ESC working group on cardiac cellular electrophysiology position paper: relevance, opportunities, and limitations of experimental models for cardiac electrophysiology research

Abstract

Cardiac arrhythmias are a major cause of death and disability. A large number of experimental cell and animal models have been developed to study arrhythmogenic diseases. These models have provided important insights into the underlying arrhythmia mechanisms and translational options for their therapeutic management. This position paper from the ESC Working Group on Cardiac Cellular Electrophysiology provides an overview of (i) currently available in vitro, ex vivo, and in vivo electrophysiological research methodologies, (ii) the most commonly used experimental (cellular and animal) models for cardiac arrhythmias including relevant species differences, (iii) the use of human cardiac tissue, induced pluripotent stem cell (hiPSC)-derived and in silico models to study cardiac arrhythmias, and (iv) the availability, relevance, limitations, and opportunities of these cellular and animal models to recapitulate specific acquired and inherited arrhythmogenic diseases, including atrial fibrillation, heart failure, cardiomyopathy, myocarditis, sinus node, and conduction disorders and channelopathies. By promoting a better understanding of these models and their limitations, this position paper aims to improve the quality of basic research in cardiac electrophysiology, with the ultimate goal to facilitate the clinical translation and application of basic electrophysiological research findings on arrhythmia mechanisms and therapies.

Keywords: Animal models; Arrhythmias; Atrial fibrillation; Cardiac electrophysiology; Cellular electrophysiology; Experimental models; Ion channels; Mechanisms; Position paper.

Figure 1

Hierarchy of preparations and techniques in cardiac electrophysiology. Preparations range from organism (mouse-to-human), isolated heart, multicellular preparations (e.g. slice/wedge or papillary/trabeculae preparations), isolated cardiac cells (e.g. atrial, ventricular, nodal or Purkinje cells) to ion-channel expression systems (e.g. HEK). The associated techniques for measuring cardiac function are shown on the right. Comparable preparations (syncytium and single cell) for stem-cell-derived cardiomyocytes are indicated in a separate panel.

Figure 2

Species differences in cellular electrophysiology. Schematic representation of action potentials (A) and major ionic currents (B) in commonly used species for cardiac electrophysiology research.

Figure 3

Comparison of morphological and electrophysiological features of adult ventricular cardiomyocytes and human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. (A) Microscopic image of an adult cardiomyocyte from mouse stained with anti-alpha-actinin (red) and a hiPSC-derived cardiomyocyte stained with anti-alpha-actinin (red), DAPI (blue), and Nav1.5 (green). Scale bars are 20 µm. (B) Schematic of ventricular action potentials (APs) during rapid upstroke (Phase 0), early repolarization (1), plateau (2), late repolarization (3), and diastole (4). The ionic currents involved are shown below the AP traces.

Figure 4

Summary of the role of computational modelling in cardiac electrophysiology. Experimental and clinical data are combined with biophysical laws and concepts for the development and validation of multi-scale (channel, cardiomyocyte, two-dimensional, and three-dimensional tissue) computational models. These models provide perfect control over parameters and perfect observability. Applications of these models are indicated with dashed arrows and include dynamic clamp (direct application of ion-channel models in patch-clamp experiments), as well as mechanistic, regulatory and clinical applications.