Advances in Mass Spectrometry-Based Blood Metabolomics Profiling for Non-Cancer Diseases: A Comprehensive Review.

Blood metabolomics profiling using mass spectrometry has emerged as a powerful approach for investigating non-cancer diseases and understanding their underlying metabolic alterations. Blood, as a readily accessible physiological fluid, contains a diverse repertoire of metabolites derived from various physiological systems. Mass spectrometry offers a universal and precise analytical platform for the comprehensive analysis of blood metabolites, encompassing proteins, lipids, peptides, glycans, and immunoglobulins. In this comprehensive review, we present an overview of the research landscape in mass spectrometry-based blood metabolomics profiling. While the field of metabolomics research is primarily focused on cancer, this review specifically highlights studies related to non-cancer diseases, aiming to bring attention to valuable research that often remains overshadowed. Employing natural language processing methods, we processed 507 articles to provide insights into the application of metabolomic studies for specific diseases and physiological systems. The review encompasses a wide range of non-cancer diseases, with emphasis on cardiovascular disease, reproductive disease, diabetes, inflammation, and immunodeficiency states. By analyzing blood samples, researchers gain valuable insights into the metabolic perturbations associated with these diseases, potentially leading to the identification of novel biomarkers and the development of personalized therapeutic approaches. Furthermore, we provide a comprehensive overview of various mass spectrometry approaches utilized in blood metabolomics research, including GC-MS, LC-MS, and others discussing their advantages and limitations. To enhance the scope, we propose including recent review articles supporting the applicability of GC×GC-MS for metabolomics-based studies. This addition will contribute to a more exhaustive understanding of the available analytical techniques. The Integration of mass spectrometry-based blood profiling into clinical practice holds promise for improving disease diagnosis, treatment monitoring, and patient outcomes. By unraveling the complex metabolic alterations associated with non-cancer diseases, researchers and healthcare professionals can pave the way for precision medicine and personalized therapeutic interventions. Continuous advancements in mass spectrometry technology and data analysis methods will further enhance the potential of blood metabolomics profiling in non-cancer diseases, facilitating its translation from the laboratory to routine clinical application.

Unsupervised deep network for image texture transformation: Improving the quality of cross-correlation analysis and mechanical vortex visualisation during cardiac fibrillation.

Visualisation of cardiac fibrillation plays a very considerable role in cardiophysiological study and clinical applications. One of the ways to obtain the image of these phenomena is the registration of mechanical displacement fields reflecting the track from electrical activity. In this work, we read these fields using cross-correlation analysis from the video of open pig's epicardium at the start of fibrillation recorded with electrocardiogram. However, the quality of obtained displacement fields remains low due to the weak pixels heterogeneity of the frames. It disables to see more clearly such interesting phenomena as mechanical vortexes that underline the mechanical dysfunction of fibrillation. The applying of chemical or mechanical markers to solve this problem can affect the course of natural processes and falsify the results. Therefore, we developed a novel scheme of an unsupervised deep neural network that is based on the state-of-art positional coding technology for a multilayer perceptron. This network enables to generate a couple of frames with a more heterogeneous pixel texture, that is more suitable for cross-correlation analysis methods, from two consecutive frames. The novel network scheme was tested on synthetic pairs of images with different texture heterogeneity and frequency of displacement fields and also it was compared with different filters on our cardiac tissue image dataset. The testing showed that the displacement fields obtained with our method are closer to the ground truth than those which were computed only with the cross-correlation analysis in low contrast images case where filtering is impossible. Moreover, our model showed the best results comparing with the one of the popular filter CLAHE on our dataset. As a result, using our approach, it was possible to register more clearly a mechanical vortex on the epicardium at the start of fibrillation continuously for several milliseconds for the first time.

Early Tibial Baseplate Fracture After Medial Unicondylar Knee Arthroplasty: A Report of 2 Cases.

