Creation and application of virtual patient cohorts of heart models.

Patient-specific cardiac models are now being used to guide therapies. The increased use of patient-specific cardiac simulations in clinical care will give rise to the development of virtual cohorts of cardiac models. These cohorts will allow cardiac simulations to capture and quantify inter-patient variability. However, the development of virtual cohorts of cardiac models will require the transformation of cardiac modelling from small numbers of bespoke models to robust and rapid workflows that can create large numbers of models. In this review, we describe the state of the art in virtual cohorts of cardiac models, the process of creating virtual cohorts of cardiac models, and how to generate the individual cohort member models, followed by a discussion of the potential and future applications of virtual cohorts of cardiac models. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

Biophysical modeling to simulate the response to multisite left ventricular stimulation using a quadripolar pacing lead.

BACKGROUND: Response to cardiac resynchronization therapy (CRT) is reduced in patients with posterolateral scar. Multipolar pacing leads offer the ability to select desirable pacing sites and/or stimulate from multiple pacing sites concurrently using a single lead position. Despite this potential, the clinical evaluation and identification of metrics for optimization of multisite CRT (MCRT) has not been performed. METHODS: The efficacy of MCRT via a quadripolar lead with two left ventricular (LV) pacing sites in conjunction with right ventricular pacing was compared with single-site LV pacing using a coupled electromechanical biophysical model of the human heart with no, mild, or severe scar in the LV posterolateral wall. RESULT: The maximum dP/dt(max) improvement from baseline was 21%, 23%, and 21% for standard CRT versus 22%, 24%, and 25% for MCRT for no, mild, and severe scar, respectively. In the presence of severe scar, there was an incremental benefit of multisite versus standard CRT (25% vs 21%, 19% relative improvement in response). Minimizing total activation time (analogous to QRS duration) or minimizing the activation time of short-axis slices of the heart did not correlate with CRT response. The peak electrical activation wave area in the LV corresponded with CRT response with an R(2) value between 0.42 and 0.75. CONCLUSION: Biophysical modeling predicts that in the presence of posterolateral scar MCRT offers an improved response over conventional CRT. Maximizing the activation wave area in the LV had the most consistent correlation with CRT response, independent of pacing protocol, scar size, or lead location.

Solvers for the cardiac bidomain equations.

The bidomain equations are widely used for the simulation of electrical activity in cardiac tissue. They are especially important for accurately modeling extracellular stimulation, as evidenced by their prediction of virtual electrode polarization before experimental verification. However, solution of the equations is computationally expensive due to the fine spatial and temporal discretization needed. This limits the size and duration of the problem which can be modeled. Regardless of the specific form into which they are cast, the computational bottleneck becomes the repeated solution of a large, linear system. The purpose of this review is to give an overview of the equations and the methods by which they have been solved. Of particular note are recent developments in multigrid methods, which have proven to be the most efficient.

A rule-based method for predicting the electrical activation of the heart with cardiac resynchronization therapy from non-invasive clinical data.

BACKGROUND: Cardiac Resynchronization Therapy (CRT) is one of the few effective treatments for heart failure patients with ventricular dyssynchrony. The pacing location of the left ventricle is indicated as a determinant of CRT outcome. OBJECTIVE: Patient specific computational models allow the activation pattern following CRT implant to be predicted and this may be used to optimize CRT lead placement. METHODS: In this study, the effects of heterogeneous cardiac substrate (scar, fast endocardial conduction, slow septal conduction, functional block) on accurately predicting the electrical activation of the LV epicardium were tested to determine the minimal detail required to create a rule based model of cardiac electrophysiology. Non-invasive clinical data (CT or CMR images and 12 lead ECG) from eighteen patients from two centers were used to investigate the models. RESULTS: Validation with invasive electro-anatomical mapping data identified that computer models with fast endocardial conduction were able to predict the electrical activation with a mean distance errors of 9.2 ±â€¯0.5 mm (CMR data) or (CT data) 7.5 ±â€¯0.7 mm. CONCLUSION: This study identified a simple rule-based fast endocardial conduction model, built using non-invasive clinical data that can be used to rapidly and robustly predict the electrical activation of the heart. Pre-procedural prediction of the latest electrically activating region to identify the optimal LV pacing site could potentially be a useful clinical planning tool for CRT procedures.

Evaluating intramural virtual electrodes in the myocardial wedge preparation: simulations of experimental conditions.

