A new computational model of human ventricular cardiac action potential

Research Project

The present research project in based on computational modelling and simulation to expand and augment the information extracted from experimental and clinical methods used in cardiac electrophysiology analysis at a single cell level.

To study the cardiac action potential and all its features, it is necessary to acquire specific knowledge about single ionic currents that contribute to the cardiac activity and to describe them quantitatively through mathematical models. In particular the focus of this project in on the human ventricular cardiac models.

Many of the mathematical models used to investigate cardiac physiology and arrhythmia mechanisms, however, suffer from important limitations. For example, the rate dependence of the action potential is inaccurate for several human atrial and ventricular models and models may not exhibit expected arrhythmia-relevant dynamics such as early afterdepolarizations, repolarization alternans or how the extracellular calcium concentration ([Ca2+]o) affects cardiac action potential (AP).In addition, models generally present the behavior of average or typical cells and may not accurately reproduce electrophysiological properties of particular, individual myocytes. This represents another aspect to take into account when we design a new mathematical model in order to going in the direction of a more patient-specific description.

Both biomedical research and clinical practice rely on complex datasets for the physiological and genetic characterization of human hearts in health and disease. The information shaping our knowledge of human hearts is obtained from a variety of techniques and models, including recordings obtained in vivo invasively and noninvasively, in ex vivo tissue and isolated human adult cardiomyocytes recordings, and more recently in vitro using human stem-cell-derived cardiomyocytes. Increasing evidence suggests that non-human animal models may have limited ability to predict human in vivo effects due to important species differences between humans, dogs, guinea pigs, and rabbits. Thus, methods firmly rooted in understanding physiology and pathophysiology in humans are clearly needed. For this reason,human mathematical models can be used as a powerful tool for preliminary investigation and for studying physiological variability which is difficult to investigate with experimental methods alone due to the need to average data to control experimental error.

Starting from the importance of human mathematical model we will focus the attention on the most recent one, whichwas published by O’Hara and Rudy in 2011 (ORd model) and it is the ventricular human model most cited and used to strengthen clinical studies.The aim of this project is to update and integrate this new model.Some aspects on which we want to act concern: strengthen the calcium dependent inactivation of L-type calcium current, modify the formulation of the calcium releaseflux from the sarcoplasmatic reticulum, upgrade the description of how Ca2+/calmodulin-dependent protein kinase II (CaMK) modulated rate dependence of Ca2+ cycling, include the adrenergic upregulation of IKs that is thought to contribute to reverse use dependence, or apply recent Sarkar and Sobie’s parameter sensitivity tests to provide worthwhile insights regarding inter-relatedness of processes in the human ventricle, in addition to formally testing parameter constraint.

Activity Plan

The activities plan is well structured and includes:

  1. Detailed analysis of the ORd model
  2. Strengths and weaknesses study of the model and its improvement in order to reproduce certain physiological mechanisms which are not well reproduced by the ORd model
  3. Validation of the new version of the model against the same experimental data used for the original one
  4. Applications of the new model to study and investigate different physiological and pathophysiological conditions