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We introduce a modelling and simulation framework for cell aggregates in three dimensions based on interacting active surfaces. Cell mechanics is captured by a physical description of the acto-myosin cortex that includes cortical flows, viscous forces, active tensions, and bending moments. Cells interact with each other via short-range forces capturing the effect of adhesion molecules. We discretise the model equations using a finite element method, and provide a parallel implementation in C++. We discuss examples of application of this framework to small and medium-sized aggregates: we consider the shape and dynamics of a cell doublet, a planar cell sheet, and a growing cell aggregate. This framework opens the door to the systematic exploration of the cell to tissue-scale mechanics of cell aggregates, which plays a key role in the morphogenesis of embryos and organoids.

Aim of the present analysis was to collect and pool all available data currently in the literature regarding outcomes and complications of all approved TAVR prosthesis and to assess the transition from first to next generation TAVR devices by directly comparing both in regard of procedure related complications. Transcatheter aortic valve replacement is a well established treatment modality in patients with severe aortic stenosis deemed to be inoperable or at unacceptable risk for open heart surgery. First generation prostheses were associated with a high rate of peri-procedural complications like paravalvular regurgitation, valve malpositioning, vascular complications and conduction disorders. Refinement of the available devices incorporate features to address the limitations of the first-generation devices. A PRISMA checklist-guided systematic review and meta-analysis of prospective observational studies, national and device specific registries or randomized clinical trials was conducted. Studies were identified by searching PUBMED, SCOPUS, Cochrane Central Register of Controlled Trials and LILACs from January 2000 to October 2017. We extracted and pooled data on both mortality and complications from 273 studies for twelve different valves prostheses in a total of 68,193 patients. In second generation prostheses as compared to first generation devices, we observed a significant decrease in mortality (1.47 ± 1.73% vs. 5.41 ± 4.35%; p < 0.001), paravalvular regurgitation (1.75 ± 2.43vs. 12.39 ± 9.38, p < 0.001) and MACE. TAVR with contemporary next generation devices has led to an impressive improvement in TAVR safety driven by refined case selection, improved procedural techniques and increased site experience.

Pulmonary arterial hypertension is a severe and progressive disease characterized by a pulmonary vascular remodeling process with expansion of collateral endothelial cells and total vessel occlusion. Endothelial cells are believed to be at the forefront of the disease process. Vascular endothelial growth factor (VEGF) and its tyrosine kinase receptor, VEGF receptor-2 (VEGFR-2), play a central role in angiogenesis, endothelial cell protection, but also in the destabilization of endothelial barrier function. Therefore, we investigated the consequences of altered VEGF signaling in an experimental model, and looked for translational correlates of this observation in patients. We performed an endothelial cell-specific conditional deletion of the kinase insert domain protein receptor ( kdr ) gene, coding for VEGFR-2, in C57/BL6 mice ( Kdr ∆end ) and held them in an environmental chamber with 10% FiO 2 or under normoxia for 6 weeks. Kdr knockout led to a mild PH phenotype under normoxia that worsened under hypoxia. Kdr ∆end mice exhibited a significant increase in pulmonary arterial wall thickness, muscularization, and VEGFR-3 + endothelial cells obliterating the pulmonary artery vessel lumen. We observed the same proliferative vasculopathy in our rodent model as seen in patients receiving anti-angiogenic therapy. Serum VEGF-a levels were elevated both in the experimental model and in humans receiving bevacizumab. Interrupted VEGF signaling leads to a pulmonary proliferative arteriopathy in rodents after direct ablative gene manipulation of Kdr. Histologically, similar vascular lesions can be observed in patients receiving anti-VEGF treatment. Our findings illustrate the importance of VEGF signaling for maintenance of pulmonary vascular patency.

Background Left ventricular thrombus (LVT) is a rare but dreaded complication during the acute phase of acute coronary syndrome (ACS). However, profound data on long‐term outcome and associated antithrombotic treatment strategies of this highly vulnerable patient population are scarce in current literature. Methods Patients presenting with ACS were screened for presence of LVT and subsequently included within a prospective clinical registry. All‐cause mortality and the composite of major adverse cardiac events (MACE) and thromboembolic events were defined as primary and secondary endpoint. Results Within 43 patients presenting with LVT, thrombus resolution during patient follow‐up was observed in 27 individuals (62.8%). Patients that reached a resolution of LVT experienced lower incidence rates of death (−23.9%; p = .022), MACE (−37.8%; p = .005), and thromboembolic events (−35.2%; p = .008). Even after adjustment for clinical variables, thrombus resolution showed an independent inverse association with all‐cause death with a hazard ratio (HR) of 0.14 (95% CI: 0.03–0.75; p = .021) and as well with MACE with a HR of 0.22 (95% CI: 0.07–0.68; p = .008) and thromboembolic events with a HR of 0.22 (95% CI: 0.06–0.75; p = .015). Triple antithrombotic therapy (TAT) with ticagrelor/prasugrel showed a strong and independent association with thrombus resolution with an adjusted HR of 3.25 (95% CI: 1.22–8.68; p = .019) compared to other strategies. Conclusion The presented data indicate a poor outcome of ACS patients experiencing LVT. In terms of a personalized risk stratification, thrombus resolution has a strong protective impact on both all‐cause death and MACE with the potential to tailor treatment decisions—including an intensified antithrombotic treatment approach—in this patient population.

