Left atrial appendage inversion: First computational study to shed light on the phenomenon.

Inversion of the left atrial appendage is a rare phenomenon, which may occur during the de-airing maneuvers associated to routinely performed surgery procedures, such as cardiopulmonary bypass or left ventricular assist device implantation. In this case, the body of the inverted appendage can obstruct the mitral valve leading to severe complications. The mechanisms are still poorly known, and more specific studies are needed to better understand its causes and identify mitigating strategies. The current study attempts to gain a better comprehension of the conditions and the factors favourable to left atrial appendage inversion. Four patient specific appendage morphologies, obtained from computerised tomography and representative of the main typologies commonly used for the appendage classification (chicken wing, cactus, cauliflower, and windsock), were used for the study. The numerical models were subjected to the same loading pattern, made of subsequent different pressure curves. Results show that the morphologies invert and recover their original anatomical configuration at different pressure loads, indicating that their tendency to invert is associated to their specific morphological features. Moreover, the analysis highlights that, although restoring the physiological left atrium pressure is not sufficient to induce appendage recovery, pressures well below the ventricular ones can induce the return to the natural configuration. All models recovered the anatomical configuration at pressures well below the ventricular pressure (about 100 mmHg), suggesting that basic trans-catheter maneuvers, e.g. producing temporary mitral regurgitation, could be attempted to correct the appendage configuration, prior to opt for more invasive surgical approaches.

Fluid-structure interaction analysis of the thromboembolic risk in the left atrial appendage under atrial fibrillation: Effect of hemodynamics and morphological features.

BACKGROUND: Complications of atrial fibrillation (AF) include ischemic events originating within the left atrial appendage (LAA), a protrusion of the left atrium with variable morphological characteristics. The role of the patient specific morphology and pathological haemodynamics on the risk of ischemia remains unclear. METHODS: This work performs a comparative assessment of the hemodynamic parameters among patient-specific LAA morphologies through fluid-structure interaction computational analyses. Three LAA models per each of the four commons patient-specific morphological families (chicken wing, cactus, windsock, and cauliflower) were analysed. Mechanical properties of the tissue were based on experimental uniaxial tests on a young pig's heart. Boundary conditions were imposed based on clinical assessments of filling and emptying volumes. Sinus rhythm and atrial fibrillation operative conditions were simulated and analysed. RESULTS: For each model, the effect of morphological and functional parameters, such as the number of trabeculae and LAA stroke volume, over the hemodynamics established into the appendage was analysed. Comparison between results obtained in healthy and diseased conditions suggested the introduction of a new parameter to quantify the risk of thrombosis, here called blood stasis factor (BSF). This is defined as the LAA surface area which permanently experiences levels of shear strain rate inferior to a threshold value, set to 5 s-1 (BSF5). CONCLUSIONS: This work suggests that the current morphological classification is unsuitable to evaluate the probability of thrombus formation. However, hemodynamic parameters easy to determine from clinical examinations, such as normalised stroke volume, LAA orifice flow rate and presence of extensive trabeculations can identify departures from healthy hemodynamics in AF and support a more systematic stratification of the thromboembolic risk.

Hydrodynamic ex vivo analysis of valve-sparing techniques: assessment and comparison.

OBJECTIVES: Valve-sparing procedures are surgical techniques allowing to restore adequate function of the native aortic valve by replacing the dysfunctional ascending aorta with a prosthetic conduit. A number of techniques are currently used, such as Yacoub's remodelling and David's reimplantation, based on a regular straight conduit. More recently, the De Paulis proposed the use of bulging conduits to reconstruct the shape of the Valsalva sinuses. This work investigates the impact of the valve-sparing technique on the aortic valve function. METHODS: The performance of 3 porcine aortic roots (Medtronic Freestyle™) was assessed in a cardiovascular pulse duplicator before and after performing 3 alternative valve-sparing procedures: David's reimplantation, Yacoub's remodelling and De Paulis' reimplantation. RESULTS: The porcine aortic roots, representative of the healthy native configuration, were characterized by the highest efficiency, with a mean energetic dissipation under normal operating conditions of 26 mJ. David's and Yacoub's techniques resulted in significantly lower performance (with mean energetic loss of about 70 mJ for both cases). The De Paulis' procedure exhibited intermediate behaviour, with superior systolic performance and valve dynamics similar to the native case, and a mean energetic loss of 38 mJ. CONCLUSIONS: The dynamics and performance after valve-sparing strongly depend on the adopted technique, with the use of conduits replicating the presence of Valsalva sinuses restoring more physiological conditions.

