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In contrast to acute preparations such as the exteriorized mesentery or the cremaster muscle, chronically instrumented chamber models allow one to study the microcirculation under 'physiological' conditions, i.e., in the absence of trauma-induced leukocyte rolling along the venular endothelium. To underscore the importance of studying the naive microcirculation, we implanted titanium dorsal skinfold chambers in hamsters and used intravital fluorescence microscopy to study venular leukocyte rolling in response to ischemia-reperfusion injury or extracorporeal blood circulation. The experiments were performed in chambers that fulfilled all well-established criteria for a physiological microcirculation as well as in chambers that showed various extents of leukocyte rolling due to trauma, hemorrhage, or inflammation. In ideal chambers with a physiological microcirculation ( 100 leukocytes/mm), we observed a paradoxical reduction of leukocyte rolling after ischemia-reperfusion injury or extracorporeal blood circulation. A similar effect was observed when we superfused leukotriene [B.sub.4] (LTB4) onto the chamber tissue. The initial increase in leukocyte rolling in response to an LT[B.sub.4] challenge was reversed by a second superfusion 90 rain later. These observations underscore 1) the benefit of studying leukocyte-endothelial cell interaction in chronically instrumented chamber models and 2) the necessity to strictly adhere to well-established criteria of a physiological microcirculation. leukotriene [B.sub.4]; animal model; intravital microscopy

Aims Abnormal intracellular calcium (Ca2+) handling contributes to the progressive nature of atrial fibrillation (AF), the most common sustained cardiac arrhythmia. Evidence in mouse models suggests that activation of the nuclear factor of activated T-cell (NFAT) signalling pathway contributes to atrial remodelling. Our aim was to determine the role of NFATc2 in AF in humans and mouse models. Methods and results Expression levels of NFATc1–c4 isoforms were assessed by quantitative reverse transcription–polymerase chain reaction in right atrial appendages from patients with chronic AF (cAF). NFATc1 and NFATc2 mRNA levels were elevated in cAF patients compared with those in normal sinus rhythm (NSR). Western blotting revealed increased cytosolic and nuclear levels of NFATc2 in AF patients. Similar findings were obtained in CREM-IbΔC-X transgenic (CREM) mice, a model of progressive AF. Telemetry ECG recordings revealed age-dependent spontaneous AF in CREM mice, which was prevented by NFATc2 knockout in CREM:NFATc2–/– mice. Programmed electrical stimulation revealed that CREM:NFATc2–/– mice lacked an AF substrate. Morphometric analysis and histology revealed increased atrial weight and atrial fibrosis in CREM mice compared with wild-type controls, which was reversed in CREM:NFATc2–/– mice. Confocal microscopy showed an increased Ca2+ spark frequency despite a reduced sarcoplasmic reticulum (SR) Ca2+ load in CREM mice compared with controls, whereas these abnormalities were normalized in CREM:NFATc2–/– mice. Western blotting revealed that genetic inhibition of Ca2+/calmodulin-dependent protein kinase II-mediated phosphorylation of S2814 on ryanodine receptor type 2 (RyR2) in CREM:RyR2-S2814A mice suppressed NFATc2 activation observed in CREM mice, suggesting that NFATc2 is activated by excessive SR Ca2+ leak via RyR2. Finally, chromatin immunoprecipitation sequencing from AF patients identified Ras and EF-hand domain-containing protein (Rasef) as a direct target of NFATc2-mediated transcription. Conclusion Our findings reveal activation of the NFAT signalling pathway in patients of Chinese and European descent. NFATc2 knockout prevents the progression of AF in the CREM mouse model. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the outcomes of transapical and transaortic transcatheter aortic valve replacement (TAVR) in high-risk patients who were not suitable for transfemoral access and had a logistic EuroSCORE-I ≥ 25% and Society of Thoracic Surgeons (STS) score >6%. 'STS/ACC TAVR In-Hospital Mortality Risk App' was evaluated. Between January 2016 and May 2020, 126 patients at very high risk for aortic valve replacement underwent transapical (n = 121) or transaortic (n = 5) transcatheter aortic valve replacement. TAVR was performed using SAPIEN 3™ or ACURATE TA™ prosthesis. The logistic EuroSCORE-I was 40.6 ± 14.0%, the STS-score 7.9 ± 4.6%, and STS/ACC-score 8.4 ± 3.4%. Valve implantation was successful in all patients. Operative, in-hospital and 30-days mortality, were 0, 7.9, and 13.5%, respectively. Survival was 72% at one year and 48% at four years. Expected/observed in-hospital mortality was 1.0 for the STS-score and 1.06 for the STS/ACC-score. Renal failure, low ejection fraction, and postoperative acute kidney injury, hemorrhage, and vascular complications were identified as independent predictors for 30-day mortality. Transapical and transaortic TAVR in high-risk patients unsuitable for transfemoral access is still a reasonable alternative in these patients. STS and STS/ACC-score appear to be highly accurate in predicting in-hospital mortality in high-risk patients undergoing TAVR. [ABSTRACT FROM AUTHOR]

