Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges

Abstract

The pathophysiology of atrial fibrillation (AF) is broad, with components related to the unique and diverse cellular electrophysiology of atrial myocytes, structural complexity, and heterogeneity of atrial tissue, and pronounced disease-associated remodeling of both cells and tissue. A major challenge for rational design of AF therapy, particularly pharmacotherapy, is integrating these multiscale characteristics to identify approaches that are both efficacious and independent of ventricular contraindications. Computational modeling has long been touted as a basis for achieving such integration in a rapid, economical, and scalable manner. However, computational pipelines for AF-specific drug screening are in their infancy, and while the field is progressing quite rapidly, major challenges remain before computational approaches can fill the role of workhorse in rational design of AF pharmacotherapies. In this review, we briefly detail the unique aspects of AF pathophysiology that determine requirements for compounds targeting AF rhythm control, with emphasis on delimiting mechanisms that promote AF triggers from those providing substrate or supporting reentry. We then describe modeling approaches that have been used to assess the outcomes of drugs acting on established AF targets, as well as on novel promising targets including the ultra-rapidly activating delayed rectifier potassium current, the acetylcholine-activated potassium current and the small conductance calcium-activated potassium channel. Finally, we describe how heterogeneity and variability are being incorporated into AF-specific models, and how these approaches are yielding novel insights into the basic physiology of disease, as well as aiding identification of the important molecular players in the complex AF etiology.

Biophysical Psychiatry—How Computational Neuroscience Can Help to Understand the Complex Mechanisms of Mental Disorders

“…Both of these characteristics have been developed for many congenital diseases of cardiac electrophysiology. This has been achieved in part by specifically seeking systematic understanding of diseases with clear distinguishing phenotypes, and in part through incrementally extending fundamental knowledge of cardiac bioelectricity to allow well-defined hypothesis generation and testing (126). While, as mentioned above, mental illnesses pose a greater set of challenges, there is no clear reason for these principles not to be similarly applied to the brain.…”

Arrhythmia mechanisms and spontaneous calcium release: Bi-directional coupling between re-entrant and focal excitation

“…Whereas multiple experimental and simulation studies have investigated the tissue substrate for the emergence and perpetuation of re-entrant excitation [8,9], the multi-scale mechanisms of arrhythmia triggers, and their dynamic interaction with the tissue substrate, remain elusive [10]. Malfunction of the intracellular calcium (Ca 2+ ) handling system has been implicated in the development of rapid arrhythmias, linking sub-cellular spontaneous Ca 2+ release events (SCRE) to pro-arrhythmic triggers in single cell [11–15].…”

Doxycycline Improves Fibrosis-Induced Abnormalities in Atrial Conduction and Vulnerability to Atrial Fibrillation in Chronic Intermittent Hypoxia Rats

“…Unfortunately, there is still no a comprehensive and clear understanding of the specific pathogenesis of AF. Clinical and experimental evidence suggest that fibrosis activates reentry circuits in the atrium by increasing inhomogeneous electrical conduction, which is considered to be a crucial contributor to AF [2][3][4].…”