Fast and accurate prediction of drug induced proarrhythmic risk with sex specific cardiac emulators.

In silico trials for drug safety assessment require many high-fidelity 3D cardiac simulations to predict drug-induced QT interval prolongation, which is often computationally prohibitive. To streamline this process, we developed sex-specific emulators for a fast prediction of QT interval, trained on a dataset of 900 simulations. Our results show significant differences between 3D and 0D single-cell models as risk levels increase, underscoring the ability of 3D modeling to capture more complex cardiac responses.

Virtual clinical QT exposure-response studies - A translational computational approach.

Background And Purpose: A recent paradigm shift in proarrhythmic risk assessment suggests that the integration of clinical, non-clinical, and computational evidence can be used to reach a comprehensive understanding of the proarrhythmic potential of drug candidates. While current computational methodologies focus on predicting the incidence of proarrhythmic events after drug administration, the objective of this study is to predict concentration-response relationships of QTc as a clinical endpoint.

Experimental Approach: Full heart computational models reproducing human cardiac populations were created to predict the concentration-response relationship of changes in the QT interval as recommended for clinical trials.

HPC Framework for Performing in Silico Trials Using a 3D Virtual Human Cardiac Population as Means to Assess Drug-Induced Arrhythmic Risk.

Following the 3 R's principles of animal research-replacement, reduction, and refinement-a high-performance computational framework was produced to generate a platform to perform human cardiac in-silico clinical trials as means to assess the pro-arrhythmic risk after the administrations of one or combination of two potentially arrhythmic drugs. The drugs assessed in this study were hydroxychloroquine and azithromycin. The framework employs electrophysiology simulations on high-resolution three-dimensional, biventricular human heart anatomies including phenotypic variabilities, so as to determine if differential QT-prolongation responds to drugs as observed clinically.

Impact of endocrine disruptors from mother's diet on immuno-hormonal orchestration of brain development and introduction of the virtual human twin tool.

Diet has long been known to modify physiology during development and adulthood. However, due to a growing number of manufactured contaminants and additives over the last few decades, diet has increasingly become a source of exposure to chemicals that has been associated with adverse health risks. Sources of food contaminants include the environment, crops treated with agrochemicals, inappropriate storage (e.

Ventricular anatomical complexity and sex differences impact predictions from electrophysiological computational models.

The aim of this work was to analyze the influence of sex hormones and anatomical details (trabeculations and false tendons) on the electrophysiology of healthy human hearts. Additionally, sex- and anatomy-dependent effects of ventricular tachycardia (VT) inducibility are presented. To this end, four anatomically normal, human, biventricular geometries (two male, two female), with identifiable trabeculations, were obtained from high-resolution, ex-vivo MRI and represented by detailed and smoothed geometrical models (with and without the trabeculations).

Concomitant Respiratory Failure Can Impair Myocardial Oxygenation in Patients with Acute Cardiogenic Shock Supported by VA-ECMO.

Venous-arterial extracorporeal membrane oxygenation (VA-ECMO) treatment for acute cardiogenic shock in patients who also have acute lung injury predisposes development of a serious complication called "north-south syndrome" (NSS) which causes cerebral hypoxia. NSS is poorly characterized and hemodynamic studies have focused on cerebral perfusion ignoring the heart. We hypothesized in NSS the heart would be more likely to receive hypoxemic blood than the brain due to the proximity of the coronary arteries to the aortic annulus.

Sensitivity analysis of a strongly-coupled human-based electromechanical cardiac model: Effect of mechanical parameters on physiologically relevant biomarkers.

The human heart beats as a result of multiscale nonlinear dynamics coupling subcellular to whole organ processes, achieving electrophysiologically-driven mechanical contraction. Computational cardiac modelling and simulation have achieved a great degree of maturity, both in terms of mathematical models of underlying biophysical processes and the development of simulation software. In this study, we present the detailed description of a human-based physiologically-based, and fully-coupled ventricular electromechanical modelling and simulation framework, and a sensitivity analysis focused on its mechanical properties.

Three-dimensional cardiac fibre disorganization as a novel parameter for ventricular arrhythmia stratification after myocardial infarction.

Aims: Myocardial infarction (MI) alters cardiac fibre organization with unknown consequences on ventricular arrhythmia. We used diffusion tensor imaging (DTI) of three-dimensional (3D) cardiac fibres and scar reconstructions to identify the main parameters associated with ventricular arrhythmia inducibility and ventricular tachycardia (VT) features after MI.

Methods And Results: Twelve pigs with established MI and three controls underwent invasive electrophysiological characterization of ventricular arrhythmia inducibility and VT features.

Complex Congenital Heart Disease Associated With Disordered Myocardial Architecture in a Midtrimester Human Fetus.

Background: In the era of increasingly successful corrective interventions in patients with congenital heart disease (CHD), global and regional myocardial remodeling are emerging as important sources of long-term morbidity/mortality. Changes in organization of the myocardium in CHD, and in its mechanical properties, conduction, and blood supply, result in altered myocardial function both before and after surgery. To gain a better understanding and develop appropriate and individualized treatment strategies, the microscopic organization of cardiomyocytes, and their integration at a macroscopic level, needs to be completely understood.

Fully coupled fluid-electro-mechanical model of the human heart for supercomputers.

In this work, we present a fully coupled fluid-electro-mechanical model of a 50th percentile human heart. The model is implemented on Alya, the BSC multi-physics parallel code, capable of running efficiently in supercomputers. Blood in the cardiac cavities is modeled by the incompressible Navier-Stokes equations and an arbitrary Lagrangian-Eulerian (ALE) scheme.