The Role of Patient-Specific Morphological Features of the Left Atrial Appendage on the Thromboembolic Risk Under Atrial Fibrillation.

Background: A large majority of thrombi causing ischemic complications under atrial fibrillation (AF) originate in the left atrial appendage (LAA), an anatomical structure departing from the left atrium, characterized by a large morphological variability between individuals. This work analyses the hemodynamics simulated for different patient-specific models of LAA by means of computational fluid-structure interaction studies, modeling the effect of the changes in contractility and shape resulting from AF. Methods: Three operating conditions were analyzed: sinus rhythm, acute atrial fibrillation, and chronic atrial fibrillation. These were simulated on four patient-specific LAA morphologies, each associated with one of the main morphological variants identified from the common classification: chicken wing, cactus, windsock, and cauliflower. Active contractility of the wall muscle was calibrated on the basis of clinical evaluations of the filling and emptying volumes, and boundary conditions were imposed on the fluid to replicate physiological and pathological atrial pressures, typical of the various operating conditions. Results: The LAA volume and shear strain rates were analyzed over time and space for the different models. Globally, under AF conditions, all models were well aligned in terms of shear strain rate values and predicted levels of risk. Regions of low shear rate, typically associated with a higher risk of a clot, appeared to be promoted by sudden bends and focused at the trabecule and the lobes. These become substantially more pronounced and extended with AF, especially under acute conditions. Conclusion: This work clarifies the role of active and passive contraction on the healthy hemodynamics in the LAA, analyzing the hemodynamic effect of AF that promotes clot formation. The study indicates that local LAA topological features are more directly associated with a thromboembolic risk than the global shape of the appendage, suggesting that more effective classification criteria should be identified.

Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential.

Human CD4+CD25hiFOXP3+ regulatory T (Treg) cells are key players in the control of immunological self-tolerance and homeostasis. Here, we report that signals of pseudo-starvation reversed human Treg cell in vitro anergy through an integrated transcriptional response, pertaining to proliferation, metabolism, and transmembrane solute carrier transport. At the molecular level, the Treg cell proliferative response was dependent on the induction of the cystine/glutamate antiporter solute carrier (SLC)7A11, whose expression was controlled by the nuclear factor erythroid 2-related factor 2 (NRF2). SLC7A11 induction in Treg cells was impaired in subjects with relapsing-remitting multiple sclerosis (RRMS), an autoimmune disorder associated with reduced Treg cell proliferative capacity. Treatment of RRMS subjects with dimethyl fumarate (DMF) rescued SLC7A11 induction and fully recovered Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmunity and unveil SLC7A11 as major target for the rescue of Treg cell proliferation.

Effect of the Alterations in Contractility and Morphology Produced by Atrial Fibrillation on the Thrombosis Potential of the Left Atrial Appendage.

Atrial fibrillation (AF) is a common arrhythmia mainly affecting the elderly population, which can lead to serious complications such as stroke, ischaemic attack and vascular dementia. These problems are caused by thrombi which mostly originate in the left atrial appendage (LAA), a small muscular sac protruding from left atrium. The abnormal heart rhythm associated with AF results in alterations in the heart muscle contractions and in some reshaping of the cardiac chambers. This study aims to verify if and how these physiological changes can establish hemodynamic conditions in the LAA promoting thrombus formation, by means of computational fluid dynamic (CFD) analyses. In particular, sinus and fibrillation contractility was replicated by applying wall velocity/motion to models based on healthy and dilated idealized shapes of the left atrium with a common LAA morphology. The models were analyzed and compared in terms of shear strain rate (SSR) and vorticity, which are hemodynamic parameters directly associated with thrombogenicity. The study clearly indicates that the alterations in contractility and morphology associated with AF pathologies play a primary role in establishing hemodynamic conditions which promote higher incidence of ischaemic events, consistently with the clinical evidence. In particular, in the analyzed models, the impairment in contractility determined a decrease in SSR of about 50%, whilst the chamber pathological dilatation contributed to a 30% reduction, indicating increased risk of clot formation. The equivalent rigid wall model was characterized by SSR values about one order of magnitude smaller than in the contractile models, and substantially different vortical behavior, suggesting that analyses based on rigid chambers, although common in the literature, are inadequate to provide realistic results on the LAA hemodynamics.

