers with the MPA diameter to allow other ways of detecting PH in patients with severe AS.194 patients with severe AS undergoing transcatheter aortic valve replacement (TAVR) were included in this study and were divided into two groups based on the CT-angiographically determined MPA diameter. In accordance with ESC guidelines, a cut-off value of 29 mm was determined in this study, with the absence of PH defined by an MPA diameter29 mm (n = 79/194) and the presence of PH defined by an MPA diameter ≥ 29 mm (115/194). Immediately before interventional aortic valve replacement, blood samples were drawn from the subjects and relevant cardiovascular biomarkers such as BNP, cTnI, GDF-15, H-FABP, IGF-BP2 and suPAR were assessed.Patients with an MPA diameter ≥ 29 mm had significantly higher BNP (p = 0.004), cTnI (p = 0.039) and HFABP (p = 0.015) plasma levels, whereas GDF-15 (p = 0.140), IGF-BP2 ( p = 0.088) and suPAR (p = 0.140) showed no significant differences. In addition, cut-off values were calculated to predict an MPA diameter ≥ 29 mm. Significant results were shown with 1634.00 pg/ml for BNP (p = 0.004), with 16.50 pg/ml for cTnI (p = 0.039) and with 1.16 ng/ml for H-FABP (p = 0.016). In a combined biomarker analysis, the 2-way combination of BNP and IGF-BP2 (AUC 0.671; 95%CI 0.538 - 0.805; p = 0.023) and the 3-way combination of BNP, H-FABP and IGF-BP2 (AUC 0.685; 95%CI 0.551 - 0.818; p = 0.015) showed the best results. Biomarker follow-up at 3 and 12 months after TAVR did not require additional information gain. Regarding 1-year survival, no significant difference could be detected between patients with an MPA diameter29 mm compared to patients with ≥ 29 mm (log-rank test: p = 0.262).The MPA diameter remains a controversial parameter for the detection of PH in patients with severe AS. Standing on its own, this non-invasive parameter may not be precise enough to detect PH accurately. Combining this parameter with several biomarkers did not provide significant additional information.

Aims 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. Methods and results Methods: Phase 1: EAM was induced in 12 male Balb/c mice, 10 animals served as controls. After sacrifice, next-generation sequencing (NGS) of the microRNA 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. Results: Phase 1: EAM resulted in a significant upregulation 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. Conclusions 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. Translational perspective Based on the findings of our study, silencing of miR-21a-5p by synthetic antagomiR could constitute a novel therapeutic approach in myocarditis. Hence, research on this matter certainly warrants further scientific attention and investigation.

Due to the advances in catheter-based interventional techniques, a wide range of heart diseases can now be treated with a purely interventional approach. Little is yet known regarding biological effects at the intracardiac implantation site or the effects on endothelialization and vascular inflammation in an in vivo environment. Detailed knowledge of ongoing vascular response, the process of endothelialization, and possible systemic inflammatory reactions after implantation is crucial for the clinical routine, since implants usually remain in the body for a lifetime.For this narrative review, we conducted an extensive profound PubMed analysis of the current literature on the endothelialization processes of intracardially implanted devices, such as persistent foramen ovale (PFO) occluders, atrial septal defect (ASD) occluders, left atrial appendage (LAA) occluders, transcatheter aortic valve implantations (TAVIs), and leadless pacemakers. Additionally, the known biological activities of common metallic and synthetic components of intracardiac devices in an "in vivo" setting have been evaluated.Nitinol, an alloy of nickel and titanium, is by far the most commonly used material found in intracardiac devices. Although allergies to both components are known, implantation can be performed safely in the vast majority of patients. Depending on the device used, endothelialization can be expected within a time frame of 3-6 months. For those patients with a known allergy, gold coating may be considered as a viable alternative.Based on our analysis, we conclude that the vast majority of devices are made of a material that is both safe to implant and nontoxic in long-term treatment according to the current knowledge. The literature on the respective duration of endothelialization of individual devices however is highly divergent.

Prognostication after cardiopulmonary resuscitation (CPR) is complex. Novel biomarkers like soluble suppression of tumorigenicity 2 (sST2) may provide an objective approach. A total of 106 post-CPR patients were included in this single-center observational prospective study. Serum sST2 levels were obtained 24 h after admission. Individuals were assigned to two groups: patients below and above the overall cohort’s median sST2 concentration. Primary outcome was a combined endpoint at 6 months (death or Cerebral Performance Category > 2); secondary endpoint 30-day mortality. A uni- and multivariate logistic regression analysis were conducted. Elevated sST2-levels were associated with an increased risk for the primary outcome (OR 1.011, 95% CI 1.004–1.019, p = 0.004), yet no patients with poor neurological outcome were observed at 6 months. The optimal empirical cut-off for sST2 was 46.15 ng/ml (sensitivity 81%, specificity 53%, AUC 0.69). Levels above the median (> 53.42 ng/ml) were associated with higher odds for both endpoints (death or CPC > 2 after 6 months: 21% vs. 49%, OR 3.59, 95% CI 1.53–8.45, p = 0.003; death after 30 days: 17% vs. 43.3%, OR 3.75, 95% CI 1.52–9.21, p = 0.003). A positive correlation of serum sST2 after CPR with mortality at 30 days and 6 months after cardiac arrest could be demonstrated.