CASE: Implant failure after unicondylar knee arthroplasty (UKA) is a rare but well-described complication in the arthroplasty literature. However, there is a paucity of literature regarding rapid catastrophic failure of modern implant designs. This is a case report of 2 patients with early catastrophic failure of the tibial baseplate after UKA with a Stryker Restoris MultiCompartmental Knee System implant using Mako robotic assistance, both requiring revision to total knee arthroplasty. CONCLUSION: Improved awareness and understanding of early UKA tibial baseplate failure may help identify both patient and surgical risk factors that could help prevent further instances in the future.

Combination of personalized computational modeling and machine learning for optimization of left ventricular pacing site in cardiac resynchronization therapy.

Introduction: The 30-50% non-response rate to cardiac resynchronization therapy (CRT) calls for improved patient selection and optimized pacing lead placement. The study aimed to develop a novel technique using patient-specific cardiac models and machine learning (ML) to predict an optimal left ventricular (LV) pacing site (ML-PS) that maximizes the likelihood of LV ejection fraction (LVEF) improvement in a given CRT candidate. To validate the approach, we evaluated whether the distance DPS between the clinical LV pacing site (ref-PS) and ML-PS is associated with improved response rate and magnitude. Materials and methods: We reviewed retrospective data for 57 CRT recipients. A positive response was defined as a more than 10% LVEF improvement. Personalized models of ventricular activation and ECG were created from MRI and CT images. The characteristics of ventricular activation during intrinsic rhythm and biventricular (BiV) pacing with ref-PS were derived from the models and used in combination with clinical data to train supervised ML classifiers. The best logistic regression model classified CRT responders with a high accuracy of 0.77 (ROC AUC = 0.84). The LR classifier, model simulations and Bayesian optimization with Gaussian process regression were combined to identify an optimal ML-PS that maximizes the ML-score of CRT response over the LV surface in each patient. Results: The optimal ML-PS improved the ML-score by 17 ± 14% over the ref-PS. Twenty percent of the non-responders were reclassified as positive at ML-PS. Selection of positive patients with a max ML-score >0.5 demonstrated an improved clinical response rate. The distance DPS was shorter in the responders. The max ML-score and DPS were found to be strong predictors of CRT response (ROC AUC = 0.85). In the group with max ML-score > 0.5 and DPS< 30 mm, the response rate was 83% compared to 14% in the rest of the cohort. LVEF improvement in this group was higher than in the other patients (16 ± 8% vs. 7 ± 8%). Conclusion: A new technique combining clinical data, personalized heart modelling and supervised ML demonstrates the potential for use in clinical practice to assist in optimizing patient selection and predicting optimal LV pacing lead position in HF candidates for CRT.

The importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes.

Background: Populations of in silico electrophysiological models of human cardiomyocytes represent natural variability in cell activity and are thoroughly calibrated and validated using experimental data from the human heart. The models have been shown to predict the effects of drugs and their pro-arrhythmic risks. However, excitation and contraction are known to be tightly coupled in the myocardium, with mechanical loads and stretching affecting both mechanics and excitation through mechanisms of mechano-calcium-electrical feedback. However, these couplings are not currently a focus of populations of cell models. Aim: We investigated the role of cardiomyocyte mechanical activity under different mechanical conditions in the generation, calibration, and validation of a population of electro-mechanical models of human cardiomyocytes. Methods: To generate a population, we assumed 11 input parameters of ionic currents and calcium dynamics in our recently developed TP + M model as varying within a wide range. A History matching algorithm was used to generate a non-implausible parameter space by calibrating the action potential and calcium transient biomarkers against experimental data and rejecting models with excitation abnormalities. The population was further calibrated using experimental data on human myocardial force characteristics and mechanical tests involving variations in preload and afterload. Models that passed the mechanical tests were validated with additional experimental data, including the effects of drugs with high or low pro-arrhythmic risk. Results: More than 10% of the models calibrated on electrophysiological data failed mechanical tests and were rejected from the population due to excitation abnormalities at reduced preload or afterload for cell contraction. The final population of accepted models yielded action potential, calcium transient, and force/shortening outputs consistent with experimental data. In agreement with experimental and clinical data, the models demonstrated a high frequency of excitation abnormalities in simulations of Dofetilide action on the ionic currents, in contrast to Verapamil. However, Verapamil showed a high frequency of failed contractions at high concentrations. Conclusion: Our results highlight the importance of considering mechanoelectric coupling in silico cardiomyocyte models. Mechanical tests allow a more thorough assessment of the effects of interventions on cardiac function, including drug testing.

