Some cardiovascular and non-cardiovascular drugs frequently cause excessive prolongation of the cardiac action potential (AP) and lead to the development of early afterdepolarisations (EADs), which trigger lethal ventricular arrhythmias. Combining computer simulations in APs with numerical calculations based on dynamical system theory, we investigated stability changes of APs observed in a paced human ventricular myocyte model by decreasing and/or increasing the rapid (I _Kr) and slow (I _Ks) components of delayed rectifying K⁺ current. Upon reducing I _Kr, the APs without EADs (no-EAD response) showed gradual prolongation of AP duration (APD), and were annihilated without AP configuration changes due to the occurrence of saddle-node bifurcations. This annihilation caused a transition to an AP with EADs as a new stable steady state. Furthermore, reducing repolarisation currents (repolarisation reserve attenuation) evoked multi-stable states consisting of APs with different APDs, and caused multiple hysteretic dynamics. Depending on initial ion circumstances within ventricular myocytes, these multi-stable AP states might increase the local/global heterogeneity of AP repolarisations in the ventricle. Thus, the EAD-induced arrhythmias with repolarisation reserve attenuation might be attributed to the APD variability caused by multi-stability in cardiac AP dynamics.

An organism stems from assemblies of a variety of cells and proteins. This complex system serves as a unit, and it exhibits highly sophisticated functions in response to exogenous stimuli that change over time. The complete sequencing of the entire human genome has allowed researchers to address the enigmas of life and disease at the gene- or molecular-based level. The consequence of such studies is the rapid accumulation of a multitude of data at multiple levels, ranging from molecules to the whole body, that has necessitated the development of entirely new concepts, tools, and methodologies to analyze and integrate these data. This necessity has given birth to systems biology, an advanced theoretical and practical research framework that has totally changed the directions of not only basic life science but also medicine. During the symposium of the 95th Annual Meeting of The Physiological Society of Japan 2018, five researchers reported on their respective studies on systems biology. The topics included reactions of drugs, ion-transport architecture in an epithelial system, multi-omics in renal disease, cardiac electrophysiological systems, and a software platform for computer simulation. In this review article these authors have summarized recent achievements in the field and discuss next-generation studies on health and disease.