Introduction: Among the causes of de novo diagnosed cardiomyopathy, Takotsubo cardiomyopathy (TTC) plays a minor role, with an occurrence of 50,000–100,000 cases per annum in the United States. In clinical practice, a differentiation of a TTC toward an ischemic cardiomyopathy (ICMP) or a dilatative cardiomyopathy (DCMP) appears to be challenging, especially in a subacute setting or in atypical types of TTC.Methods: To investigate this issue, we analyzed serum levels of sST2, GDF-15, suPAR, HFABP, and clinical parameters including echocardiography in 51 patients with TTC, 52 patients with ischemic cardiomyopathy (ICMP) and 65 patients with dilated cardiomyopathy (DCMP).Results: sST-2 seemed to be the most promising biomarker for prediction of a TTC in differential diagnosis to an ICMP (AUC: 0.879, p = < 0.001, Cut off values: 12,140.5 pg/ml) or to a DCMP (AUC: 0.881, p = < 0.001, cut off value: 14521.9 pg/ml). GDF-15 evidenced a slightly lower AUC for prediction of a TTC in differential diagnosis to an ICMP (AUC: 0.626, p = 0.028) and to a DCMP (AUC: 0.653, p = 0.007). A differential diagnostic value was found for H-FABP in the prediction of a DCMP compared to TTC patients (AUC: 0.686, p = < 0.001). In propensity score matching for left ventricular ejection fraction, sex, and cardiovascular risk factors, differences in the plasma levels of sST2 and H-FABP in the matched cohort of TTC vs. DCMP remained statistically significant. In the matched cohort of TTC vs. ICMP, differences in sST2 also remained statistically significantConclusion: As medical therapy, long term prognosis, interval of follow-ups, rehabilitation program and recommendations differ completely between TTC and ICMP/DCMP, biomarkers for differential diagnosis, or rather for confirmation of diagnosis, are warranted in cases of cardiomyopathies with unsure origin. sST-2, GDF-15 and H-FABP might facilitate the classification.

Introduction: Takotsubo cardiomyopathy (TTC) remains a life-threatening disease with the risk of decompensated heart failure and arrhythmias. Valid markers for the prediction of outcome are unavailable. The novel biomarkers fetuin-A, matrix metalloproteinases-2 (MMP-2), myeloperoxidase (MPO), Syndecan-1 and CD40-L show promising results for risk stratification of cardiovascular patients. Nevertheless, clinical implementation has not been investigated in TTC patients. Methods: To investigate this issue, we evaluated clinical complications in 51 patients hospitalized for TTC and measured the serum levels of fetuin-A, MPO, MMP-2, Syndecan-1 and CD40-L within 24 h after admission. Results: Serum levels of Fetuin-A correlated inversely with the risk of cardiac decompensation and all cause complications within the acute phase of TTC. Fetuin-A levels over 190.1 µg/mL (AUC: 0.738, sensitivity 87.5%, specificity: 52.6%) indicate an acute phase of TTC without cardiac decompensation. Despite lower fetuin-A levels in patients with all cause complications, the combined endpoint remained slightly unmet (p = 0.058, AUC: 0.655). Patients with fetuin-A levels over 213.3 µg/mL are at risk of experiencing hemodynamic relevant rhythm disorders (AUC: 0.794, sensitivity: 75.0%, specificity: 79.1%). Other biomarkers failed to reveal a prognostic impact. Pro-BNP and hs troponin levels at admission did not predict adverse cardiac events. Conclusion: Fetuin-A is a promising marker in our study and could be of benefit for the prediction of short-term adverse cardiac events in TTC patients. Therefore, fetuin-A might be of value to evaluate an individual’s risk for complications within the acute phase of TTC and to individually choose the time of intensive care and hospitalization.

Background Systemic inflammation has been identified as a major cardiovascular risk factor in patients undergoing transcatheter aortic valve replacement (TAVR), yet currently, it is not adequately portrayed in scores for pre‐interventional risk assessment. The aim of this study was to investigate the predictive ability of TNF‐α in TAVR. Methods A total of 431 patients undergoing transfemoral TAVR were enrolled in this study. Blood samples were drawn prior to intervention, 24 h post‐intervention, 4, 5, and 7 days post‐intervention, and 1, 3, and 6 months post‐TAVR. Results In a univariate Cox proportional hazard analysis, plasma concentrations of TNF‐α after 24 h and after 5 days were associated with mortality after 12 months (after 24 h: HR 1.002 (1.000–1.004), p = 0.028; after 5d: HR 1.003 (1.001–1.005), p = 0.013). This association remained significant even after correction for confounders in a multivariate Cox regression analysis. Additionally, cut‐offs were calculated. Patients above the cut‐off for TNF‐α after 5d had a significantly worse 12‐month mortality than patients below the cut‐off (18.8% vs. 2.8%, p = 0.046). Conclusion Plasma levels of TNF‐α after 24 h and 5 days were independently associated with 12‐month mortality in patients undergoing TAVR. Thus, TNF‐α could represent a novel biomarker for enhanced risk stratification in these patients., A total of 431 patients undergoing transfemoral TAVR were enrolled in this study. In Cox proportional hazards analysis, plasma concentrations of TNF‐α after 24 h and after 5 days were independently associated with mortality after 12 months, which remained significant even after correction for confounders in a multivariate analysis. Thus, TNF‐α could represent a novel biomarker for enhanced risk stratification in these patients.

