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Preterm neonates are susceptible to perinatal hypoxic-ischemic brain injury, for which no treatment is available. In a preclinical animal model of hypoxic-ischemic brain injury in ovine fetuses, we have demonstrated the neuroprotective potential of systemically administered mesenchymal stromal cells (MSCs). The mechanism of MSC treatment is unclear but suggested to be paracrine, through secretion of extracellular vesicles (EVs). Therefore, we investigated in this study the protective effects of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) in a preclinical model of preterm hypoxic-ischemic brain injury. Ovine fetuses were subjected to global hypoxia-ischemia by transient umbilical cord occlusion, followed by in utero intravenous administration of MSC-EVs. The therapeutic effects of MSC-EV administration were assessed by analysis of electrophysiological parameters and histology of the brain. Systemic administration of MSC-EVs improved brain function by reducing the total number and duration of seizures, and by preserving baroreceptor reflex sensitivity. These functional protections were accompanied by a tendency to prevent hypomyelination. Cerebral inflammation remained unaffected by the MSC-EV treatment. Our data demonstrate that MSC-EV treatment might provide a novel strategy to reduce the neurological sequelae following hypoxic-ischemic injury of the preterm brain. Our study results suggest that a cell-free preparation comprising neuroprotective MSC-EVs could substitute MSCs in the treatment of preterm neonates with hypoxic-ischemic brain injury, thereby circumventing the potential risks of systemic administration of living cells. Bone marrow-derived mesenchymal stromal cells (MSCs) show promise in treating hypoxic-ischemic injury of the preterm brain. Study results suggest administration of extracellular vesicles, rather than intact MSCs, is sufficient to exert therapeutic effects and avoids potential concerns associated with administration of living cells. The therapeutic efficacy of systemically administered mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) on hypoxia-ischemia-induced injury was assessed in the preterm ovine brain. Impaired function and structural injury of the fetal brain was improved following global hypoxia-ischemia. A cell-free preparation of MSC-EVs could substitute for the cellular counterpart in the treatment of preterm neonates with hypoxic-ischemic brain injury. This may open new clinical applications for \"off-the-shelf\" interventions with MSC-EVs.

BackgroundPrevious models describing the fetal-to-neonatal transition often lack oxygen saturation levels, homeostatic control mechanisms, phasic hemodynamic signals, or describe the heart with a time-varying elastance model.MethodsWe incorporated these elements in the adapted CircAdapt model with the one-fiber model for myocardial contraction, to simulate the hemodynamics of the healthy term human fetal circulation and its transition during the first 24 h after birth. The fetal-to-neonatal model was controlled by a time- and event-based script of changes occurring at birth, such as lung aeration and umbilical cord clamping. Model parameters were based on and validated with human and animal data.ResultsThe fetal circulation showed low pulmonary blood flow, right ventricular dominance, and inverted mitral and tricuspid flow velocity patterns, as well as high mean ductus venosus flow velocity. The neonatal circulation showed oxygen saturation levels to gradually increase to 98% in the first 15 min after birth as well as temporary left ventricular volume overload.ConclusionsHemodynamics of the term fetus and 24-h-old neonate, as well as the events occurring directly after birth and the transition during the first 24 h after birth, were realistically represented, allowing the model to be used for educational purposes and future research.ImpactWith the addition of oxygen saturation levels, homeostatic pressure-flow control mechanisms, and the one-fiber model for myocardial contraction, a new closed-loop cardiovascular model was constructed to give more insight into the healthy term human fetal circulation and its cardiovascular transition during the first 24 h after birth.Extensive validation confirmed that the hemodynamics of the term fetus and the fetal-to-neonatal transition were realistically represented with the model.This well-validated and versatile model can serve as an education as well as a research platform for in silico investigation of fetal-to-neonatal hemodynamic changes under a wide range of physiological and pathophysiological conditions.

The hemodynamic benefit of novel arteriovenous graft (AVG) designs is typically assessed using computational models that assume highly idealized graft configurations and/or simplified boundary conditions representing the peripheral vasculature. The objective of this study is to evaluate whether idealized AVG models are suitable for hemodynamic evaluation of new graft designs, or whether more realistic models are required. An idealized and a realistic, clinical imaging based, parametrized AVG geometry were created. Furthermore, two physiological boundary condition models were developed to represent the peripheral vasculature. We assessed how graft geometry (idealized or realistic) and applied boundary condition models of the peripheral vasculature (physiological or distal zero-flow) impacted hemodynamic metrics related to AVG dysfunction. Anastomotic regions exposed to high WSS (>7, [less than or equal to]40 Pa), very high WSS (>40 Pa) and highly oscillatory WSS were larger in the simulations using the realistic AVG geometry. The magnitude of velocity perturbations in the venous segment was up to 1.7 times larger in the realistic AVG geometry compared to the idealized one. When applying a (non-physiological zero-flow) boundary condition that neglected blood flow to and from the peripheral vasculature, we observed large regions exposed to highly oscillatory WSS. These regions could not be observed when using either of the newly developed distal boundary condition models. Hemodynamic metrics related to AVG dysfunction are highly dependent on the geometry and the distal boundary condition model used. Consequently, the hemodynamic benefit of a novel graft design can be misrepresented when using idealized AVG modelling setups.

