Arrhythmic risk biomarkers for the assessment of drug cardiotoxicity: from experiments to computer simulations

In this paper, we illustrate how advanced computational modelling and simulation can be used to investigate drug-induced effects on cardiac electrophysiology and on specific biomarkers of pro-arrhythmic risk. To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels. The review highlights the variety of proposed biomarkers, the complexity of the mechanisms of drug-induced pro-arrhythmia and the existence of significant animal species differences in drug-induced effects on cardiac electrophysiology. Predicting drug-induced pro-arrhythmic risk solely using experiments is challenging both preclinically and clinically, as attested by the rise in the cost of releasing new compounds to the market. Computational modelling and simulation has significantly contributed to the understanding of cardiac electrophysiology and arrhythmias over the last 40 years. In the second part of this paper, we illustrate how state-of-the-art open source computational modelling and simulation tools can be used to simulate multi-scale effects of drug-induced ion channel block in ventricular electrophysiology at the cellular, tissue and whole ventricular levels for different animal species. We believe that the use of computational modelling and simulation in combination with experimental techniques could be a powerful tool for the assessment of drug safety pharmacology

Investigation of Absolute Refractory Period Pacing to Prevent Lethal Arrhythmias in Humans

Sudden cardiac death (SCD) is a major health issue, being the commonest cause of natural death in the industrialised world. SCD frequently results from the development of erratic heart rhythms which are usually preceded by repolarisation alternans (RA). Previous studies suggest that the abolishment of RA may prevent the onset of arrhythmia. In a recent swine study, absolute refractory period pacing (ARPP) showed promising results in RA modulation. However, the cellular mechanisms underlying this therapy and its efficiency in human patients remains unclear. Single cell in silico modelling showed that ARPP might be used to both increase or decrease action potential duration (APD) with the degree of modulation depending mainly on stimulus duration, magnitude and coupling interval. ICaL, IKr and IK1 were the main currents involved, and conductance of Ito and ICaL strongly influenced results. APD alternans was successfully reduced in a population of alternating models. In vivo results obtained using an epicardial sock during cardiac surgery showed significant changes in repolarisation when applying ARPP. However, elevated morphological signal alterations led to question the results’ validity. The investigation of signal processing methodology led to the acknowledgement of high-pass filter interference in signal morphology due to the ARPP artefact, resulting in altered markers. Further in vivo data showed no significant effect of ARPP on local RT at the whole heart level. Small effects on RT, spectral method and Tend markers close to the pacing site were observed, suggesting a localised effect. One dimensional in silico modelling showed a rapid decline of the ARPP effect, being limited to around 10mm from the pacing site, correlating with the in vivo results. These results provide important new knowledge regarding the effects of ARPP in the human ventricle at the cellular and organ level. It also provides relevant information for further development, analysis and translation of pacing based therapies

New approaches to predicting the risk of sudden death.

In this review article, we will explore some of the contemporary methods for predicting sudden cardiac death (SCD). These include experimental methods yet to be adopted in the clinical setting, and methods that have been extrapolated from observational data in those with a history of SCD. We will discuss how these relate to the different aetiologies and disease processes. We will also explore how these may be used in the clinical setting to decide on management

High arrhythmic risk in antero-septal acute myocardial ischemia is explained by increased transmural reentry occurrence

Acute myocardial ischemia is a precursor of sudden arrhythmic death. Variability in its manifestation hampers understanding of arrhythmia mechanisms and challenges risk stratification. Our aim is to unravel the mechanisms underlying how size, transmural extent and location of ischemia determine arrhythmia vulnerability and ecG alterations. High performance computing simulations using a human torso/biventricular biophysically-detailed model were conducted to quantify the impact of varying ischemic region properties, including location (LAD/LcX occlusion), transmural/subendocardial ischemia, size, and normal/slow myocardial propagation. ecG biomarkers and vulnerability window for reentry were computed in over 400 simulations for 18 cases evaluated. Two distinct mechanisms explained larger vulnerability to reentry in transmural versus subendocardial ischemia. Macro-reentry around the ischemic region was the primary mechanism increasing arrhythmic risk in transmural versus subendocardial ischemia, for both LAD and LcX occlusion. transmural micro-reentry at the ischemic border zone explained arrhythmic vulnerability in subendocardial ischemia, especially in LAD occlusion, as reentries were favoured by the ischemic region intersecting the septo-apical region. St elevation reflected ischemic extent in transmural ischemia for LCX and LAD occlusion but not in subendocardial ischemia (associated with mild St depression). the technology and results presented can inform safety and efficacy evaluation of anti-arrhythmic therapy in acute myocardial ischemia

Analysing electrocardiographic traits and predicting cardiac risk in UK biobank.

The electrocardiogram (ECG) is a commonly used clinical tool that reflects cardiac excitability and disease. Many parameters are can be measured and with the improvement of methodology can now be quantified in an automated fashion, with accuracy and at scale. Furthermore, these measurements can be heritable and thus genome wide association studies inform the underpinning biological mechanisms. In this review we describe how we have used the resources in UK Biobank to undertake such work. In particular, we focus on a substudy uniquely describing the response to exercise performed at scale with accompanying genetic information

Human-based approaches to pharmacology and cardiology: an interdisciplinary and intersectorial workshop.

Both biomedical research and clinical practice rely on complex datasets for the physiological and genetic characterization of human hearts in health and disease. Given the complexity and variety of approaches and recordings, there is now growing recognition of the need to embed computational methods in cardiovascular medicine and science for analysis, integration and prediction. This paper describes a Workshop on Computational Cardiovascular Science that created an international, interdisciplinary and inter-sectorial forum to define the next steps for a human-based approach to disease supported by computational methodologies. The main ideas highlighted were (i) a shift towards human-based methodologies, spurred by advances in new in silico, in vivo, in vitro, and ex vivo techniques and the increasing acknowledgement of the limitations of animal models. (ii) Computational approaches complement, expand, bridge, and integrate in vitro, in vivo, and ex vivo experimental and clinical data and methods, and as such they are an integral part of human-based methodologies in pharmacology and medicine. (iii) The effective implementation of multi- and interdisciplinary approaches, teams, and training combining and integrating computational methods with experimental and clinical approaches across academia, industry, and healthcare settings is a priority. (iv) The human-based cross-disciplinary approach requires experts in specific methodologies and domains, who also have the capacity to communicate and collaborate across disciplines and cross-sector environments. (v) This new translational domain for human-based cardiology and pharmacology requires new partnerships supported financially and institutionally across sectors. Institutional, organizational, and social barriers must be identified, understood and overcome in each specific setting