In silico analysis of the contribution of cardiomyocyte-fibroblast electromechanical interaction to the arrhythmia.

Although fibroblasts are about 5-10 times smaller than cardiomyocytes, their number in the ventricle is about twice that of cardiomyocytes. The high density of fibroblasts in myocardial tissue leads to a noticeable effect of their electromechanical interaction with cardiomyocytes on the electrical and mechanical functions of the latter. Our work focuses on the analysis of the mechanisms of spontaneous electrical and mechanical activity of the fibroblast-coupled cardiomyocyte during its calcium overload, which occurs in a variety of pathologies, including acute ischemia. For this study, we developed a mathematical model of the electromechanical interaction between cardiomyocyte and fibroblasts and used it to simulate the impact of overloading cardiomyocytes. In contrast to modeling only the electrical interaction between cardiomyocyte and fibroblasts, the following new features emerge in simulations with the model that accounts for both electrical and mechanical coupling and mechano-electrical feedback loops in the interacting cells. First, the activity of mechanosensitive ion channels in the coupled fibroblasts depolarizes their resting potential. Second, this additional depolarization increases the resting potential of the coupled myocyte, thus augmenting its susceptibility to triggered activity. The triggered activity associated with the cardiomyocyte calcium overload manifests itself in the model either as early afterdepolarizations or as extrasystoles, i.e., extra action potentials and extra contractions. Analysis of the model simulations showed that mechanics contribute significantly to the proarrhythmic effects in the cardiomyocyte overloaded with calcium and coupled with fibroblasts, and that mechano-electrical feedback loops in both the cardiomyocyte and fibroblasts play a key role in this phenomenon.

Acetabular fixation in total hip arthroplasty in the previously irradiated pelvis: a review of basic science and clinical outcomes.

Radiation therapy is a common primary, adjuvant, or palliative treatment for many intrapelvic tumors, including primary gastrointestinal, genitourinary, and hematopoietic tumors, as well as metastatic disease to bone. Radiation has well documented microbiologic and clinical effects on bone ranging from radiation osteitis to early degenerative changes of the hip joint and avascular necrosis of the femoral head. Conventional total hip arthroplasty methods have demonstrated high rates of failure in this population, with historical data describing aseptic loosening rates as high as 44-52%, as radiation have been shown to preferentially diminish osteoblast and osteocyte number and function and limit capacity for both cement interdigitation and biologic bony ingrowth. A review of the clinical literature suggests that patients with prior pelvic irradiation are at higher risk for both septic and aseptic loosening of acetabular components, as well as lower postoperative Harris Hip Score (HHS) when compared to historical controls. With limited evidence, trabecular metal shells with multi-screw fixation and cemented polyethene liners, as well as cemented cup-cage constructs both appear to be durable acetabular fixation options, though the indications for each remains elusive. Further prospective data are needed to better characterize this difficult clinical problem.

Peculiarities of the Acetylcholine Action on the Contractile Function of Cardiomyocytes from the Left and Right Atria in Rats.