Ex vivo characterisation of arterial biomechanics enables detailed discrimination of the various cellular and extracellular contributions to arterial stiffness. However, ex vivo biomechanical studies are commonly performed under quasi-static conditions, whereas dynamic biomechanical behaviour (as relevant in vivo) may differ substantially. Hence, we aim to (1) develop an integrated set-up for quasi-static and dynamic biaxial biomechanical testing, (2) quantify set-up reproducibility, and (3) illustrate the differences in measured arterial stiffness between quasi-static and dynamic conditions. Twenty-two mouse carotid arteries were mounted between glass micropipettes and kept fully vasodilated. While recording pressure, axial force ( F ), and inner diameter, arteries were exposed to (1) quasi-static pressure inflation from 0 to 200 mmHg; (2) 300 bpm dynamic pressure inflation (peaking at 80/120/160 mmHg); and (3) axial stretch (λ z ) variation at constant pressures of 10/60/100/140/200 mmHg. Measurements were performed in duplicate. Single-point pulse wave velocities (PWV; Bramwell-Hill) and axial stiffness coefficients ( c ax  = d F /dλ z ) were calculated at the in vivo value of λ z . Within-subject coefficients of variation were ~ 20%. Dynamic PWVs were consistently higher than quasi-static PWVs ( p  < 0.001); c ax increased with increasing pressure. We demonstrated the feasibility of ex vivo biomechanical characterisation of biaxially-loaded murine carotid arteries under pulsatile conditions, and quantified reproducibility allowing for well-powered future study design.

Cardiac electrical asynchrony occurs as a result of cardiac pacing or conduction disorders such as left bundle-branch block (LBBB). Electrically asynchronous activation causes myocardial contraction heterogeneity that can be detrimental for cardiac function. Computational models provide a tool for understanding pathological consequences of dyssynchronous contraction. Simulations of mechanical dyssynchrony within the heart are typically performed using the finite element method, whose computational intensity may present an obstacle to clinical deployment of patient-specific models. We present an alternative based on the CircAdapt lumped-parameter model of the heart and circulatory system, called the MultiPatch module. Cardiac walls are subdivided into an arbitrary number of patches of homogeneous tissue. Tissue properties and activation time can differ between patches. All patches within a wall share a common wall tension and curvature. Consequently, spatial location within the wall is not required to calculate deformation in a patch. We test the hypothesis that activation time is more important than tissue location for determining mechanical deformation in asynchronous hearts. We perform simulations representing an experimental study of myocardial deformation induced by ventricular pacing, and a patient with LBBB and heart failure using endocardial recordings of electrical activation, wall volumes, and end-diastolic volumes. Direct comparison between simulated and experimental strain patterns shows both qualitative and quantitative agreement between model fibre strain and experimental circumferential strain in terms of shortening and rebound stretch during ejection. Local myofibre strain in the patient simulation shows qualitative agreement with circumferential strain patterns observed in the patient using tagged MRI. We conclude that the MultiPatch module produces realistic regional deformation patterns in the asynchronous heart and that activation time is more important than tissue location within a wall for determining myocardial deformation. The CircAdapt model is therefore capable of fast and realistic simulations of dyssynchronous myocardial deformation embedded within the closed-loop cardiovascular system.

Background Reliable ECGs are crucial for diagnosing arrhythmias, yet a lack of standardization impedes arrhythmia diagnosis and treatment in horses. Objectives To objectively determine an optimal position of Einthoven's triangle for ECG recordings in horses at rest, which can form the basis for standardized ECG recording and improve diagnosis and treatment of arrhythmias. Animals The study involved 72 healthy, warmblood horses aged between 3 and 20 years. Methods In view of future 12‐lead studies and vectorcardiography, requiring an orthogonal system, Einthoven's triangle was positioned around the heart, in the transverse plane. Therefore, 11 electrodes were placed encircling the thorax behind the olecranon, to construct triangles with a horizontal base. Electrocardiogram recordings from different triangles were analyzed. Signal processing involved filtering, R peak detection, and median complex generation. Principal component analysis (PCA) and Euclidean distance measures were employed for data analysis. Results The left mid‐thoracic and ventral regions had high PCA scores, indicating high information content. Base‐down triangles exhibited higher summed Euclidean distances, contributing to enhanced diagnostic capabilities. A base‐down triangle, called “Delta (Δ) configuration” emerged as most informative, while meeting all criteria. Conclusions and Clinical Importance The base‐down “Delta configuration” is the optimal Einthoven's triangle adapted for horses, providing large amplitudes and potential to provide basic insights into the mechanisms and origins of cardiac arrhythmias. Because the Delta configuration is positioned in the transverse plane, it forms the ideal basis for 12‐lead ECG recordings that provide vectorcardiograms in an orthogonal coordinate system. Standardizing electrode positioning could improve ECG data comparability in equine cardiology.

