1. Research Interests

Researcher ID: ResearcherID Orcid ID: OrcidID. Research Gate: Research Gate.
SRK draft CV (pdf)
UWO CV
Canada Common CV
Ethics info
UWO Research Ethics

Computational Medicine is an interdisciplinary research area with following A, B, C headings.

A. Clinical goal: To improve the lives of critically ill patients.

B. Basic science, simulate human pathophysiology mechanisms.

C. Basic science, maths, physics, and computer science tools of the trade.

Science Writing & Communication. I am passionate about communicating our research and that of our peers to the broader scientific community as well as to the public. This is being done by means of blogs, magazines, as well as education journals.

2. Collaborators

University of Western Ontario, Canada

Canada national

Inter-national

3. Projects

Multi-scale modelling of the effects of cooling on cardiac electrophysiology

Submitted to JASN 2019, further elucidation of mechanisms in summer 2019.

0D circulation model to explain effectiveness of therapy in a paediatric patient: case study.

Please see the open forum preprint in November 2018.preprint.

Effect of dialysis on liver and kidney blood flow, blood volume: role of arterioles

WIP. Simulated CT, pathophysiological flow simulation.

Modelling the causes of perfusion blood flow heterogeneity

Computational Assessment of Blood Flow Heterogeneity in Peritoneal Dialysis Patients' Cardiac Ventricles, Kharche et al.

Dialysis prolongs life but augments cardiovascular mortality. Imaging data suggests that dialysis increases myocardial blood flow (BF) heterogeneity, but its causes remain poorly understood. A biophysical model of human coronary vasculature was used to explain the imaging observations, and highlight causes of coronary BF heterogeneity. Post-dialysis CT images from patients under control, pharmacological stress (adenosine), therapy (cooled dialysate), and adenosine and cooled dialysate conditions were obtained. The data presented disparate phenotypes. To dissect vascular mechanisms, a 3D human vasculature model based on known experimental coronary morphometry and a space filling algorithm was implemented. Steady state simulations were performed to investigate the effects of altered aortic pressure and blood vessel diameters on myocardial BF heterogeneity. Imaging showed that stress and therapy potentially increased mean and total BF, while reducing heterogeneity. BF histograms of one patient showed multi-modality. Using the model, it was found that total coronary BF increased as coronary perfusion pressure was increased. BF heterogeneity was differentially affected by large or small vessel blocking. BF heterogeneity was found to be inversely related to small blood vessel diameters. Simulation of large artery stenosis indicates that BF became heterogeneous (increase relative dispersion) and gave multi-modal histograms. The total transmural BF as well as transmural BF heterogeneity reduced due to large artery stenosis, generating large patches of very low BF regions downstream. Blocking of arteries at various orders showed that blocking larger arteries results in multi-modal BF histograms and large patches of low BF, whereas smaller artery blocking results in augmented relative dispersion and fractal dimension. Transmural heterogeneity was also affected. Finally, the effects of augmented aortic pressure in the presence of blood vessel blocking shows differential effects on BF heterogeneity as well as transmural BF. Improved aortic blood pressure may improve total BF. Stress and therapy may be effective if they dilate small vessels. A potential cause for the observed complex BF distributions (multi-modal BF histograms) may indicate existing large vessel stenosis. The intuitive BF heterogeneity methods used can be readily used in clinical studies. Further development of the model and methods will permit personalized assessment of patient BF status.

Link: Frontiers in Physiology, Computational 2018.
Frontiers2018

Modelling the effects of perfusion defects

Computational assessment of arrhythmia potential in the herogeneously perfused ventricle.