Acetylcholine (ACh) is the neurotransmitter of the parasympathetic nervous system that modulates cardiac function, and its high concentrations may induce atrial fibrillation. We compared the ACh action on the mechanical function of single cardiomyocytes from the left atria (LA) and the right atria (RA). We exposed single rat LA and RA cardiomyocytes to 1, 10, and 100 µM ACh for 10-15 min and measured the parameters of sarcomere shortening-relengthening and cytosolic calcium ([Ca2+]i) transients during cell contractions. We also studied the effects of ACh on cardiac myosin function using an in vitro motility assay and analyzed the phosphorylation level of sarcomeric proteins. In LA cardiomyocytes, ACh decreased the time to peak sarcomere shortening, time to 50% relengthening, and time to peak [Ca2+]i transients. In RA cardiomyocytes, ACh affected the time of shortening and relengthening only at 10 µM. In the in vitro motility assay, ACh reduced to a greater extent the sliding velocity of F-actin over myosin from LA cardiomyocytes, which was accompanied by a more pronounced decrease in phosphorylation of the myosin regulatory light chain (RLC) in LA cardiomyocytes than in RA cardiomyocytes. Our findings indicate that ACh plays an important role in modulating the contractile function of LA and RA, provoking more pronounced changes in the time course of sarcomere shortening-relengthening and the kinetics of actin-myosin interaction in LA cardiomyocytes.

Biosimilar erythropoietin in anemia treatment (BEAT)-Efficacy and safety of a 1:1 dose conversion from EPREX® to EPIAO® in patients with end-stage renal disease on hemodialysis: A prospective, randomized, double blind, parallel group study.

BACKGROUND: EPREX®/ERYPO®/PROCRIT® (epoetin alfa, Janssen-Cilag GmbH) was the first available recombinant human erythropoietin (rHuEPO) and was universally reference product as per the recommendation provided by European Medicines Agency. EPIAO® is a biosimilar formulation of EPREX®, and making it a 1:1 dose conversion from EPREX® according to recommendation of European Medicines Agency. This study evaluated the clinical efficacy and safety of EPIAO® in subjects with end-stage renal disease receiving hemodialysis after intravenous administration. METHODS: This study was a multicenter, prospective, randomized, double-blind, parallel-group, 2-cohort, maintenance phase, therapeutic equivalence study to evaluate a 1:1 dose conversion from EPREX® to EPIAO® in terms of clinical efficacy and safety that was conducted at 20 sites in 2 countries in patients with end-stage renal disease on hemodialysis. Eligible subjects were treated with EPREX® (reference product of epoetin) for a period of at least 3 months before the treatment period, and then were randomly assigned to the group of EPREX® or EPIAO®. Primary endpoints were mean absolute change in hemoglobin level and mean absolute change in weekly epoetin dosage from baseline to 6 months after treatment with EPIAO®/EPREX® in parallel groups. RESULTS: A total of 200 people received the random intervention and were included in the safety set. After 6, 9, and 12 months of treatment with EPIAO® or EPREX®, there were no significant differences in the hemoglobin levels of the 2 groups compared with baseline. The 95% confidence interval for the treatment difference was within the predetermined acceptable range: ±0.5 g/dL. There were no significant differences in the epoetin dosage of the 2 groups compared with the baseline. The 95% confidence interval for the treatment difference was within the predetermined acceptable range: ± 45 IU/kg. There were no significant differences in the incidence of adverse events between the EPIAO® and EPREX® groups. Most adverse events were mild to moderate and were reverted/resolved. CONCLUSION: EPIAO® demonstrated promising effectiveness and manageable safety in patients with end-stage renal disease on hemodialysis.

The Role of the Innate Immune System in Wear Debris-Induced Inflammatory Peri-Implant Osteolysis in Total Joint Arthroplasty.

Periprosthetic osteolysis remains a leading complication of total hip and knee arthroplasty, often resulting in aseptic loosening of the implant and necessitating revision surgery. Wear-induced particulate debris is the main cause initiating this destructive process. The purpose of this article is to review recent advances in understanding of how wear debris causes osteolysis, and emergent strategies for the avoidance and treatment of this disease. A strong activator of the peri-implant innate immune this debris-induced inflammatory cascade is dictated by macrophage secretion of TNF-α, IL-1, IL-6, and IL-8, and PGE2, leading to peri-implant bone resorption through activation of osteoclasts and inhibition of osteoblasts through several mechanisms, including the RANK/RANKL/OPG pathway. Therapeutic agents against proinflammatory mediators, such as those targeting tumor necrosis factor (TNF), osteoclasts, and sclerostin, have shown promise in reducing peri-implant osteolysis in vitro and in vivo; however, radiographic changes and clinical diagnosis often lag considerably behind the initiation of osteolysis, making timely treatment difficult. Considerable efforts are underway to develop such diagnostic tools, therapies, and identify novel targets for therapeutic intervention.