Objectives Within the presented prospective study, we aimed to illuminate the effect of long-term physical exercise on serum levels of adipsin (complement factor D) and angiopoietin-like 4 (ANGPTL4). Although past studies already outlined the effects of acute exercise, our trial design aimed to depict the development under long-term physical activity conditions. Design & methods 98 participants were included in the study and were asked to perform eight months of moderate physical activity for at least 150 minutes/week and/or vigorous-intensity exercise for at least 75 minutes/week. According to initial performance and performance gain throughout the study period, four groups were formed and subsequently compared. Blood sampling for the determination of routine laboratory parameters was done at baseline, after 2, 6, and 8 months. Additionally, adipsin and ANGPTL4 serum levels were concurrently quantified using commercially available ELISA kits. Results The study cohort consisted of 61.2% male participants with an average age of 49.3±6.7 years. Adipsin and ANGPTL4 were found to be strongly increased by long-term physical exercise. Participants displaying a performance gain of > 2.9% throughout the study showed significantly increased serum levels of both biomarkers. Conclusions Serum levels of adipsin and ANGPTL4 were closely tied to the individual performance gain of the participating probands. An association of adipsin levels, initial performance, and serum triglycerides was found at baseline. Interestingly, this interrelationship was not detectable after eight months of physical training. This finding might indicate adipsin's involvement in linking triglyceride-balance to individual performance and energy demands in a homeostatic state.

Background Leadless pacemaker technology is a promising upcoming field in clinical rhythmology. Today, the most commonly used system in the clinical setting is the Micra™ leadless pacemaker system (Medtronic). In autopsies of patients who witnessed non-pacemaker associated death, unexpected ingrowth/encapsulation within the wall of the right ventricle was reported. The occurrence of a complete encapsulation was not expected and the process of endothelialisation remains unclear. We hypothesized, that a local inflammatory response might be the cause of these findings. The aim of our experimental in-vitro study was to investigate the effect of the Micra™ system and its single components on inflammatory processes. Methods For this purpose, whole Micra™ pacemakers were incubated in heparin plasma from 25 healthy volunteers for 48 h at 37 °C. Furthermore, 1 g gold, steel, titanium, tungsten and nitinol wires were incubated in heparin plasma for 48 h at 37 °C as well (n = 10). To detect eventual inflammatory processes, interleukin- (IL) 1β, IL-6, and tumor necrosis factor alpha (TNF-α), the chemokine IL-8 were measured using enzyme-linked immunosorbent assay (ELISA). Additionally, the level of transforming growth factor beta 1 (TGF-β1) and vascular endothelial growth factor (VEGF) were analysed. Results ELISA analyses showed that the whole Micra system leads to a significant increase in the inflammatory cytokine IL-6 which correlates with the data gained by the incubation of whole blood with the different wires. In particular, 0.5 g of tungsten showed a significant rise of IL-6 which could also be found for IL-1β and IL-8. Conclusions The in vitro study of the Micra system showed that the material composition led to an onset of inflammatory processes in whole blood. Consequently, one may speculate that the composition of Micra pacemaker may have a local inflammatory, though subclinical, effects in patients implanted with a Micra™ pacemakers.

Introduction Severe aortic stenosis (AS) caused by degenerative calcification is the most frequent acquired valvular heart disease worldwide and mortality rates are considerably high. Transcatheter Aortic Valve Implantation (TAVI) is a well-established method for valve replacement in high risk patients with AS. However, there is a lack of reliable predictors for patients undergoing TAVI since commonly used scores were developed for surgical populations. Materials and methods 208 patients subjected to TAVI were included in this study. Plasma samples were obtained before TAVI and were evaluated for IGFBP-2 using commercially available ELISA kits. IGFBP-2 levels were analyzed for their ability for risk prediction after TAVI. Results IGFBP-2 levels measured before TAVI correlated significantly with left ventricular ejection fraction, EUROSCORE and other functional and prognostic parameters like the 6-minute walking test. When patients were retrospectively divided in two groups with a cut-off of serum IGFBP-2 levels of 275 ng/ml, IGFBP-2 was a strong predictor for 30-day and one-year mortality (3% vs. 11%, p = 0.05 and 18.2% vs. 46.2%; p Conclusions Our results indicate that IGFBP-2 could serve as new outcome predictor for patients undergoing TAVI procedure. By providing additional information to the commonly used EUROSCORE, IGFPB-2 analysis could further assist Heart Team decision making.