Abstract: The heterogeneity in the human left ventricle is augmented by heterogeneous perfusion defects in dialysis patients. We hypothesized that ischemic zones generated by heterogeneous perfusion are a cause of clinically observed post-dialysis arrhythmia. This preliminary study assessed the arrhythmia potential in a heterogeneously perfused 2D human ventricle computational model.
Our aim was to ascertain a relationship between the number of ischemia zones and incidence of multiple re-entrant waves in a 2D model of the human ventricle.
A human ventricle action potential model was modified to include the adenosine triphosphate (ATP) sensitive potassium current. Within ischemic zones, cell electrophysiological alterations due to ischemia were implemented as increased extracellular potassium, reduced intracellular ATP concentrations, as well as reduced upstroke current conductances. The cell model was incorporated into a spatial 2D model. The inter-cellular gap junction coupling was adjusted to simulate slow conduction in dialysis patient hearts. CT imaging data of the heart obtained during dialysis was analysed to estimate the approximate spatial size of ischemic zones. An ischemic border zone between the normal and central ischemic zones was implemented which had smoothly varying electrophysiological parameters. Arrhythmic potential was assessed using the paths of the centres of the re-entrant waves, called tip trajectories, and dominant frequency maps.
Extracellular potassium elevated the resting potential and IKATP reduced the action potential’s duration. In the absence of ischemic zones, the propensity of the model to induce multiple re-entrant waves was low. The inclusion of ischemic zones provided the substrate for initiation of re-entrant wave fibrillation. The dominant frequency which measured the highest rate of pacing in the tissue increased drastically with the inclusion of ischemic zones, going from 3 Hz in the pre-dialysis state to over 6 Hz in the post-dialysis state. Re-entrant wave tip numbers increased from 1 tip in the pre-dialysis case to 34 in the post-dialysis case, a 34 fold increase. The increase of tip number was found to be strongly correlated to tissue heterogeneity in terms of ischemic zone numbers. Computational factors limiting a more extensive simulation of cause-effect combinations were identified.
A dialysis session restores systemic homeostasis, but promotes deleterious arrhythmias. Structure-function mechanistic modelling will permit patient-specific assessment of health status. Such an effort is expected to lead to application of wider physical sciences methods in the improvement of the lives of critically ill patients. High performance computing is a crucial requirement for such mechanistic assessment of health status.

Authors: Sanjay Kharche, C W McIntyre.

Journal link: Lecture Notes in Computer Science, 2017 (HPCS 2017, Canada.)

Figure
HPCS 2017, Kingston

Spatially extended cardiomyocyte

News in 2018: Under review, preprint unavailable.

3D model of human SAN

Title: Computational assessment of the functional role of sinoatrial node exit pathways in the human heart.

Authors: Kharche SR, Vigmond E, Efimov IR, Dobrzynski H
Abstract
Aim
The human right atrium and sinoatrial node (SAN) anatomy is complex. Optical mapping experiments suggest that the SAN is functionally insulated from atrial tissue except at discrete SAN-atrial electrical junctions called SAN exit pathways, SEPs. Additionally, histological imaging suggests the presence of a secondary pacemaker close to the SAN. We hypothesise that a) an insulating border-SEP anatomical configuration is related to SAN arrhythmia; and b) a secondary pacemaker, the paranodal area, is an alternate pacemaker but accentuates tachycardia. A 3D electro-anatomical computational model was used to test these hypotheses.
Methods
A detailed 3D human SAN electro-anatomical mathematical model was developed based on our previous anatomical reconstruction. Electrical activity was simulated using tissue specific variants of the Fenton-Karma action potential equations. Simulation experiments were designed to deploy this complex electro-anatomical system to assess the roles of border-SEPs and paranodal area by mimicking experimentally observed SAN arrhythmia. Robust and accurate numerical algorithms were implemented for solving the mono domain reaction-diffusion equation implicitly, calculating 3D filament traces, and computing dominant frequency among other quantitative measurements.
Results
A centre to periphery gradient of increasing diffusion was sufficient to permit initiation of pacemaking at the centre of the 3D SAN. Re-entry within the SAN, micro re-entry, was possible by imposing significant SAN fibrosis in the presence of the insulating border. SEPs promoted the micro re-entry to generate more complex SAN-atrial tachycardia. Simulation of macro re-entry, i.e. re-entry around the SAN, was possible by inclusion of atrial fibrosis in the presence of the insulating border. The border shielded the SAN from atrial tachycardia. However, SAN micro-structure intercellular gap junctional coupling and the paranodal area contributed to prolonged atrial fibrillation. Finally, the micro-structure was found to be sufficient to explain shifts of leading pacemaker site location.
Conclusions
The simulations establish a relationship between anatomy and SAN electrical function. Microstructure, in the form of intercellular gap junction coupling, was found to regulate SAN function and arrhythmia.
Link: Plos ONE 2017.