The Acute Effects of Leptin on the Contractility of Isolated Rat Atrial and Ventricular Cardiomyocytes.

Leptin is a pleiotropic peptide playing an important role in the regulation of cardiac functions. It is not clear whether leptin directly modulates the mechanical function of atrial cardiomyocytes. We compared the acute effects of leptin on the characteristics of mechanically non-loaded sarcomere shortening and cytosolic Ca2+ concentration ([Ca2+]i) transients in single rat atrial and ventricular cardiomyocytes. We also studied the functional properties of myosin obtained from cardiomyocytes using an in vitro motility assay and assessed the sarcomeric protein phosphorylation. Single cardiomyocytes were exposed to 5, 20, and 60 nM leptin for 60 min. In ventricular cardiomyocytes, 60 nM leptin depressed sarcomere shortening amplitude and decreased the rates of shortening and relaxation. These effects were accompanied by a decrease in the phosphorylation of cMyBP-C, an increase in Tpm phosphorylation, and a slowdown of the sliding velocity of thin filaments over myosin in the in vitro motility assay. In contrast, in atrial cardiomyocytes, the phosphorylation of cMyBP-C and TnI increased, and the characteristics of sarcomere shortening did not change. Leptin had no effect on the characteristics of [Ca2+]i transients in ventricular cardiomyocytes, while 5 nM leptin prolonged [Ca2+]i transients in atrial cardiomyocytes. Thus, leptin-induced changes in contractility of ventricular cardiomyocytes may be attributed to the direct effects of leptin on cross-bridge kinetics and sarcomeric protein properties rather than changes in [Ca2+]i. We also suggest that the observed differences between atrial and ventricular cardiomyocytes may be associated with the peculiarities of the expression of leptin receptors, as well as signaling pathways in the atrial and ventricular myocardium.

Optimization of tissue adhesive curing time for surgical wound closure.

AIMS: Tissue adhesives (TAs) are a commonly used adjunct to traditional surgical wound closures. However, TAs must be allowed to dry before application of a surgical dressing, increasing operating time and reducing intraoperative efficiency. The goal of this study is to identify a practical method for decreasing the curing time for TAs. METHODS: Six techniques were tested to determine which one resulted in the quickest drying time for 2-octyle cyanoacrylate (Dermabond) skin adhesive. These were nothing (control), fanning with a hand (Fanning), covering with a hand (Covering), bringing operating room lights close (OR Lights), ultraviolet lights (UV Light), or prewarming the TA applicator in a hot water bath (Hot Water Bath). Equal amounts of TA were applied to a reproducible plexiglass surface and allowed to dry while undergoing one of the six techniques. The time to complete dryness was recorded for ten specimens for each of the six techniques. RESULTS: Use of the Covering, OR Lights, and Hot Water Bath techniques were associated with a 25- (p = 0.042), 27- (p = 0.023), and 30-second (p = 0.009) reduction in drying time, respectively, when compared to controls. The UV Light (p = 0.404) and Fanning (p = 1.000) methods had no effect on drying time. CONCLUSION: Use of the Covering, OR Lights, and Hot Water Bath techniques present a means for reducing overall operating time for surgeons using TA for closure augmentation, which can increase intraoperative efficiency. Further studies are needed to validate this in vivo.Cite this article: Bone Jt Open 2022;3(8):607-610.

Single cardiomyocytes from papillary muscles show lower preload-dependent activation of force compared to cardiomyocytes from the left ventricular free wall.