Influence of systemic infection and comorbidities on rehabilitation outcomes in severe acquired brain injury.

BACKGROUND: Severe infectious complications are a frequent problem in patients with disability due to a severe acquired brain injury. Previous studies reported that the rehabilitation outcome is significantly lower in patients colonized or infected. However, these results could be influenced by comorbidities of those patients admitted in rehabilitation hospital with a lower functional status. AIM: To explore the influence of systemic infection, in particular concerning multidrug resistant bacteria and analyze the role of comorbidities, as a risk factor for the development of systemic infection, on rehabilitation outcomes in patients with severe brain injury. DESIGN: This research is a cohort, prospective-observational study, comparing patients with and without systemic infections, in terms of rehabilitation outcomes. SETTING: An Italian Intensive Care Rehabilitation Department. POPULATION: A group of 221 patients (mean age: 59 years, range: 16-93 years, 127 males, 94 females) with severe acquired brain injury admitted to rehabilitation hospital. METHODS: We compared the rehabilitation outcomes between patients with and without a systemic infection (at least a positive blood culture) during the rehabilitation period. A secondary analysis was performed on 70 patients with infection versus 70 patients without infection, matched for functional status at admission. The used clinical scores were: Cumulative Illness Rating Scale for Geriatrics (CIRS-G), Coma Recovery Scale Revised (CRS-R), Glasgow Coma Scale (GCS), Functional Independence Measure (FIM), Glasgow Outcome Scale (GOS), Disability Rating Scale (DRS), Levels of Cognitive Functioning (LCF) administered at admission and discharge. Length of hospitalization and the role of comorbidities were also considered. RESULTS: The group of patients with systemic infection (in particular due to Gram-negative bacteria) had a significantly lower outcome for 5 out 6 clinical scales and with a more than doubled length of hospitalization (P<0.001). However, these patients with, at least, a positive blood culture resulted having lower functional status at admission. In the secondary analysis, worst outcome was found in patients with positive blood culture in terms of FIM (P=0.033), GOS (P=0.048), and CRS-R (P=0.001). CONCLUSIONS: Systemic infections during rehabilitation increased the length of hospitalization and reduce the rehabilitative outcomes, even when the analysis was performed on groups matched for the functional status at admission. Moreover, the cardiological and endocrine metabolic comorbidities seem to influence the outcome, without representing a further risk factor for systemic infection. CLINICAL REHABILITATION IMPACT: The impact of infections during rehabilitation inpatient should be more taken into account, with specific procedures and suitable environments to avoid the diffusions of infections.

MTGO-SC, A Tool to Explore Gene Modules in Single-Cell RNA Sequencing Data.

The identification of functional modules in gene interaction networks is a key step in understanding biological processes. Network interpretation is essential for unveiling biological mechanisms, candidate biomarkers, or potential targets for drug discovery/repositioning. Plenty of biological module identification algorithms are available, although none is explicitly designed to perform the task on single-cell RNA sequencing (scRNA-seq) data. Here, we introduce MTGO-SC, an adaptation for scRNA-seq of our biological network module detection algorithm MTGO. MTGO-SC isolates gene functional modules by leveraging on both the network topological structure and the annotations characterizing the nodes (genes). These annotations are provided by an external source, such as databases and literature repositories (e.g., the Gene Ontology, Reactome). Thanks to the depth of single-cell data, it is possible to define one network for each cell cluster (typically, cell type or state) composing each sample, as opposed to traditional bulk RNA-seq, where the emerging gene network is averaged over the whole sample. MTGO-SC provides two complexity levels for interpretation: the gene-gene interaction and the intermodule interaction networks. MTGO-SC is versatile in letting the users define the rules to extract the gene network and integrated with the Seurat scRNA-seq analysis pipeline. MTGO-SC is available at https://github.com/ne1s0n/MTGOsc.