Objective Generalized convulsive seizures (GCS) are associated with high demands on the cardiovascular system, thereby facilitating cardiac complications. To investigate occurrence, influencing factors, and extent of cardiac stress or injury, the alterations and time course of the latest generation of cardiac blood markers were investigated after documented GCS. Methods Adult patients with refractory epilepsy who underwent video-electroencephalography (EEG) monitoring along with simultaneous one-lead electrocardiography (ECG) recordings were included. Cardiac biomarkers (cardiac troponin I [cTNI]; high-sensitive troponin T [hsTNT]; N-terminal prohormone of brain natriuretic peptide [NT-proBNP]; copeptin; suppression of tumorigenicity-2 [SST-2]; growth differentiation factor 15, [GDF-15]; soluble urokinase plasminogen activator receptor [suPAR]; and heart-type fatty acid binding protein [HFABP]) and catecholamines were measured at inclusion and at different time points after GCS. Periictal cardiac properties were assessed by analyzing heart rate (HR), HR variability (HRV), and corrected QT intervals(QTc). Results Thirty-six GCS (6 generalized-onset tonic-clonic seizures and 30 focal to bilateral tonic-clonic seizures) were recorded in 30 patients without a history of cardiac or renal disease. Postictal catecholamine levels were elevated more than twofold. A concomitant increase in HR and QTc, as well as a decrease in HRV, was observed. Elevations of cTNI and hsTNT were found in 3 of 30 patients (10%) and 6 of 23 patients (26%), respectively, which were associated with higher dopamine levels. Copeptin was increased considerably after most GCS, whereas SST-2, HFABP, and GDF-15 displayed only subtle variations, and suPAR was unaltered in the postictal period. Cardiac symptoms did not occur in any patient. Significance The use of more sensitive biomarkers such as hsTNT suggests that signs of cardiac stress occur in about 25% of the patients with GCS without apparent clinical symptoms. SuPAR may indicate clinically relevant troponin elevations. Copeptin could help to diagnose GCS, but specificity needs to be tested.

Herein, we report the case of a 67-year-old woman who was admitted to our hospital because of dyspnoea and oedema of the lower extremities. Transthoracic echocardiography revealed severe tricuspid and mitral regurgitation, and the leaflets of the tricuspid valve were found to be rigid and almost immobile. The plasma concentrations of serotonin and chromogranin A were elevated, and hence, suspicion for carcinoid heart disease was raised. In addition to the diagnostic workup and medical and surgical treatment, we analysed levels of novel cardiovascular biomarkers throughout the entire follow-up by means of enzyme-linked immunosorbent assay. A dopa positron emission tomography (DOPA-PET) was conducted and showed a neoplasm in the terminal ileum. Tricuspid valve replacement, mitral valve repair, and a closure of the patent foramen ovale (PFO) were conducted. Two months later, hemicolectomy and liver segment resection were performed. The tumour was resected, and the diagnosis of a neuroendocrine tumour (NET) was confirmed. Throughout the follow-up, we observed a decrease in the plasma levels of novel biomarkers [e.g. interleukin-8 (IL-8), soluble suppression of tumorigenicity-2 (sST2), and heart-type fatty acid-binding protein (H-FABP)] over the follow-up period. In our case, carcinoid heart disease resulted in a severe tricuspid regurgitation as commonly seen in these patients. Moreover, a pre-existent mitral regurgitation was likely aggravated by fibrotic remodelling, because a PFO has led to a right-to-left shunt and might have caused left heart involvement. As IL-8 was associated with adverse outcomes in patients with NETs, and sST2 and H-FABP were associated with adverse outcomes in patients with heart failure previously, these biomarkers could aid in the risk stratification of patients with NET.

Regular physical exercise was found to be associated with an improved immune response in previous studies. RANTES and CD40L play a pivotal role in host defense, and individuals lacking adequate expression are prone to virus and opportunistic infections. A total of 98 participants were enrolled in this study. The probands were asked to perform moderate physical activity, and bicycle stress tests were performed at the baseline and after 8 months of training to evaluate individual performance. RANTES and CD40L were found to be increased by long-term physical exercise. In particular, probands with a performance gain of ≥3% displayed a pronounced elevation of both markers, paired with a decrease in circulating IL6 levels and an improved lipid profile. In summary, we were able to highlight rising levels of serum RANTES and CD40L under the conditions of physical exercise. Taking their role in host defense into account, a conjunction of physical activity and the adaptive immune system could therefore be assumed. Furthermore, low inflammatory profiles in probands with a significant performance gain suggest a modulation through exercise rather than a generalized pro-inflammatory status.