Background: Mitral valve regurgitation (MR) is a common finding in patients with end‐stage heart failure. The aim of the study was to analyze the impact of preoperative moderate‐to‐severe MR on postoperative outcomes and survival after durable left‐ventricular assist device (LVAD) implantation. Methods: From August 2010 to May 2021, 246 patients underwent a durable LVAD implantation. We stratified the patients into two groups: Group A (n = 109) presented with MR 0‐I°, and Group B presented with MR II‐III° (n = 137). MR II‐III° was defined according to the current recommendations (i.e., vena contracta ≥ 7 mm, regurgitation volume ≥ 30 ml or effective regurgitation orifice area ≥ 20 mm2). Results: Significantly more patients in Group B suffered from pulmonary hypertension and presented with chronic obstructive lung disease. We observed significantly higher rates of tricuspid regurgitation (TR) II‐III° in Group B (76.1%) versus Group A (14.8%) (p < 0.001) and TR III° in Group B (30.4%) versus Group A (3.7%) (p < 0.001). There was no difference in the incidence of right heart failure between the groups. Within our cohort, the in‐hospital, 1‐year, 3‐year, and 5‐year mortality was 22.4%, 32.1%, 50.7%, and 64.4%, respectively. Group B showed significantly worse overall survival (p = 0.05). Patients with preoperative TR II‐III° had a significantly worse survival than those with TR 0‐I° (p = 0.048). In patients presenting with MR II‐III°, we discovered that TR III° seems to predict both in‐hospital and mid‐term mortality. Conclusion: MR II‐III° negatively affects the outcomes in patients requiring LVAD implantation. Persisting MR II‐III° is an independent predictor of mortality. Patients with concomitant preoperative TR II‐III° are at increased risk of developing postoperative major adverse events. Addressing the MR might be considered for these patients. [ABSTRACT FROM AUTHOR]

Background: The use of left ventricular assist devices (LVAD) in patients with advance heart failure is still associated with an important risk of immune dysregulation and infections. The aim of this study was to determine whether extracorporeal blood purification using the CytoSorb device benefits patients after LVAD implantation in terms of complications and overall survival. Materials and Methods: Between August 2010 and January 2020, 207 consecutive patients underwent LVAD implantation, of whom 72 underwent CytoSorb therapy and 135 did not. Overall survival, major adverse events, and laboratory parameters were compared between 112 propensity score‐matched patients (CytoSorb: 72 patients; non‐CytoSorb: 40 patients). Results: WBC (p =.033), CRP (p =.001), and IL‐6 (p <.001), significantly increased with LVAD implantation, while CytoSorb did not influence this response. In‐hospital mortality and overall survival during follow‐up were similar with CytoSorb. However, patients treated with CytoSorb were more likely to develop respiratory failure (54.2% vs. 30.0%, p =.024), need mechanical ventilation for longer than 6 days post‐implant (50.0% vs. 27.5%, p =.035), and require tracheostomy during hospitalization (31.9% vs. 12.5%, p =.040). No other significant differences were observed with regard to major adverse events during follow‐up. Conclusions: Overall, our results showed that CytoSorb might not convey a significant morbidity or mortality benefit for patients undergoing LVAD implantation. [ABSTRACT FROM AUTHOR]