3D model of human atrium, effects of clinical drugs

Title: Effects of human atrial ionic remodelling by beta-blocker therapy on mechanisms of atrial fibrillation: a computer simulation.

Abstract
AIMS: Atrial anti-arrhythmic effects of beta-adrenoceptor antagonists (beta-blockers) may involve both a suppression of pro-arrhythmic effects of catecholamines, and an adaptational electrophysiological response to chronic beta-blocker use; so-called 'pharmacological remodelling'. In human atrium, such remodelling decreases the transient outward (Ito) and inward rectifier (IK1) K(+) currents, and increases the cellular action potential duration (APD) and effective refractory period (ERP). However, the consequences of these changes on mechanisms of genesis and maintenance of atrial fibrillation (AF) are unknown. Using mathematical modelling, we tested the hypothesis that the long-term adaptational decrease in human atrial Ito and IK1 caused by chronic beta-blocker therapy, i.e. independent of acute electrophysiological effects of beta-blockers, in an otherwise un-remodelled atrium, could suppress AF.
METHODS AND RESULTS: Contemporarily, biophysically detailed human atrial cell and tissue models were used to investigate effects of the beta-blocker-based pharmacological remodelling. Chronic beta-blockade remodelling prolonged atrial cell APD and ERP. The incidence of small amplitude APD alternans in the CRN model was reduced. At the 1D tissue level, beta-blocker remodelling decreased the maximum pacing rate at which APs could be conducted. At the three-dimensional organ level, beta-blocker remodelling reduced the life span of re-entry scroll waves.
CONCLUSION: This study improves our understanding of the electrophysiological mechanisms of AF suppression by chronic beta-blocker therapy. Atrial fibrillation suppression may involve a reduced propensity for maintenance of re-entrant excitation waves, as a consequence of increased APD and ERP.

Keywords: Arrhythmia; Atrial fibrillation; Computer simulation; Ion channel; beta-Blockers.

Link: Europace 2014 DOI

Simulating cardiac cell electrophysiology, mouse SAN

Title:A mathematical model of action potentials of mouse sinoatrial node cells with molecular bases

Authors: Kharche S et al.

Abstract: Genetically modified mice are popular experimental models for studying the molecular bases and mechanisms of cardiac arrhythmia. A postgenome challenge is to classify the functional roles of genes in cardiac function. To unveil the functional role of various genetic isoforms of ion channels in generating cardiac pacemaking action potentials (APs), a mathematical model for spontaneous APs of mouse sinoatrial node (SAN) cells was developed. The model takes into account the biophysical properties of membrane ionic currents and intracellular mechanisms contributing to spontaneous mouse SAN APs. The model was validated by its ability to reproduce the physiological exceptionally short APs and high pacing rates of mouse SAN cells. The functional roles of individual membrane currents were evaluated by blocking their coding channels. The roles of intracellular Ca(2+)-handling mechanisms on cardiac pacemaking were also investigated in the model. The robustness of model pacemaking behavior was evaluated by means of one- and two-parameter analyses in wide parameter value ranges. This model provides a predictive tool for cellular level outcomes of electrophysiological experiments. It forms the basis for future model development and further studies into complex pacemaking mechanisms as more quantitative experimental data become available.