MTGO: PPI Network Analysis Via Topological and Functional Module Identification.

Protein-protein interaction (PPI) networks are viable tools to understand cell functions, disease machinery, and drug design/repositioning. Interpreting a PPI, however, it is a particularly challenging task because of network complexity. Several algorithms have been proposed for an automatic PPI interpretation, at first by solely considering the network topology, and later by integrating Gene Ontology (GO) terms as node similarity attributes. Here we present MTGO - Module detection via Topological information and GO knowledge, a novel functional module identification approach. MTGO let emerge the bimolecular machinery underpinning PPI networks by leveraging on both biological knowledge and topological properties. In particular, it directly exploits GO terms during the module assembling process, and labels each module with its best fit GO term, easing its functional interpretation. MTGO shows largely better results than other state of the art algorithms (including recent GO-based ones) when searching for small or sparse functional modules, while providing comparable or better results all other cases. MTGO correctly identifies molecular complexes and literature-consistent processes in an experimentally derived PPI network of Myocardial infarction. A software version of MTGO is available freely for non-commercial purposes at https://gitlab.com/d1vella/MTGO .

From protein-protein interactions to protein co-expression networks: a new perspective to evaluate large-scale proteomic data.

The reductionist approach of dissecting biological systems into their constituents has been successful in the first stage of the molecular biology to elucidate the chemical basis of several biological processes. This knowledge helped biologists to understand the complexity of the biological systems evidencing that most biological functions do not arise from individual molecules; thus, realizing that the emergent properties of the biological systems cannot be explained or be predicted by investigating individual molecules without taking into consideration their relations. Thanks to the improvement of the current -omics technologies and the increasing understanding of the molecular relationships, even more studies are evaluating the biological systems through approaches based on graph theory. Genomic and proteomic data are often combined with protein-protein interaction (PPI) networks whose structure is routinely analyzed by algorithms and tools to characterize hubs/bottlenecks and topological, functional, and disease modules. On the other hand, co-expression networks represent a complementary procedure that give the opportunity to evaluate at system level including organisms that lack information on PPIs. Based on these premises, we introduce the reader to the PPI and to the co-expression networks, including aspects of reconstruction and analysis. In particular, the new idea to evaluate large-scale proteomic data by means of co-expression networks will be discussed presenting some examples of application. Their use to infer biological knowledge will be shown, and a special attention will be devoted to the topological and module analysis.

Aortic root 3D parametric morphological model from 2D-echo images.

The gold standard for the study of the macro-anatomy of the aortic root are multi-detector computed tomography (MDCT) and magnetic resonance (MR) imaging. Both technologies have major advantages and limitations. Although 4D echo is entering the study of the aortic root, 2D echo is the most commonly used diagnostic tool in daily practice. We designed and developed an algorithm for 3D modeling of the aortic root based on measures taken routinely at 2D echocardiography from 20 healthy individuals with normal aortic root. The tool was then translated in 12 patients who underwent both echo and MDCT. The results obtained with the 3D modeling program were quantitatively and qualitatively compared with 3D reconstruction from MDCT. Ad hoc ratios describing the morphology of the aortic root in MDCT and in the 3D model were used for comparison. In 12 patients with aortic root dilatation, the ratios obtained with our model are in good agreement with those from MDCT. Linear correlation for both long axis and short axis ratios was strong. The 3D modeling software can be easily adopted by cardiologists routinely involved in clinical evaluation of the pathology of the aortic root. The tool is easy to apply, does not require additional costs, and may be used to generate a set of data images for monitoring the evolution of the morphology and dimension of the aortic root, flanking the 3D MDCT and MR that remain the gold standard tools.