Efficient pumping of the healthy left ventricle (LV) requires heterogeneities in mechanical function of individual cardiomyocytes (CM). Deformation of sub-endocardial (Endo) tissue is greater than that of sub-epicardial (Epi) regions. Papillary muscles (PM), often considered to be part of Endo tissue, show lower beat-by-beat length variation than Epi (or Endo) regions, even though they contribute to the shift in atrio-ventricular valve plane, which is essential for LV pump function. Thus far, no comparative assessment of CM mechanics for PM and LV free wall has been published. Here, we investigate contractility and cytosolic calcium concentration ([Ca2+]c) transients in rabbit single CM, freshly isolated from PM, Endo and Epi regions of the LV (free wall tissue was further subdivided into near-basal [Base], equatorial [Centre], and near-apical [Apex] parts). Functional parameters were measured in the absence of external mechanical loads (non-loaded), or during afterloaded (auxotonic) CM contractions, initiated from different levels of preload (diastolic axial stretch), using the carbon fibre technique. We note significant differences in time-course and amplitudes of sarcomere shortening between PM, Endo and Epi CM. In non-loaded CM, sarcomere shortening between regions compares as follows: Endo > Epi and Endo > PM. During afterloaded contractions, the slope of auxotonic tension-length relation and the Frank-Starling gain index (preload-dependent increase in tension and shortening) follow the sequence of Endo > Epi > PM. In terms of apico-basal gradients, time-to-peak sarcomere shortening was greater in Apex compared to Centre and Base in non-loaded CM only. Thus, CM from PM show the least pronounced preload-dependent activation of force across the LV regions assessed, while CM from Endo regions show the strongest response. This is in keeping with prior in situ observations on the smaller extent of PM shortening and their thus lower functional requirement for sensitivity to preload, compared to LV free wall. The here identified regional differences in cellular Frank-Starling responses illustrate the extent to which CM mechanical responses appear to be in keeping with in situ differences in mechanical demand.

Type 1 Diabetes Impairs Cardiomyocyte Contractility in the Left and Right Ventricular Free Walls but Preserves It in the Interventricular Septum.

Type 1 diabetes (T1D) leads to ischemic heart disease and diabetic cardiomyopathy. We tested the hypothesis that T1D differently affects the contractile function of the left and right ventricular free walls (LV, RV) and the interventricular septum (IS) using a rat model of alloxan-induced T1D. Single-myocyte mechanics and cytosolic Ca2+ concentration transients were studied on cardiomyocytes (CM) from LV, RV, and IS in the absence and presence of mechanical load. In addition, we analyzed the phosphorylation level of sarcomeric proteins and the characteristics of the actin-myosin interaction. T1D similarly affected the characteristics of actin-myosin interaction in all studied regions, decreasing the sliding velocity of native thin filaments over myosin in an in vitro motility assay and its Ca2+ sensitivity. A decrease in the thin-filament velocity was associated with increased expression of ß-myosin heavy-chain isoform. However, changes in the mechanical function of single ventricular CM induced by T1D were different. T1D depressed the contractility of CM from LV and RV; it decreased the auxotonic tension amplitude and the slope of the active tension-length relationship. Nevertheless, the contractile function of CM from IS was principally preserved.

Generative adversarial networks for construction of virtual populations of mechanistic models: simulations to study Omecamtiv Mecarbil action.

Biophysical models are increasingly used to gain mechanistic insights by fitting and reproducing experimental and clinical data. The inherent variability in the recorded datasets, however, presents a key challenge. In this study, we present a novel approach, which integrates mechanistic modeling and machine learning to analyze in vitro cardiac mechanics data and solve the inverse problem of model parameter inference. We designed a novel generative adversarial network (GAN) and employed it to construct virtual populations of cardiac ventricular myocyte models in order to study the action of Omecamtiv Mecarbil (OM), a positive cardiac inotrope. Populations of models were calibrated from mechanically unloaded myocyte shortening recordings obtained in experiments on rat myocytes in the presence and absence of OM. The GAN was able to infer model parameters while incorporating prior information about which model parameters OM targets. The generated populations of models reproduced variations in myocyte contraction recorded during in vitro experiments and provided improved understanding of OM's mechanism of action. Inverse mapping of the experimental data using our approach suggests a novel action of OM, whereby it modifies interactions between myosin and tropomyosin proteins. To validate our approach, the inferred model parameters were used to replicate other in vitro experimental protocols, such as skinned preparations demonstrating an increase in calcium sensitivity and a decrease in the Hill coefficient of the force-calcium (F-Ca) curve under OM action. Our approach thereby facilitated the identification of the mechanistic underpinnings of experimental observations and the exploration of different hypotheses regarding variability in this complex biological system.