Nosocomial infections are a common complication in clinical practice with major impact on surgical success and patient outcome. The probability of nosocomial infections is rapidly increasing during hospitalization. Therefore, we investigated the impact of a prolonged pre-operative hospital stay on the development of post-operative infection. Within this prospective observational study, 200 patients scheduled for elective cardiac surgery were enrolled. Patients were followed during hospital admission and screened for the development of nosocomial infection. Logistic regression analysis was used to assess the impact of a prolonged pre-operative hospital stay on the development of infection. A total of 195 patients were suitable for the final analysis. We found a strong and direct association of the duration of pre-operative hospital stay and the number of patients developing infection (+23.5%; p = 0.006). Additionally, the length of patients’ pre-operative hospital stay was independently associated with the development of post-operative nosocomial infection, with an adjusted OR per day of 1.38 (95%CI: 1.02–1.86; p = 0.036). A prolonged pre-operative hospital stay was significantly associated with the development of nosocomial infection after cardiac surgery. Those findings need to be considered in future clinical patient management in order to prevent unnecessary antibiotic use and potential harm to patients.

Aim of the present study was to investigate the frequency and predictors of premature discontinuation or switch of ADP receptor blockers and its association with serious adverse events. For this purpose 571 consecutive ACS patients receiving ticagrelor (n = 258, 45%) or prasugrel (n = 313, 55%) undergoing PCI were enrolled in this prospective, observational, multicenter ATLANTIS-SWITCH substudy. Predictors of premature discontinuation or switch of antiplatelet therapy and their association with major adverse cardiovascular events and TIMI bleeding events were evaluated. Premature stop/switch was found in 72 (12.6%) patients: 34 (5.9%) stopped and 38 (6.7%) switched the ADP blocker. Ticagrelor treated patients were significantly more likely to stop/switch therapy as compared to prasugrel (15.9% vs. 9.2%, p  = 0.016). We identified 4 independent predictors for stop/switch of ADP blocker: major surgery, need for oral anticoagulation (OAC), TIMI major bleeding and drug intolerance. TIMI major bleeding was a driver of stop/switch actions and occurred in 4.3% vs 0.2% in patients with vs without stop/switch ( p  = 0.001). The majority of stop/switch actions (75%) were physicians driven decisions. Importantly, stop/switch of therapy was not associated with increased risk of MACE ( p  = 0.936). In conclusion premature switch/stop of ADP blockers appears to be safe when mainly driven by physician’s decision and clinical indication.

Background Right ventricular-to-pulmonary artery (RV–PA) coupling has recently been shown to be associated with outcome in valvular heart disease. However, longitudinal data on RV dysfunction and reverse cardiac remodeling in patients following transcatheter edge-to-edge mitral valve repair (M-TEER) are scarce. Methods Consecutive patients with primary as well as secondary mitral regurgitation (MR) were prospectively enrolled and had comprehensive echocardiographic and invasive hemodynamic assessment at baseline. Kaplan–Meier estimates and multivariable Cox-regression analyses were performed, using a composite endpoint of heart failure hospitalization and death. Results Between April 2018 and January 2021, 156 patients (median 78 y/o, 55% female, EuroSCORE II: 6.9%) underwent M-TEER. On presentation, 64% showed impaired RV–PA coupling defined as tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) ratio < 0.36. Event-free survival rates at 2 years were significantly lower among patients with impaired coupling (57 vs. 82%, p  < 0.001), both in patients with primary (64 vs. 91%, p  = 0.009) and secondary MR (54 vs. 76%, p  = 0.026). On multivariable Cox-regression analyses adjusted for baseline, imaging, hemodynamic, and procedural data, TAPSE/PASP ratio < 0.36 was independently associated with outcome (adj.HR 2.74, 95% CI 1.17–6.43, p  = 0.021). At 1-year follow-up, RV–PA coupling improved (TAPSE: ∆ + 3 mm, PASP: ∆ − 10 mmHg, p for both < 0.001), alongside with a reduction in tricuspid regurgitation (TR) severity (grade ≥ II: 77–54%, p  < 0.001). Conclusions TAPSE/PASP ratio was associated with outcome in patients undergoing M-TEER for primary as well as secondary MR. RV–PA coupling, alongside with TR severity, improved after M-TEER and might thus provide prognostic information in addition to established markers of poor outcome. Graphical abstract