Peripheral arterial disease (PAD) is one of the most common manifestations of systemic atherosclerosis. The prevalence of unrecognized PAD is high, leading to a lack of opportunity to detect subjects at a high risk for cardiovascular events. Inflammatory processes play an important role in the disease initiation as well as in the disease progression. Vascular cell adhesion molecule 1 (VCAM-1), a biomarker of endothelial dysfunction, appears to be an important mediator in inflammatory processes. Therefore, we hypothesized that in patients with PAD, circulating VCAM-1 might be elevated due to its function in mediating adhesion of immune cells to the vascular endothelium in the process of endothelial dysfunction and inflammation, and, therefore, applicable as a diagnostic biomarker. A total of 126 non-consecutive patients were enrolled in this study, of whom 51 patients had typical clinical manifestations of PAD and as controls 75 patients with no history of PAD or cardiovascular disease. All serum samples were obtained either during hospitalization or during out-patient visits and analyzed for VCAM-1 by the ELISA. Compared with controls, median levels of VCAM-1 were significantly elevated in patients suffering from PAD (953 vs. 1352 pg/ml; p

Introduction Takotsubo syndrome (TTS) is clinically indistinguishable from an acute coronary syndrome (ACS). In the absence of valid markers for differential diagnosis, coronary angiography has been indispensable. Methods In our study, we evaluated the serum levels of sST-2, GDF-15, suPAR and H-FABP in 92 patients with the suspicion of TTS (51 TTS and 41 ACS patients) and 40 gender matched controls (no coronary artery disease or signs of heart failure) at baseline. Results H-FABP was significantly higher in ACS patients compared to TTS patients. Even in in propensity score matching for left ventricular ejection fraction, sex and cardiovascular risk factors, differences in the plasma levels of H-FABP in the matched cohort of TTS vs ACS remained statistically significant. Whereas, sST-2 was significantly elevated in TTS patients. H-FABP was superior for prediction of an ACS with even higher accuracy than hs troponin in differential diagnosis (AUC 0.797, p ≤ 0.0001); the optimal cut off for discrimination towards a TTS was calculated as 2.93 ng/ml (sensitivity 70.0%, specificity 82.4%, PPV 75.7%, NPV 77.4%). sST-2 seemed most appropriate for identification of a TTS (AUC 0.653, p = 0.012). The optimal cut off for differential diagnosis was 11018.06 pg/ml (sensitivity 82.0%, specificity 51.2%, PPV 69.4%, NPV 71.9 %). Conclusion H-FABP and sST-2 are the most promising markers with better accuracy than preexisting biomarkers in differential diagnosis in our study and therefore, could be crucial for the guidance of treatment in patients with high bleeding risk, advanced renal failure or multimorbidity. Graphical abstract

Introduction: Takotsubo syndrome (TTS) is clinically indistinguishable from an ACS. Despite the implementation of clinical scoring systems and novel biomarkers, coronary angiography currently remains necessary for differential diagnosis. Methods: 93 patients with chest pain and the suspicion of TTS were enrolled in two study centers. Fetuin-A, IGFBP-2, Galectin-3, and TNF α were determined in serum samples, collected within 24 h after the onset of symptoms. Serum levels of biomarkers were analyzed for the differential diagnostic value between TTS and ACS. Results: Compared to TTS, patients with ACS had significantly lower serum levels of Fetuin-A and IGFBP-2. The cut-off value of Fetuin-A for the identification of TTS compared to ACS was 55.74 μg/mL (sensitivity: 100.0%, specificity: 82.6%, PPV: 63.2%, NPV: 100.0%). An optimal cut-off value for IGFBP-2 for the differential diagnosis between TTS and ACS was determined as 171.77 ng/mL (sensitivity: 76.0%, specificity: 82.6%, PPV: 76.4%, NPV 72.7%). Conclusion: Fetuin-A and IGFBP-2 might facilitate the triage between TTS and ACS and could be therefore of great benefit for the guidance of treatment.

Aims Blood coagulation is one of the most important host-defending mechanisms in vivo by maintaining the blood pressure after injury. However, besides maintaining homeostasis, blood coagulation and the contributing factors are directly linked to pathological conditions, such as thromboembolism and inflammation, leading to cardiovascular diseases, among others. As anti-inflammatory drugs may reduce cardiovascular events, we hypothesized in this study that the direct thrombin inhibitor dabigatran may reduce cytokine, growth factor and chemokine expression in vitro. Main methods Initially, human whole blood was incubated in tubes for serum, EDTA plasma, and heparinized plasma. Furthermore, human PBMCs were isolated and incubated under different culture conditions, including the treatment with human serum or thrombin, respectively. The effect of the oral anticoagulant dabigatran on pro-inflammatory cytokines, growth factors and chemokines was investigated by ELISA. Key findings Conditioned serum resulted in a significant alteration of the secretome's protein levels after 24 h. However, solely ANG showed a dose-dependent increment by the addition of serum (79.8 ± 9.2 ng/mL) in comparison to baseline (0.2 ± 0.2 ng/mL), as it was in trend for thrombin treatment. Furthermore, the pre-treatment of PBMCs with different doses of dabigatran significantly lowered supernatant protein levels measured. Moreover, dabigatran was shown to decrease most notably the growth factor and chemokine levels in the PBMC's secretome that were treated with 200 ng/mL thrombin in a dose-dependent manner. Significance In conclusion, novel oral anticoagulants, such as dabigatran, could help to reduce not only procoagulatory effects in inflammatory conditions but could also reduce proinflammatory stimuli via reduced expression of cytokines and chemokines.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been linked to a higher risk of mortality compared to influenza, which is mainly due to severe secondary diseases, such as acute respiratory distress syndrome (ARDS). In turn, ARDS is characterized by an acute inflammation and an excessive activity of the coagulation cascade, rising the vulnerability for venous thromboembolic events. In order to investigate the relation of inflammation and the influence of coagulation factors on their release, human peripheral mononuclear blood cells (PBMCs) were treated with autologous serum, heparinized plasma and different doses of fibrin. Thereafter, the concentration of pro-inflammatory cytokines and chemokines in the secretome of PBMCs was measured by enzyme-linked immunosorbent assay. Our analyses revealed autologous serum to significantly increase the secretion of cytokines and chemokines after 24 h of incubation time. Furthermore, the addition of fibrin markedly increased the secretion of cytokines and chemokines by PBMCs in a dose-dependent manner. Consequently, in accordance with previous studies, our study outlines that anti-coagulation may constitute a promising tool for the treatment of SARS-CoV-2, reducing both, the cytokine storm, as well as the risk for thrombotic complications.