Machine Learning Prediction of Cardiac Resynchronisation Therapy Response From Combination of Clinical and Model-Driven Data.

Background: Up to 30-50% of chronic heart failure patients who underwent cardiac resynchronization therapy (CRT) do not respond to the treatment. Therefore, patient stratification for CRT and optimization of CRT device settings remain a challenge. Objective: The main goal of our study is to develop a predictive model of CRT outcome using a combination of clinical data recorded in patients before CRT and simulations of the response to biventricular (BiV) pacing in personalized computational models of the cardiac electrophysiology. Materials and Methods: Retrospective data from 57 patients who underwent CRT device implantation was utilized. Positive response to CRT was defined by a 10% increase in the left ventricular ejection fraction in a year after implantation. For each patient, an anatomical model of the heart and torso was reconstructed from MRI and CT images and tailored to ECG recorded in the participant. The models were used to compute ventricular activation time, ECG duration and electrical dyssynchrony indices during intrinsic rhythm and BiV pacing from the sites of implanted leads. For building a predictive model of CRT response, we used clinical data recorded before CRT device implantation together with model-derived biomarkers of ventricular excitation in the left bundle branch block mode of activation and under BiV stimulation. Several Machine Learning (ML) classifiers and feature selection algorithms were tested on the hybrid dataset, and the quality of predictors was assessed using the area under receiver operating curve (ROC AUC). The classifiers on the hybrid data were compared with ML models built on clinical data only. Results: The best ML classifier utilizing a hybrid set of clinical and model-driven data demonstrated ROC AUC of 0.82, an accuracy of 0.82, sensitivity of 0.85, and specificity of 0.78, improving quality over that of ML predictors built on clinical data from much larger datasets by more than 0.1. Distance from the LV pacing site to the post-infarction zone and ventricular activation characteristics under BiV pacing were shown as the most relevant model-driven features for CRT response classification. Conclusion: Our results suggest that combination of clinical and model-driven data increases the accuracy of classification models for CRT outcomes.

Parameter variations in personalized electrophysiological models of human heart ventricles.

The objectives of this study were to evaluate the accuracy of personalized numerical simulations of the electrical activity in human ventricles by comparing simulated electrocardiograms (ECGs) with real patients' ECGs and analyzing the sensitivity of the model output to variations in the model parameters. We used standard 12-lead ECGs and up to 224 unipolar body-surface ECGs to record three patients with cardiac resynchronization therapy devices and three patients with focal ventricular tachycardia. Patient-tailored geometrical models of the ventricles, atria, large vessels, liver, and spine were created using computed tomography data. Ten cases of focal ventricular activation were simulated using the bidomain model and the TNNP 2006 cellular model. The population-based values of electrical conductivities and other model parameters were used for accuracy analysis, and their variations were used for sensitivity analysis. The mean correlation coefficient between the simulated and real ECGs varied significantly (from r = 0.29 to r = 0.86) among the simulated cases. A strong mean correlation (r > 0.7) was found in eight of the ten model cases. The accuracy of the ECG simulation varied widely in the same patient depending on the localization of the excitation origin. The sensitivity analysis revealed that variations in the anisotropy ratio, blood conductivity, and cellular apicobasal heterogeneity had the strongest influence on transmembrane potential, while variation in lung conductivity had the greatest influence on body-surface ECGs. Futhermore, the anisotropy ratio predominantly affected the latest activation time and repolarization time dispersion, while the cellular apicobasal heterogeneity mainly affected the dispersion of action potential duration, and variation in lung conductivity mainly led to changes in the amplitudes of ECGs and cardiac electrograms. We also found that the effects of certain parameter variations had specific regional patterns on the cardiac and body surfaces. These observations are useful for further developing personalized cardiac models.