Deleterious inflammatory responses are seen to be the trigger of heart failure in myocarditis and therapies directed towards immunomodulation have been assumed to be beneficial. The objective of the present review was to systematically assess the effect of immunomodulation in lymphocytic myocarditis. Studies were included if diagnosis of lymphocytic myocarditis was based on EMB as well as on the exclusion of other etiologies of heart failure and if the patients had at least moderately decreased left ventricular ejection fraction (< 45%). All immunomodulatory treatments at any dose that target the cause of myocarditis leading to cardiomyopathy were included. Retrieval of PUBMED, SCOPUS, Cochrane Central Register of Controlled Trials, and LILACs from January 1950 to January 2016 revealed 444 abstracts of which nine studies with a total of 612 patients were included. As primary effectivity endpoint, a change in left ventricular ejection was chosen. No benefits of corticosteroids or intravenous immunoglobulin alone were reported. Immunoadsorption and subsequent IVIG substitution was associated with a greater improvement in left ventricular ejection fraction (LVEF) in one study. Single studies found a beneficial effect of interferon and statins on LVEF. We performed a meta-analysis for the combination of corticosteroids with immunosuppressants and found a non-significant increase of LVEF of + 13.06% favoring combined treatment (95%CI 1.71 to + 27.84%, p = 0.08). The current evidence does not support the routine use of immunosuppression in traditional lymphocytic myocarditis. Nevertheless, in histologically proven virus-negative myocarditis of high-risk patients, combined immunosuppression might be beneficial. Future research should focus on translation of these effects to clinical outcome.

Aims Fluid overload (FO) puts aortic stenosis (AS) patients at risk for heart failure (HF) and death. However, conventional FO assessment, including rapid weight gain, peripheral oedema, or chest radiography, is inaccurate. Bioelectrical impedance spectroscopy (BIS) allows objective and reproducible FO quantification, particularly if clinically unapparent. It is used in dialysis patients to establish dry weight goals. BIS has not been tested for prognostication in AS. This study aimed to evaluate whether BIS adds prognostic information in stable patients undergoing transcatheter aortic valve replacement (TAVR). Methods and results Consecutive patients scheduled for TAVR underwent BIS in addition to echocardiographic, clinical, and laboratory assessment. On BIS, mild FO was defined as >1.0 L and severe as >3.0 L. Combined HF hospitalization and/or all‐cause death was defined as primary endpoint. Three hundred forty‐four patients (81.5 ± 7.2 years old, 47.4% female) were prospectively included. FO by BIS was associated with clinical congestion signs, higher serum markers of cardiac injury, poorer left ventricular function, higher pulmonary pressures, and more severe tricuspid regurgitation (all P < 0.05). Yet, clinical examination was unremarkable in >30% in mild FO, only detected by BIS. During 12.1 ± 5.5 months, 67 (19.5%) events were recorded (40 deaths, 15 HF hospitalizations, and 12 both). Quantitatively, every 1 L increase in FO was associated with a 24% (HR 1.24, 95% CI 1.13–1.35, P < 0.001) increase in event hazard. This association persisted after adjustment for STS/EuroSCORE‐II, NT‐proBNP, left ventricular ejection fraction, and renal function. Conclusions In patients undergoing TAVR, FO by BIS is strongly associated with adverse outcomes. BIS measurement conveys prognostic information not represented in any currently used AS/TAVR risk assessments.

Aims We aim to explore the relationship of heart failure (HF) and diabetes with cardiovascular (CV) death or hospitalization for HF (HHF) and to study the clinical utility of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) in an unselected patient population with atrial fibrillation (AF). Methods and results Patients with AF admitted to a tertiary academic center between January 2005 and July 2019 were identified through a search of electronic health records. We used Cox regression models adjusted for age, sex, estimated glomerular filtration rate, diabetes, HF, body mass index, prior myocardial infarction, coronary artery disease, hypertension, smoking, C‐reactive protein, and low‐density lipoprotein cholesterol. To select the most informative variables, we performed a least absolute shrinkage and selection operator Cox regression with 10‐fold cross‐validation. In total, 7412 patients (median age 70 years, 39.7% female) were included in this analysis and followed over a median of 4.5 years. Both diabetes [adjusted (Adj.) HR 1.87, 95% CI 1.55–2.25] and HF (Adj. HR 2.57, 95% CI 2.22–2.98) were significantly associated with CV death/HHF after multivariable adjustment. Compared with patients with diabetes, HF patients had a higher risk of HHF but a similar risk of CV and all‐cause death. NT‐proBNP showed good discriminatory performance (area under the curve 0.78, 95% CI 0.77–0.80) and the addition of NT‐proBNP to the covariates used for adjustment resulted in a significant area under the curve improvement (Δ = 0.04, P < 0.001). With least absolute shrinkage and selection operator, the strongest associations for CV death/HHF were obtained for NT‐proBNP [HR 1.91 per 1‐SD in log‐transformed biomarker], HF (HR 1.72), and diabetes (HR 1.56). Conclusions Diabetes and HF were independently associated with an increased risk of CV death/HHF in an unselected AF patient population, and NT‐proBNP improved risk assessment. These findings suggest that AF patients with diabetes and/or HF should be managed not only for their risk of stroke and systemic embolic events but also for CV death/HHF.