Activated STING in a vascular and pulmonary syndrome.

BACKGROUND: The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS: We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-ß, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS: We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibroblasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients' lymphocytes was reduced by JAK inhibitors. CONCLUSIONS: STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173. (Funded by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; ClinicalTrials.gov number, NCT00059748.).

Dimensional reductions of a cardiac model for effective validation and calibration.

Complex 3D beating heart models are now available, but their complexity makes calibration and validation very difficult tasks. We thus propose a systematic approach of deriving simplified reduced-dimensional models, in "0D"-typically, to represent a cardiac cavity, or several coupled cavities-and in "1D"-to model elongated structures such as muscle samples or myocytes. We apply this approach with an earlier-proposed 3D cardiac model designed to capture length-dependence effects in contraction, which we here complement by an additional modeling component devised to represent length-dependent relaxation. We then present experimental data produced with rat papillary muscle samples when varying preload and afterload conditions, and we achieve some detailed validations of the 1D model with these data, including for the length-dependence effects that are accurately captured. Finally, when running simulations of the 0D model pre-calibrated with the 1D model parameters, we obtain pressure-volume indicators of the left ventricle in good agreement with some important features of cardiac physiology, including the so-called Frank-Starling mechanism, the End-Systolic Pressure-Volume Relationship, as well as varying elastance properties. This integrated multi-dimensional modeling approach thus sheds new light on the relations between the phenomena observed at different scales and at the local versus organ levels.

Personalization of a cardiac electromechanical model using reduced order unscented Kalman filtering from regional volumes.

Patient-specific cardiac modeling can help in understanding pathophysiology and therapy planning. However it requires to combine functional and anatomical data in order to build accurate models and to personalize the model geometry, kinematics, electrophysiology and mechanics. Personalizing the electromechanical coupling from medical images is a challenging task. We use the Bestel-Clément-Sorine (BCS) electromechanical model of the heart, which provides reasonable accuracy with a reasonable number of parameters (14 for each ventricle) compared to the available clinical data at the organ level. We propose a personalization strategy from cine MRI data in two steps. We first estimate global parameters with an automatic calibration algorithm based on the Unscented Transform which allows to initialize the parameters while matching the volume and pressure curves. In a second step we locally personalize the contractilities of all AHA (American Heart Association) zones of the left ventricle using the reduced order unscented Kalman filtering on Regional Volumes. This personalization strategy was validated synthetically and tested successfully on eight healthy and three pathological cases.

Fundamental principles of data assimilation underlying the Verdandi library: applications to biophysical model personalization within euHeart.

We present the fundamental principles of data assimilation underlying the Verdandi library, and how they are articulated with the modular architecture of the library. This translates--in particular--into the definition of standardized interfaces through which the data assimilation library interoperates with the model simulation software and the so-called observation manager. We also survey various examples of data assimilation applied to the personalization of biophysical models, in particular, for cardiac modeling applications within the euHeart European project. This illustrates the power of data assimilation concepts in such novel applications, with tremendous potential in clinical diagnosis assistance.

Sequential identification of boundary support parameters in a fluid-structure vascular model using patient image data.

Viscoelastic support has been previously established as a valuable modeling ingredient to represent the effect of surrounding tissues and organs in a fluid-structure vascular model. In this paper, we propose a complete methodological chain for the identification of the corresponding boundary support parameters, using patient image data. We consider distance maps of model to image contours as the discrepancy driving the data assimilation approach, which then relies on a combination of (1) state estimation based on the so-called SDF filtering method, designed within the realm of Luenberger observers and well adapted to handling measurements provided by image sequences, and (2) parameter estimation based on a reduced-order UKF filtering method which has no need for tangent operator computations and features natural parallelism to a high degree. Implementation issues are discussed, and we show that the resulting computational effectiveness of the complete estimation chain is comparable to that of a direct simulation. Furthermore, we demonstrate the use of this framework in a realistic application case involving hemodynamics in the thoracic aorta. The estimation of the boundary support parameters proves successful, in particular in that direct modeling simulations based on the estimated parameters are more accurate than with a previous manual expert calibration. This paves the way for complete patient-specific fluid-structure vascular modeling in which all types of available measurements could be used to estimate additional uncertain parameters of biophysical and clinical relevance.

Patient-specific electromechanical models of the heart for the prediction of pacing acute effects in CRT: a preliminary clinical validation.