Evaluating the roles of detailed endocardial structures on right ventricular haemodynamics by means of CFD simulations.

Computational modelling plays an important role in right ventricular (RV) haemodynamic analysis. However, current approaches use smoothed ventricular anatomies. The aim of this study is to characterise RV haemodynamics including detailed endocardial structures like trabeculae, moderator band, and papillary muscles.

Left Ventricular Trabeculations Decrease the Wall Shear Stress and Increase the Intra-Ventricular Pressure Drop in CFD Simulations.

The aim of the present study is to characterize the hemodynamics of left ventricular (LV) geometries to examine the impact of trabeculae and papillary muscles (PMs) on blood flow using high performance computing (HPC). Five pairs of detailed and smoothed LV endocardium models were reconstructed from high-resolution magnetic resonance images (MRI) of human hearts. The detailed model of one LV pair is characterized only by the PMs and few big trabeculae, to represent state of art level of endocardial detail.

Attenuation of wave reflection by wave entrapment creates a "horizon effect" in the human aorta.

Wave reflection is thought to be important in the augmentation of blood pressure. However, identification of distal reflections sites remains unclear. One possible explanation for this is that wave reflection is predominately determined by an amalgamation of multiple proximal small reflections rather than large discrete reflections originating from the distal peripheries.

Patient-specific modeling of dyssynchronous heart failure: a case study.

The development and clinical use of patient-specific models of the heart is now a feasible goal. Models have the potential to aid in diagnosis and support decision-making in clinical cardiology. Several groups are now working on developing multi-scale models of the heart for understanding therapeutic mechanisms and better predicting clinical outcomes of interventions such as cardiac resynchronization therapy.

The arterial reservoir pressure increases with aging and is the major determinant of the aortic augmentation index.

The augmentation index predicts cardiovascular mortality and is usually explained as a distally reflected wave adding to the forward wave generated by systole. We propose that the capacitative properties of the aorta (the arterial reservoir) also contribute significantly to the augmentation index and have calculated the contribution of the arterial reservoir, independently of wave reflection, and assessed how these contributions change with aging. In 15 subjects (aged 53 +/- 10 yr), we measured pressure and Doppler velocity simultaneously in the proximal aorta using intra-arterial wires.

Effect of transmurally heterogeneous myocyte excitation-contraction coupling on canine left ventricular electromechanics.

The excitation-contraction coupling properties of cardiac myocytes isolated from different regions of the mammalian left ventricular wall have been shown to vary considerably, with uncertain effects on ventricular function. We embedded a cell-level excitation-contraction coupling model with region-dependent parameters within a simple finite element model of left ventricular geometry to study effects of electromechanical heterogeneity on local myocardial mechanics and global haemodynamics. This model was compared with one in which heterogeneous myocyte parameters were assigned randomly throughout the mesh while preserving the total amount of each cell subtype.

Reservoir-wave separation and wave intensity analysis applied to carotid arteries: a hybrid 1D model to understand haemodynamics.

Pressure waveforms measured at different locations in the cardiovascular system present a very similar diastolic decay. Previous work has shown the cardiovascular system can be modelled as a Windkessel and wave system. This concept has been extended to any arbitrary location in the cardiovascular system.

Differences in cardiac microcirculatory wave patterns between the proximal left mainstem and proximal right coronary artery.

Despite having almost identical origins and similar perfusion pressures, the flow-velocity waveforms in the left and right coronary arteries are strikingly different. We hypothesized that pressure differences originating from the distal (microcirculatory) bed would account for the differences in the flow-velocity waveform. We used wave intensity analysis to separate and quantify proximal- and distal-originating pressures to study the differences in velocity waveforms.

Separation of the reservoir and wave pressure and velocity from measurements at an arbitrary location in arteries.

Previous studies based on measurements made in the ascending aorta have demonstrated that it can be useful to separate the arterial pressure P into a reservoir pressure P* generated by the windkessel effect and a wave pressure p generated by the arterial waves: P = P*+p. The separation in these studies was relatively straightforward since the flow into the arterial system was measured. In this study the idea is extended to measurements of pressure and velocity at sites distal to the aortic root where flow into the arterial system is not known.

Pressure reservoir-wave separation applied to the coronary arterial data.

Pressure waveforms measured at different locations in the coronary arteries are similar. Previous work has shown the cardiovascular system can be modelled as a Windkessel and wave system. [1] We now suggest that simultaneously measured coronary pressure, P, and velocity, U, can be used to calculate the separated reservoir, P, and wave, p, pressure such that P = P + p.

Arterial pulse wave velocity in coronary arteries.

Pulse wave velocity is related to arterial stiffness. Pulse wave velocity changes with age and disease and is a useful indicator of cardiovascular disease. Different methods are used for evaluating pulse wave velocity in systemic vessels, but none is applicable to coronary arteries.

A computational study on the influence of catheter-delivered intravascular probes on blood flow in a coronary artery model.

Catheter-delivered intravascular probes are widely used in clinical practice to measure coronary arterial velocity and pressure, but the artefactual effect of the probe on the variables being measured is not well characterised. A coronary artery was simulated with a 180 degrees curved tube 3mm in diameter and the effect of catheters of different diameters was modelled numerically under pulsatile flow conditions. The presence of a catheter increased pressure by 1.