While defibrillation is the only means for prevention of sudden cardiac death, key aspects of the process, such as the intramural virtual electrodes (VEs), remain controversial. Experimental studies had attempted to assess intramural VEs by using wedge preparations and recording activity from the cut surface; however, applicability of this approach remains unclear. These studies found, surprisingly, that for strong shocks, the entire cut surface was negatively polarized, regardless of boundary conditions. The goal of this study is to examine, by means of bidomain simulations, whether VEs on the cut surface represent a good approximation to VEs in depth of the intact wall. Furthermore, we aim to explore mechanisms that could give rise to negative polarization on the cut surface. A model of wedge preparation was used, in which fiber orientation could be changed, and where the cut surface was subjected to permeable and impermeable boundary conditions. Small-scale mechanisms for polarization were also considered. To determine whether any distortions in the recorded VEs arise from averaging during optical mapping, a model of fluorescent recording was employed. The results indicate that, when an applied field is spatially uniform and impermeable boundary conditions are enforced, regardless of the fiber orientation VEs on the cut surface faithfully represent those intramurally, provided tissue properties are not altered by dissection. Results also demonstrate that VEs are sensitive to the conductive layer thickness above the cut surface. Finally, averaging during fluorescent recordings results in large negative VEs on the cut surface, but these do not arise from small-scale heterogeneities.

A finite element formulation for atrial tissue monolayer.

OBJECTIVES: Using computer models for the study of complex atrial arrhythmias such as atrial fibrillation is computationally demanding as long observation periods in the order of tens of seconds are required. A well established approach for reducing computational workload is to approximate the thin atrial walls by curved monolayers. On the other hand, the finite element method (FEM) is a well established approach to solve the underlying partial differential equations. METHODS: A generalized 2D finite element method (FEM) is presented which computes the corresponding stiffness and coupling matrix for arbitrarily shaped monolayers (ML). Compared to standard 2D FEM, only one additional coordinate transformation is required. This allows the use of existing FEM software with minor modifications. The algorithm was tested to simulate wave propagation in benchmark geometries and in a model of atrial anatomy. RESULTS: The ML model was able to simulate electric activation in curved tissue with anisotropic conductivity. Simulations in branching tissue yielded slightly different patterns when compared to a volumetric model with finite thickness. In the model of atrial anatomy the computed activation times for five different pacing protocols displayed a correlation of 0.88 compared to clinical data. CONCLUSIONS: The presented method provides a useful and easily implemented approach to model wave propagation in MLs with a few restrictions to volumetric models.

A new floating sensor array to detect electric near fields of beating heart preparations.

A new flexible sensor for in vitro experiments was developed to measure the surface potential, Phi, and its gradient, E (electric near field), at given sites of the heart. During depolarisation, E describes a vector loop from which direction and magnitude of local conduction velocity theta can be computed. Four recording silver electrodes (14 microm x 14 microm) separated by 50 microm, conducting leads, and solderable pads were patterned on a 50 microm thick polyimide film. The conductive structures, except the electrodes, were isolated with polyimide, and electrodes were chlorided. Spacer pillars mounted on the tip fulfil two functions: they keep the electrodes 70 microm from the tissue allowing non-contact recording of Phi and prevent lateral slipping. The low mass (9.1 mg) and flexibility (6.33 N/m) of the sensor let it easily follow the movement of the beating heart without notable displacement. We examined the electrodes on criteria like rms-noise of Phi, signal-to-noise ratio of Phi and E, maximum peak-slope recording dPhi/dt, and deviation of local activation time (LAT) from a common signal and obtained values of 24-28 microV, 46 and 41 dB, 497-561 V/s and no differences, respectively. With appropriate data acquisition (sampling rate 100 kHz, 24-bit), we were able to record Phi and to monitor E and theta on-line from beat-to-beat even at heart rates of 600 beats/min. Moreover, this technique can discriminate between uncoupled cardiac activations (as occur in fibrotic tissue) separated by less than 1 mm and 1 ms.

Image-Based Personalization of Cardiac Anatomy for Coupled Electromechanical Modeling.

Computational models of cardiac electromechanics (EM) are increasingly being applied to clinical problems, with patient-specific models being generated from high fidelity imaging and used to simulate patient physiology, pathophysiology and response to treatment. Current structured meshes are limited in their ability to fully represent the detailed anatomical data available from clinical images and capture complex and varied anatomy with limited geometric accuracy. In this paper, we review the state of the art in image-based personalization of cardiac anatomy for biophysically detailed, strongly coupled EM modeling, and present our own tools for the automatic building of anatomically and structurally accurate patient-specific models. Our method relies on using high resolution unstructured meshes for discretizing both physics, electrophysiology and mechanics, in combination with efficient, strongly scalable solvers necessary to deal with the computational load imposed by the large number of degrees of freedom of these meshes. These tools permit automated anatomical model generation and strongly coupled EM simulations at an unprecedented level of anatomical and biophysical detail.