Biomarkers are defined as “cellular, biochemical or molecular alterations that are measurable in biological media such as human tissues, cells, or fluids”, providing “biological characteristics that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention “according to Hulka et al [...]

Background: Low levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) were reported in patients with coronary artery disease, heart failure, chronic kidney disease and diabetes mellitus. Soluble cluster differentiation 163 (sCD163) serum levels are related to M2 macrophages, having anti-inflammatory attributes. As sport is well-known for its anti-inflammatory and cardioprotective effects we aimed to investigate the influence of eight months of physical activity on serum sCD163 and sTWEAK levels. Methods: In total, 109 subjects with at least one cardiovascular risk factor were asked to perform endurance training within the calculated training pulse for eight months. Overall, 98 finished the study. The performance gain was measured/quantified by bicycle stress tests at the beginning and end of the observation period. The cohort was divided into four groups, dependent on their baseline performance and performance gain. sCD163 and sTWEAK were measured at baseline and after two, six and eight months by ELISA. Results: Those participants who had a performance gain of &le, 2.9% (mean gain 12%) within eight months showed a significant increase in sTWEAK (group 2: from 133 to 200 pg/mL, p = 0.002 and group 4: from 166 to 212 pg/mL, p = 0.031) and sCD163 levels (group 2: from 255 to 348 ng/mL, p = 0.035 and group 4: from 247 to 288 ng/mL, p = 0.025) in contrast to subjects without performance gain (sTWEAK: group 1: from 161 to 177 pg/mL, p = 0.953 and group 3: from 153 to 176 pg/mL, p = 0.744, sCD163: group 1: from 289 to 256 ng/mL, p = 0.374 and group 4: from 291 to 271 ng/mL, p = 0.913). Baseline sCD163 correlated with erythrocyte count, hematocrit, ASAT and lipoprotein a, the presence of hypertension and a BMI &gt, 30 kg/m2. Conclusion: Regular physical activity leads to a significant increase in sCD163 and sTWEAK levels of up to 37% and 50%, respectively. It is well-known that physical activity prevents or retards the onset and genesis of chronic inflammatory disease. One possible way of how training evolves its beneficial effect might be by modifying the inflammation status using the sTWEAK&ndash, sCD163 axis. Brief Summary: Regular physical activity leads to a significant increase in sTWEAK and sCD163 levels. Both factors are diminished in patients with chronic (inflammation-based) diseases, such as coronary artery disease, heart failure, pulmonary artery hypertension, chronic kidney disease and diabetes mellitus. It seems that the amounts of soluble TWEAK and CD163 are essential for a healthy balance and modulation between pro- and anti-inflammatory processes, and regular physical training could use the sCD163&ndash, sTWEAK axis to unfold its beneficial effect.

Serum levels of FGF23 have been associated with adverse outcomes in cardiovascular diseases in patients with and without impaired renal function. Hence, this study aimed to explore the prognostic relevance of intact FGF23 (iFGF23) and its derivate C-terminal FGF23 (cFGF23) in patients undergoing transcatheter aortic valve replacement (TAVR) with regard to renal function.A total of 274 patients undergoing transfemoral TAVR were enrolled in this study. Blood samples were obtained preinterventionally and analyzed for iFGF23 and cFGF23 by means of enzyme linked immunosorbent assay (ELISA). Follow-up was obtained for 12 months.Serum levels of cFGF23 and iFGF23 both correlated positively with serum creatinine and inversely with estimated glomerular filtration rate (eGFR). Cox regression analysis revealed a significant association of cFGF23 with 1-year-mortality in patients with eGFR ≥45ml/min/1.73m², but not in patients with an eGFR45ml/min/1.73m². A cut-off was calculated for cFGF23 (6.82 pmol/l) and patients with eGFR ≥45ml/min/1.73m² were retrospectively divided into two groups (above/below cut-off). Patients above the cut-off had a significantly worse 1-year-mortality than patients below the cut-off (33.3% vs. 19.6%; OR 2.05 (95%CI 1.03-4.07), p= 0.038). The association of cFGF23 with 1-year-mortality in patients with eGFR ≥45ml/min/1.73m² remained statistically significant even after correction for possible confounders in a multivariate Cox regression analysis.cFGF23 could be an individual risk factor for mortality in patients undergoing TAVR with an eGFR ≥45ml/min/1.73m².