Cardiac resynchronisation therapy (CRT) is an effective treatment for patients with congestive heart failure and a wide QRS complex. However, up to 30% of patients are non-responders to therapy in terms of exercise capacity or left ventricular reverse remodelling. A number of controversies still remain surrounding patient selection, targeted lead implantation and optimisation of this important treatment. The development of biophysical models to predict the response to CRT represents a potential strategy to address these issues. In this article, we present how the personalisation of an electromechanical model of the myocardium can predict the acute haemodynamic changes associated with CRT. In order to introduce such an approach as a clinical application, we needed to design models that can be individualised from images and electrophysiological mapping of the left ventricle. In this paper the personalisation of the anatomy, the electrophysiology, the kinematics and the mechanics are described. The acute effects of pacing on pressure development were predicted with the in silico model for several pacing conditions on two patients, achieving good agreement with invasive haemodynamic measurements: the mean error on dP/dt(max) is 47.5±35mmHgs(-1), less than 5% error. These promising results demonstrate the potential of physiological models personalised from images and electrophysiology signals to improve patient selection and plan CRT.

External tissue support and fluid-structure simulation in blood flows.

The objective of this work is to address the formulation of an adequate model of the external tissue environment when studying a portion of the arterial tree with fluid-structure interaction. Whereas much work has already been accomplished concerning flow and pressure boundary conditions associated with truncations in the fluid domain, very few studies take into account the tissues surrounding the region of interest to derive adequate boundary conditions for the solid domain. In this paper, we propose to model the effect of external tissues by introducing viscoelastic support conditions along the artery wall, with two-possibly distributed-parameters that can be adjusted to mimic the response of various physiological tissues. In order to illustrate the versatility and effectiveness of our approach, we apply this strategy to perform patient-specific modeling of thoracic aortae based on clinical data, in two different cases and using a distinct fluid-structure interaction methodology for each, namely an Arbitrary Lagrangian-Eulerian (ALE) approach with prescribed inlet motion in the first case and the coupled momentum method in the second case. In both cases, the resulting simulations are quantitatively assessed by detailed comparisons with dynamic image sequences, and the model results are shown to be in very good adequacy with the data.

Estimation of tissue contractility from cardiac cine-MRI using a biomechanical heart model.

The objective of this paper is to propose and assess an estimation procedure-based on data assimilation principles-well suited to obtain some regional values of key biophysical parameters in a beating heart model, using actual Cine-MR images. The motivation is twofold: (1) to provide an automatic tool for personalizing the characteristics of a cardiac model in order to achieve predictivity in patient-specific modeling and (2) to obtain some useful information for diagnosis purposes in the estimated quantities themselves. In order to assess the global methodology, we specifically devised an animal experiment in which a controlled infarct was produced and data acquired before and after infarction, with an estimation of regional tissue contractility-a key parameter directly affected by the pathology-performed for every measured stage. After performing a preliminary assessment of our proposed methodology using synthetic data, we then demonstrate a full-scale application by first estimating contractility values associated with 6 regions based on the AHA subdivision, before running a more detailed estimation using the actual AHA segments. The estimation results are assessed by comparison with the medical knowledge of the specific infarct, and with late enhancement MR images. We discuss their accuracy at the various subdivision levels, in the light of the inherent modeling limitations and of the intrinsic information contents featured in the data.

Cardiac function estimation from MRI using a heart model and data assimilation: advances and difficulties.

In this paper, we present a framework to estimate local ventricular myocardium contractility using clinical MRI, a heart model and data assimilation. First, we build a generic anatomical model of the ventricles including muscle fibre orientations and anatomical subdivisions. Then, this model is deformed to fit a clinical MRI, using a semi-automatic fuzzy segmentation, an affine registration method and a local deformable biomechanical model. An electromechanical model of the heart is then presented and simulated. Finally, a data assimilation procedure is described, and applied to this model. Data assimilation makes it possible to estimate local contractility from given displacements. Presented results on fitting to patient-specific anatomy and assimilation with simulated data are very promising. Current work on model calibration and estimation of patient parameters opens up possibilities to apply this framework in a clinical environment.

[Study of the threshold dose of penicillin which induces an epileptogenic focus during ontogenesis in the rabbit]. / Etude de la dose-seuil de pénicilline induisant un foyer épileptogène au cours de l'ontogenèse chez le lapin

A local application on the cortex surface of a very small drop of Ringer solution containing Penicillin was performed to establish the threshold dose required to elicit and epileptogenic focus and consequently the occuring latency of it. Threshold doses are small (20 - 60 International Units) and show a significant decrease during the maturation of the C.N.S. On the other hand latencies, whatever the animal's age, decrease fairly. The results are confronted to the various supposed modes of action of penicillin, modes which involve a dysfonctioning of the Na+ and K+ ionic pump.

[Effect of anoxia on the evoked somesthesic response during rabbit maturation]. / Effets de l'anoxie sur la réponse évoquée somesthsique au cours de la maturation du lapereau

The resistance to anoxy of the somesthetic evoked response (S.E.R.) has been studied on the young rabbit from birth to ten days. An obvious decrease of this resistance is being observed from the eighth day. The authors drew a parallel from their results and the well known modifications of the oxydative metabolism of the C.N.S. during maturation.