Long-term outcome of Haemophilus influenzae meningitis in Navajo Indian children.

OBJECTIVES: To determine the long-term neurologic, cognitive, and educational outcomes of Navajo children who survived Haemophilus influenzae type b meningitis. DESIGN: Retrospective cohort study, with 3.6- to 15.0-year follow-up. SETTING: Navajo Indian reservation. PARTICIPANTS: Population-based cohort of 76 Navajo children with Haemophilus meningitis at less than 5 years of age between 1975 and 1986, with 41 (54%) consenting to undergo follow-up in 1990. Each case was matched to one nearest-age sibling and one unrelated age-matched control. MAIN OUTCOME MEASURES: Standard intelligence test scores, neurologic abnormalities, and school performance. RESULTS: The mean IQ for cases was lower than that for siblings (79 vs 87, P = .006) or age-matched controls (79 vs 95, P < .001). Twenty-nine percent of cases had severe neurologic sequelae, including mental retardation (24%), severe hearing loss (5%), cerebral palsy (7%), and seizure disorder (12%). Eight percent of siblings (relative risk for cases vs siblings, 8.0; P = .05) and 2% of age-matched controls (relative risk vs cases, 10.0; P = .01) had mental retardation. No siblings or age-matched controls had any other severe neurologic sequela. Twenty-nine percent of cases, 23% of siblings (relative risk, 2.5; P = .45), and 0% of age-matched controls (P = .001) required special education services, while 42% of cases, 23% of siblings (relative risk, 3.3; P = .10), and 11% of age-matched controls (relative risk, 4.0; P = .005) had been retained in a grade in school. CONCLUSIONS: Navajo survivors of Haemophilus meningitis suffer more long-term neurologic, cognitive, and school-related disability than siblings or age-matched controls. They may also suffer higher morbidity than Haemophilus meningitis survivors in the general population.

In vitro inhibition of adenosine deaminase by flavonoids and related compounds. New insight into the mechanism of action of plant phenolics.

The effects of 20 flavonoids, anthocyanes and other phenolic compounds of plant origin have been tested in vitro for their inhibitory effect on the enzyme adenosine deaminase (ADA). Significant effects were obtained with most compounds at concentrations between 0.0001 and 0.1 mg/mI. Thus, plant phenolics can be considered as natural ADA enzyme inhibitors. It is assumed that they also increase the actual adenosine (Ado) concentration in vivo. This may explain many of the pharmacological activities of these compounds on a molecular basis.

Hematopoietic growth factors. A promising future for use in bone marrow dysfunction.

The clinical future of hematopoietic growth factors appears promising. They will probably achieve broad clinical application in a wide variety of hematologic disorders. Their use in infectious diseases associated with granulocytopenia and in cancer-treatment regimens as adjuvant agents against myelosuppression and perhaps as stimulants of the natural anti-cancer effects of host cells also seems appropriate.

A new real-time mapping system to detect microscopic cardiac excitation patterns.

A new fast, high-resolution measurement system has been developed to analyze the propagation of cardiac excitation on a microscopic scale. The instrument uses a microsensor array to detect microscopic excitation patterns at the cardiac surface. Ninety-six epicardial signals are recorded simultaneously with 14-bit resolution at 200-kHz samples per second per channel. The system operates like a digital oscilloscope. Preprocessing routines (offset, gain, and triggering) are executed within a sampling interval of 5 microseconds by 48 digital signal processors. Analog-to-digital (A/D) converters are provided with 12 Mb of buffer memory, allowing continuous recording of up to 64-k samples x 96 channels. The recorded dataset is transferred rapidly (8 Mb/sec) to the memory of the integrated computer system via VXIbus. Analysis and visualization of the propagating excitation are computed by custom-designed software. The performance of the system allows recording as well as visualization of the cardiac excitation spread in a beat-to-beat manner.

[Eperythrozoon infection in swine: effect on the acid-base balance and the glucose, lactate and pyruvate content of venous blood]. / Eperythrozoon-Infektion beim Schwein: Einfluss auf Säure-Basen-Haushalt sowie Glucose-, Lactat- und Pyruvatgehalt des venösen Blutes.