Background In this trial, we analyzed the plasma levels of novel biomarkers that reflect different pathophysiological pathways (sST2: mechanical strain, IGF-BP2: metabolic pathways, suPAR and GDF-15: inflammatory processes) in patients undergoing physical exercise to investigate the effects of training on their plasma concentrations. Methods Plasma concentrations of novel biomarkers (sST2, IGF-BP2, suPAR and GDF-15) were analyzed by means of ELISA in patients with stable coronary artery disease (CAD) undergoing four weeks of high- and moderate-intensity training (EXCITE Trial) and in patients with one or more cardiovascular risk factors undergoing eight months of intensive physical exercise (IGF-BP2). Plasma levels of sST2 in patients undergoing eight months of intensive exercise have been published previously by our study group (1.13-fold change, P=0.045). Results Four weeks of high-intensity exercise training resulted in a statistically significant change in the plasma level of sST2 (1.106-fold change, P=0.0054) and IGF-BP2 (1.24-fold-change, P=0.0165). Eight months of intensive exercise resulted in a significant increase of IGF-BP2 (median 61.2 ng/mL to 80.7 ng/mL, 1.319-fold change, P=0.006). Conclusions The significant increase of sST2 after four weeks might be a short-term effect due to the mechanical strain caused by the high-intensity training program, whereas the increase in IGF-BP2 after four weeks and eight months is likely a result of metabolic changes due to physical exercise.

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 &lt, 0.005). Similarly, H-FABP evidenced a significant elevation in all heart failure entities compared to the control group (p &lt, 0.0001). Levels of sST2 were significantly elevated in ICM and DCM patients compared to the control group and HFpEF patients (p &lt, 0.0001). Regarding suPAR, a significant elevation in ICM and DCM patients compared to the control group (p &lt, 0.0001) and HFpEF patients (p &lt, 0.01) was observed. An AUC analysis identified H-FABP (0.792, 95% CI 0.713&ndash, 0.870) and GDF-15 (0.787, 95% CI 0.696&ndash, 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.

Leadless pacemaker systems are an important upcoming device in clinical rhythmology. Currently two different products are available with the Micra system (Medtronic) being the most used in the clinical setting to date. The possibility to perform magnetic resonance imaging (MRI) is an important feature of modern pacemaker devices. Even though the Micra system is suitable for MRI, little is yet known about its impact on artifacts within the images. The aim of our ex vivo study was to perform cardiac MRI to quantify the artifacts and to evaluate if artifacts limit or inhibit the assessment of the surrounding myocardium. After ex vivo implantation of the leadless pacemaker (LP) in a porcine model, hearts were filled with saline solution and fixed on wooden sticks on a plastic container. The model was examined at 1.5 T and at 3 T using conventional sequences and T2 mapping sequences. In addition, conventional X‑rays and computed tomography (CT) scans were performed. Correct implantation of the LP could be performed in all hearts. In almost all MRI sequences the right ventricle and the septal region surrounding the (LP) were altered by an artifact and therefore would sustain limited assessment; however, the rest of the myocardium remained free of artifacts and evaluable for common radiologic diagnoses. A characteristic shamrock-shaped artifact was generated which appeared to be even more intense in magnitude and brightness when using 3 T compared to 1.5 T. The use of the Micra system in cardiac MRI appeared to be feasible. In our opinion, it will still be possible to make important clinical cardiac MRI diagnoses (the detection of major ischemic areas or inflammatory processes) in patients using the Micra system. We suggest the use of 1.5 T as the preferred method in clinical practice.

Chronic heart failure (CHF) represents a major cause of hospitalization and death. Recent evidence shows that novel biomarkers such as soluble suppression of tumorigenicity (sST2), growth-differentiation factor-15 (GDF-15), soluble urokinase plasminogen activator receptor (suPAR) and heart-type fatty acid binding protein (H-FABP) are correlated with inflammatory and ischemic responses in CHF patients. In this study we examined the effects of Ivabradine that inhibited the hyperpolarization-activated cyclic nucleotide-gated channel (HCN channel, also called funny current If), thereby leading to selective heart rate reduction and improved myocardial oxygen supply on the cardiac biomarkers sST2, GDF-15, suPAR and H-FABP in 50 CHF patients at the University Hospital of Jena. Patients were divided into three groups based on the etiology of CHF: dilated cardiomyopathy (DCM, n=20), ischemic cardiomyopathy (ICM, n=20) and hypertensive cardiomyopathy (HCM, n=10). The patients were administered Ivabradine (5 mg, bid for 3 months, and 7.5 mg bid for further 3 months). Analyses of cardiovascular biomarkers were performed at baseline as well as at 3- and 6-month follow-ups. At 6-month follow-up, GDF-15 levels were significantly reduced compared to baseline levels (P=0.0215), indicating a reduction in the progress of cardiac remodeling. H-FABP concentration was significantly lower in DCM patients compared to ICM (1.89 vs 3.24 μg/mL) and HCM patients (1.89 vs 3.80 μg/mL), and decreased over the 6-month follow-up (P=0.0151). suPAR median levels remained elevated, implying major ongoing inflammatory processes. As shown by significant decreases in GDF-15 and H-FABP levels, a reduction in ventricular remodeling and sub-clinical ischemia could be assumed. However, markers of hemodynamic stress (sST2) and inflammation (suPAR) showed no change or progression after 6 months of Ivabradine treatment in CHF patients. Further studies are necessary to validate the clinical applicability of these novel cardiovascular biomarkers.