Mathematical modelling of the mechano-electric coupling in the human cardiomyocyte electrically connected with fibroblasts.

Cardiac fibroblasts are interspersed within mammalian cardiac tissue. Fibroblasts are mechanically passive; however, they may communicate electrically with cardiomyocytes via gap junctions and thus affect the electrical and mechanical activity of myocytes. Several in-silico studies at both cellular (0D) and ventricular (3D) levels analysed the effects of fibroblasts on the myocardial electrical function. However, none of them addressed possible effects of fibroblast-myocyte electrical coupling to cardiomyocyte mechanical activity. In this paper, we propose a mathematical model for studying both electrical and mechanical responses of the human cardiomyocyte to its electrotonic interaction with cardiac fibroblasts. Our simulations have revealed that electrotonic interaction with fibroblasts affects not only the mechanical activity of the cardiomyocyte, comprising either moderate or significant reduction of contractility, but also the mechano-calcium and mechano-electric feedback loops, and all these effects are enhanced as the number of coupled fibroblasts is increased. Obtained results suggest that moderate values of the myocyte-fibroblast gap junction conductance (less than 1 nS) can be attributed to physiological conditions, contrasting to the higher values (2 nS and higher) proper rather for pathological situations (e.g. for infarct and/or border zones), since all mechanical indexes falls down dramatically in the case of such high conductance.

Trochanteric Bursa Is a Source of Connective Tissue Progenitor Cells.

PURPOSE: To investigate the presence of connective tissue progenitor cells (CTPs) in the trochanteric bursa harvested over the gluteus medius muscle belly and tendon during open hip procedures. METHODS: Trochanteric bursa samples from nine patients (63.1 ± 8.6 years) undergoing total hip arthroplasty for primary osteoarthritis were obtained from 2 sites: over the gluteus medius tendon at the greater trochanter and over the muscle belly. Bursal tissue was digested with collagenase and grown in culture. The nucleated cell count, cellular concentration, cellular proliferation, fluorescence-activated cell sorting (FACS) analysis, and differentiation using immunostaining and quantitative polymerase chain reaction (PCR) were used to determine and quantify the presence of CTPs. RESULTS: Bursa-derived CTPs were identified in all harvested samples. At t = 0, there was no difference in nucleated cell count over muscle and tendon (1.69 ± 1.26 × 108 and 1.41 ± 1.12 × 108 cells/g, respectively; P = .162). Similarly, the cellular concentration at 3 weeks was not significantly different between bursa harvested over muscle and tendon (6.61 ± 5.14 × 106 and 5.58 ± 4.70 × 106 cells/g, respectively; P = .532). High cellular proliferation was identified for both bursal tissue overlying muscle and tendon (2.28 ± .95 and 1.66 ± 1.05, respectively; P = .194). FACS analysis revealed high positivity rates (>95%) of CTP-specific surface epitopes (CD105, CD90, and CD73) and low positivity rates (<1.3%) of negative markers (CD45, CD31). Osteogenic, adipogenic, and chondrogenic differentiation potential was demonstrated with immunostaining and quantitative PCR for gene expression. CONCLUSIONS: Connective tissue progenitor cells are found in the trochanteric bursa overlying the muscle and tendon of the hip abductors. CLINICAL RELEVANCE: During open hip procedures, the trochanteric bursa is often partially excised to identify muscular boundaries and tissue planes for surgical exposure. The function of the trochanteric bursa remains largely unknown. However, this tissue is a source of connective tissue progenitor cells, which may be important in the healing response of surgically repaired abductor tendons.