Keywords: computer modeling, cardiac action potential, genetic isoforms, pacemaking mechanisms.

Journal link/DOI: Am J Physiol Heart Circ Physiol. 2011 Sep; 301(3): H945–H963.
Mouse SAN 2011, 1
Figure
Mouse SAN 2011, Fig 11
Regulation of pacemaking by intracellular Ca2+ mechanisms. A: parametric analysis of basal cell firing as a function of major intracellular Ca2+ parameters for Ca2+ uptake (Pup) and Ca2+ release (ks). The “+” shows the parameter values used in the basal model. At low Pup or low ks, firing was found to be aperiodic or arrested. In B–D, the dashed gray line shows the 0-mV reference voltage. B: control APs. C: APs under Pup = 0 conditions. D: APs under ks = 0 conditions. E: APs under Ca2+ buffered at diastolic concentrations of 50 nM.

Optimising memory for OpenMP

Title:Simulation of clinical electrophysiology in 3D human atria: a high-performance computing and high-performance visualization application.

Authors: Kharche, S; Seemann, G; et al.

Abstract: Atrial fibrillation (AF) is a common cardiac disease of genuine clinical concern with high rates of morbidity, leading to major personal and National Health Service costs. Computer modelling of AF using biophysically detailed cellular models with realistic 3D anatomical geometry allows investigation of the underlying ionic mechanisms in far more detail than with experimental physiology. We have developed a 3D virtual human atrium that combines detailed cellular electrophysiology including ion channel kinetics and homeostasis of ionic concentrations with anatomical details. The segmented anatomical structure and the multi-variable nature of the system make the 3D simulations of AF computationally large and intensive. Computational demands are such that a full problem-solving environment requires access to resources of high-performance computing (HPC), high-performance visualization (HPV), remote data repositories and backend infrastructure. This is a classic example of eScience and Grid-enabled computing. This study was carried out using multiple processor shared memory systems and massively parallel distributed memory systems. With the envisaged increase in anatomical and molecular detail in our cardiac models the requirement for HPC resources is predicted to increase many fold (similar to 1-10 teraflops). Distributed computing is essential, both through massively parallel systems (a single supercomputer) and multiple parallel systems made accessible through the Grid. Analysis and interpretation of results are enhanced by HPV, which in itself is a large data computing aspect of cardiac modelling.

Keywords:3D anatomically detailed model; Computer Science, Software Engineering; Computer Science, Theory &; Methods; biophysically detailed model; large-scale simulations

Journal link:DOI to Wiley

Sensitivity Analysis

Title: A Global Sensitivity Index for Biophysically Detailed Cardiac Cell Models: A Computational Approach

Authors: Sanjay Kharche, Niklas Ludtke, et al.

Abstract: Biophysically detailed cardiac cell models are based upon stiff ordinary differential equations describing ionic channels and intracellular dynamics aiming at reproducing experimental action potentials (APs) and intracellular calcium (Ca2+) transients. Channel blocking and bifurcation analyses are local sensitivity analyses in model parameter space. However, all parameters influence model behaviour and require a global sensitivity index quantifying the influence of parameters on model responses. Identification of the influence of individual parameters increases our understanding of models. A global parameter sensitivity index for assessing the sensitivity of model responses to parameters in cardiac cell models is proposed. The robust index was applied to four widely used models. The analysis revealed that whilst models have common sets of parameters influencing AP and transients, there are subtle differences. This sensitivity analysis offers a systematic method for quantifying the influence of individual parameters on model behaviour to assist in model reduction, refinement or development.

Keywords: Cardiac simulation, global sensitivity analysis, high throughput computing, modelling and simulation tool.

Journal link:Springer
Figure
Degeneracy 2009
Degeneracy in cardiac cell models affects paramter estimation.


Home Research CV Publications Funding Software Contact Outreach Resources Teaching and for Students



August 5th, 2020. Dr. Sanjay R. Kharche.