Background: Renal sympathetic denervation (RSD) has provided promising data in its ability to treat therapy resistant arterial hypertension. The effect of RSD on sST-2, a promising biomarker for risk stratification in cardiovascular diseases, has so far not been systematically studied. Methods: We evaluated serum levels of sST-2 and clinical parameter including left ventricular mass (LVM) in 54 patients with resistant hypertension (RH) undergoing bilateral RSD at baseline as well as at one and/or three months. Results: After RSD, mean office blood pressure showed a significant decrease after one month (p < 0.001). On echocardiography a reduction of LVM was observed at three months (p < 0.01). This was accompanied by a significant decrease of sST-2 levels at three months (sST-2 baseline: 6310.1 ± 3246.0 pg/mL vs. sST-2 three months: 4703.8 ± 1585.9 pg/mL, p = 0.048). Furthermore, baseline sST-2 levels were positively correlated with systolic blood pressure at one month (r = 0.514, p < 0.01) but not three months, indicating a potential predictive value of sST-2 for early intervention success. Conclusion: In patients with RH, RSD is associated with a significant decrease of sST-2 levels after three months, indicating sST-2 to be involved in remodeling processes after RSD. Furthermore, lower sST-2 levels at baseline might be a potential predictor of early intervention success of RSD.

BACKGROUND Endothelial dysfunction is accompanied by the release of microparticles (MP). OBJECTIVE We sought to investigate the effect of moderate hypoxia on circulatory levels of microparticles, biomarkers of cardiovascular function and inflammation and on echocardiographic parameters in healthy volunteers staying at an altitude of 2978 m. METHODS Eighteen healthy volunteers were subjected to moderate hypoxia by staying at 2978 m above sea level for three days. Blood samples were evaluated for MP using flow cytometry. ELISA analysis was performed for sST2, H-FABP, suPAR and GDF-15. Moreover, the effect of dual endothelin-receptor blockade was investigated. RESULTS Oxygen saturation decreased to 93%. A significant decrease of endothelial and platelet MP levels was found. These results were corroborated by a similar response in sST2 and suPAR plasma concentration. Endothelin-receptor blockade by macitentan only had a marginal influence on MP, sST2, H-FABP, suPAR and GDF-15 levels, though it led to a significant amelioration of echocardiographic parameters of right heart function. CONCLUSIONS These experimental results show that moderate hypoxia due to altitude exposition led to a reduction in parameters of endothelial dysfunction as shown by a decrease in endothelial and platelet MP, sST2 and suPAR levels. A slight increase in pulmonary pressure at moderate altitude was decreased by dual endothelin receptor blockade.

Heart failure (HF) with reduced ejection fraction remains a major therapeutic challenge. The aim of this study was to investigate the role of novel cardiovascular biomarkers, i.e. soluble suppression of tumorigenicity (sST2), growth-differentiation factor-15 (GDF-15), soluble urokinase plasminogen activator receptor (suPAR) and heart-type fatty acid binding protein (H-FABP) in patients with ischaemic (ICM) or dilative cardiomyopathy (DCM).A total of 200 patients were enrolled in this study: 65 were diagnosed with DCM and 59 patients suffering from ICM were included. 76 patients without coronary artery disease or signs of heart failure were included as controls. Plasma samples of all patients were analyzed by use of ELISA.Levels of sST2, suPAR and H-FABP were significantly higher in ICM and DCM patients compared to the control group (p0.0001). However, there were no significant differences between ICM and DCM in biomarker levels. Ejection fraction correlated inversely with cardiac biomarkers (sST2 p0.0001, GDF-15 p=0.0394, suPAR p=0.0029, H-FABP p0.0001). Similarly, CRP levels also showed a positive correlation with cardiac biomarkers. Renal insufficiency (p0.0001) and diabetes (sST2 p=0.0021, GDF-15 p=0.0055, suPAR p=0.0339, H-FABP p=0.0010) were significantly associated with a rise in cardiac biomarkers.Novel cardiovascular biomarkers such as ST2, GDF-15, uPAR and H-FABP could offer a great potential for more precise diagnostic in ICM and DCM patients. H-FABP was the most promising marker in our study, followed by sST2, uPAR and GDF-15. Additional prospective studies will be necessary to further evaluate the potential clinical benefits in routine treatment of HF.