We propose a novel, two-degree of freedom mathematical model of mechanical vibrations of the heart that generates heart sounds in CircAdapt, a complete real-time model of the cardiovascular system. Heart sounds during rest, exercise, biventricular (BiVHF), left ventricular (LVHF) and right ventricular heart failure (RVHF) were simulated to examine model functionality in various conditions. Simulated and experimental heart sound components showed both qualitative and quantitative agreements in terms of heart sound morphology, frequency, and timing. Rate of left ventricular pressure (LV dp/dt max ) and first heart sound (S1) amplitude were proportional with exercise level. The relation of the second heart sound (S2) amplitude with exercise level was less significant. BiVHF resulted in amplitude reduction of S1. LVHF resulted in reverse splitting of S2 and an amplitude reduction of only the left-sided heart sound components, whereas RVHF resulted in a prolonged splitting of S2 and only a mild amplitude reduction of the right-sided heart sound components. In conclusion, our hemodynamics-driven mathematical model provides fast and realistic simulations of heart sounds under various conditions and may be helpful to find new indicators for diagnosis and prognosis of cardiac diseases.

Experiments have shown that the relaxation phase of cardiac sarcomeres during an isometric twitch is prolonged in muscles that reached a higher peak tension. However, the mechanism is not completely understood. We hypothesize that the binding of calcium to troponin is enhanced by the tension in the thin filament, thus contributing to the prolongation of contraction upon higher peak tension generation. To test this hypothesis, we developed a computational model of sarcomere mechanics that incorporates tension-dependence of calcium binding. The model was used to simulate isometric twitch experiments with time dependency in the form of a two-state cross-bridge cycle model and a transient intracellular calcium concentration. In the simulations, peak isometric twitch tension appeared to increase linearly by 51.1 KPa with sarcomere length from 1.9 μm to 2.2 μm. Experiments showed an increase of 47.3 KPa over the same range of sarcomere lengths. The duration of the twitch also increased with both sarcomere length and peak intracellular calcium concentration, likely to be induced by the inherently coupled increase of the peak tension in the thin filament. In the model simulations, the time to 50% relaxation (tR50) increased over the range of sarcomere lengths from 1.9 μm to 2.2 μm by 0.11s, comparable to the increased duration of 0.12s shown in experiments. Model simulated tR50 increased by 0.12s over the range of peak intracellular calcium concentrations from 0.87 μM to 1.45 μM. Our simulation results suggest that the prolongation of contraction at higher tension is a result of the tighter binding of Ca2+ to troponin in areas under higher tension, thus delaying the deactivation of the troponin.

Lower dialysate calcium (dCa) concentration and dialysate citric-acidification may positively affect calcification propensity in serum of haemodialysis (HD) patients. However, the accompanying lower ionized blood calcium concentration may lead to a prolonged cardiac action potential, which is possibly pro-arrhythmic. The aim of this study is to investigate the influence of citric-acid dialysate on the QT-interval corrected for heart rate (QTc) compared to conventional dialysate with different dCa concentrations. We conducted a four-week multicentre, randomized cross-over trial. In week one and three patients received acetic-acid dialysate with a dCa of 1.50 mmol/l (A1.5), in week two and four acetic-acid dialysate with a dCa of 1.25 mmol/l (A1.25) or citric-acid dialysate (1.0 mmol/l) with a dCa of 1.50 mmol/l (C1.5) depending on randomization. Patients had continuous ECG monitoring during one session in week one, two and four. The data of 13 patients were available for analysis. Results showed a significant though limited increase of QTc with C1.5 (from 427 to 444 ms (start to end); p = 0.007) and with A1.25 (from 431 to 449 ms; p < 0.001), but not with A1.5 (from 439 to 443 ms; p = 0.13). In conclusion, we found that the use of C1.5 or A1.25 is associated with a significant prolongation of QTc which was however relatively limited.

Geometry of the heart adapts to mechanical load, imposed by pressures and volumes of the cavities. We regarded preservation of cardiac geometry as a homeostatic control system. The control loop was simulated by a chain of models, starting with geometry of the cardiac walls, sequentially simulating circulation hemodynamics, myofiber stress and strain in the walls, transfer of mechano-sensed signals to structural changes of the myocardium, and finalized by calculation of resulting changes in cardiac wall geometry. Instead of modeling detailed mechano-transductive pathways and their interconnections, we used principles of control theory to find optimal transfer functions, representing the overall biological responses to mechanical signals. As biological responses we regarded tissue mass, extent of contractile myocyte structure and extent of the extra-cellular matrix. Mechano-structural stimulus-response characteristics were considered to be the same for atrial and ventricular tissue. Simulation of adaptation to self-generated hemodynamic load rendered physiologic geometry of all cardiac cavities automatically. Adaptation of geometry to chronic hypertension and volume load appeared also physiologic. Different combinations of mechano-sensors satisfied the condition that control of geometry is stable. Thus, we expect that for various species, evolution may have selected different solutions for mechano-adaptation.