Bridging Organ- and Cellular-Level Behavior in Ex Vivo Experimental Platforms Using Populations of Models of Cardiac Electrophysiology

Abstract

The inability to discern between pathology and physiological variability is a key issue in cardiac electrophysiology since this prevents the use of minimally invasive acquisitions to predict early pathological behavior. The goal of this work is to demonstrate how experimentally calibrated populations of models (ePoM) may be employed to inform which cellular-level pathologies are responsible for abnormalities observed in organ-level acquisitions while accounting for intersubject variability; this will be done through an exemplary computational and experimental approach. Unipolar epicardial electrograms (EGM) were acquired during an ex vivo porcine heart experiment. A population of the Ten Tusscher 2006 model was calibrated to activation–recovery intervals (ARI), measured from the electrograms, at three representative times. The distributions of the parameters from the resulting calibrated populations were compared to reveal statistically significant pathological variations. Activation–recovery interval reduction was observed in the experiments, and the comparison of the calibrated populations of models suggested a reduced L-type calcium conductance and a high extra-cellular potassium concentration as the most probable causes for the abnormal electrograms. This behavior was consistent with a reduction in the cardiac output (CO) and was confirmed by other experimental measurements. A proof of concept method to infer cellular pathologies by means of organ-level acquisitions is presented, allowing for an earlier detection of pathology than would be possible with current methods. This novel method that uses mathematical models as a tool for formulating hypotheses regarding the cellular causes of observed organ-level behaviors, while accounting for physiological variability has been unexplored.

In silico Identification of Disrupted Myocardial Calcium Homeostasis as Proarrhythmic Trigger in Arrhythmogenic Cardiomyopathy

“…To evaluate the generalizability of the findings from the single model, take into account the effect of inter-subject variability on the electrophysiological properties modeled in this study, and quantify the relative contribution of modulating factors involved in DAD generation, we used a population-of-models approach (Britton et al, 2013;Muszkiewicz et al, 2016). The maximum conductances of eight major ionic currents (I Na , I NaL , I CaL , I Kr , I K1 , I to , I NCX , I NaK ) and the activity of RyR2 and SERCA2a were scaled using Latin-hypercube sampling as previously described (Britton et al, 2013;Ledezma et al, 2018). Five-hundred models were generated, and this control population was calibrated based on AP properties.…”

Investigating the physiology of normothermic ex vivo heart perfusion in an isolated slaughterhouse porcine model used for device testing and training

“…donor heart transportation) [2, 3]. Nowadays, ex vivo models are available that offer more in-dept research possibilities such as electrophysiological studies [4, 5] and working heart studies [6, 7], in which blood is pumped in a natural way (i.e. the blood enters the heart through the left atrium, it is then pumped to the left ventricle and it is finally ejected through the aorta).…”