The influence of latent and of splenectomy-induced clinically manifest Eperythrozoon suis infection on the following parameters of the carbohydrate metabolism and the acid-base status was tested in venous blood of German Landrace pigs: Levels of glucose, lactic and pyruvic acid, blood-pH, base excess, actual bicarbonate concentration, standard bicarbonate concentration, pCO2, pO2. The latent E. suis infection resulted in a consistent decrease of blood glucose level. 23 days after infection, blood glucose was reduced by 25% of the initial value. The other parameters were not changed by latent E. suis infection. Acute Eperythrozoonosis induced severe hypoglycaemia (means Gluc, = 39.7 mg/dl and blood acidosis (means pH = 7.13). In vitro experiments showed that break-down of glucose in E. suis infected blood occurs very rapidly. There was no significant reduction of the glucose concentration in control blood that had been treated accordingly. There was an increase of lactic acid (means = 62.7 mg/dl), pyruvic acid (means = 1.86 mg/dl), and pCO2 (means = 82.1 mm Hg). The concentrations of actual bicarbonate (means = 24.8 mmol/l) and standard bicarbonate (means = 20.9 mmol/l) were lowered, and there was a negative base excess (means = -3.56 mmol/l). The ratio of lactic and pyruvic acid changed from 11:1 to 30:1. It seems likely that E. suis itself is able to metabolize glucose. Acidosis is considered to result from both the increase of lactic acid (metabolic component) and an impairment of pulmonary gas exchange (respiratory component).

A novel rule-based algorithm for assigning myocardial fiber orientation to computational heart models.

Electrical waves traveling throughout the myocardium elicit muscle contractions responsible for pumping blood throughout the body. The shape and direction of these waves depend on the spatial arrangement of ventricular myocytes, termed fiber orientation. In computational studies simulating electrical wave propagation or mechanical contraction in the heart, accurately representing fiber orientation is critical so that model predictions corroborate with experimental data. Typically, fiber orientation is assigned to heart models based on Diffusion Tensor Imaging (DTI) data, yet few alternative methodologies exist if DTI data is noisy or absent. Here we present a novel Laplace-Dirichlet Rule-Based (LDRB) algorithm to perform this task with speed, precision, and high usability. We demonstrate the application of the LDRB algorithm in an image-based computational model of the canine ventricles. Simulations of electrical activation in this model are compared to those in the same geometrical model but with DTI-derived fiber orientation. The results demonstrate that activation patterns from simulations with LDRB and DTI-derived fiber orientations are nearly indistinguishable, with relative differences ≤6%, absolute mean differences in activation times ≤3.15 ms, and positive correlations ≥0.99. These results convincingly show that the LDRB algorithm is a robust alternative to DTI for assigning fiber orientation to computational heart models.

Accelerating cardiac bidomain simulations using graphics processing units.

Anatomically realistic and biophysically detailed multiscale computer models of the heart are playing an increasingly important role in advancing our understanding of integrated cardiac function in health and disease. Such detailed simulations, however, are computationally vastly demanding, which is a limiting factor for a wider adoption of in-silico modeling. While current trends in high-performance computing (HPC) hardware promise to alleviate this problem, exploiting the potential of such architectures remains challenging since strongly scalable algorithms are necessitated to reduce execution times. Alternatively, acceleration technologies such as graphics processing units (GPUs) are being considered. While the potential of GPUs has been demonstrated in various applications, benefits in the context of bidomain simulations where large sparse linear systems have to be solved in parallel with advanced numerical techniques are less clear. In this study, the feasibility of multi-GPU bidomain simulations is demonstrated by running strong scalability benchmarks using a state-of-the-art model of rabbit ventricles. The model is spatially discretized using the finite element methods (FEM) on fully unstructured grids. The GPU code is directly derived from a large pre-existing code, the Cardiac Arrhythmia Research Package (CARP), with very minor perturbation of the code base. Overall, bidomain simulations were sped up by a factor of 11.8 to 16.3 in benchmarks running on 6-20 GPUs compared to the same number of CPU cores. To match the fastest GPU simulation which engaged 20 GPUs, 476 CPU cores were required on a national supercomputing facility.

Inter-model consistency and complementarity: learning from ex-vivo imaging and electrophysiological data towards an integrated understanding of cardiac physiology.

Computational models of the heart at various scales and levels of complexity have been independently developed, parameterised and validated using a wide range of experimental data for over four decades. However, despite remarkable progress, the lack of coordinated efforts to compare and combine these computational models has limited their impact on the numerous open questions in cardiac physiology. To address this issue, a comprehensive dataset has previously been made available to the community that contains the cardiac anatomy and fibre orientations from magnetic resonance imaging as well as epicardial transmembrane potentials from optical mapping measured on a perfused ex-vivo porcine heart. This data was used to develop and customize four models of cardiac electrophysiology with different level of details, including a personalized fast conduction Purkinje system, a maximum a posteriori estimation of the 3D distribution of transmembrane potential, the personalization of a simplified reaction-diffusion model, and a detailed biophysical model with generic conduction parameters. This study proposes the integration of these four models into a single modelling and simulation pipeline, after analyzing their common features and discrepancies. The proposed integrated pipeline demonstrates an increase prediction power of depolarization isochrones in different pacing conditions.