Quantitative systems models illuminate arrhythmia mechanisms in heart failure: Role of the Na+‐Ca2+‐Ca2+/calmodulin‐dependent protein kinase II‐reactive oxygen species feedback

Focus Article

Stefano Morotti, Eleonora Grandi

Published Online: Jul 17 2018

DOI: 10.1002/wsbm.1434

Full article on Wiley Online Library: HTML PDF

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Quantitative systems modeling aims to integrate knowledge in different research areas with models describing biological mechanisms and dynamics to gain a better understanding of complex clinical syndromes. Heart failure (HF) is a chronic complex cardiac disease that results from structural or functional disorders impairing the ability of the ventricle to fill with or eject blood. Highly interactive and dynamic changes in mechanical, structural, neurohumoral, metabolic, and electrophysiological properties collectively predispose the failing heart to cardiac arrhythmias, which are responsible for about a half of HF deaths. Multiscale cardiac modeling and simulation integrate structural and functional data from HF experimental models and patients to improve our mechanistic understanding of this complex arrhythmia syndrome. In particular, they allow investigating how disease‐induced remodeling alters the coupling of electrophysiology, Ca2+ and Na+ handling, contraction, and energetics that lead to rhythm derangements. The Ca2+/calmodulin‐dependent protein kinase II, which expression and activity are enhanced in HF, emerges as a critical hub that modulates the feedbacks between these various subsystems and promotes arrhythmogenesis. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Models of Systems Properties and Processes > Mechanistic Models Models of Systems Properties and Processes > Cellular Models Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models

Systems interplay in heart failure (HF) and multiscale systems biology approaches. Top: Schematic of systems involved in HF pathophysiology. HF phenotype includes ventricular hypertrophy, ionic and structural remodeling, and neurohormonal dysregulation leading to both impaired contractile function, and increased arrhythmia susceptibility. Bottom: Systems biology approaches for data collection, analysis, and functional and structural integration (The data images in the upper panel are reproduced with permission from Chang et al., ; Zhang et al., )

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Arrhythmogenic crosstalk and feedback of Na⁺‐Ca²⁺‐Ca²⁺/calmodulin‐dependent protein kinase II (CaMKII)‐reactive oxygen species (ROS) in heart failure (HF). Schematic of the main cellular processes linking Na⁺ and Ca²⁺ cycling, CaMKII activity, and metabolism to increased propensity for arrhythmia in failing myocytes. CaMKII, which expression and activity are enhanced in HF, phosphorylates multiple targets (red symbol “P”), directly influencing membrane electrophysiology and Na⁺ and Ca²⁺ signals, thereby facilitating the development of ectopic activity (EADs and DADs). Increased Na⁺ load enhances [Ca²⁺]_i and reduces [Ca²⁺]_m, leading to further CaMKII activation via both Ca²⁺/calmodulin‐ and oxidation‐dependent mechanisms. In turn, increased ROS production (oxidative stress) can directly affect membrane electrophysiology, Ca²⁺ handling, and myofilament function (blue starred symbol). CaMKII is also involved in HF‐induced structural remodeling that facilitates the formation of a reentrant substrate

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Mechanisms of arrhythmias. Abnormalities in impulse formation include altered automaticity, early and delayed afterdepolarizations (left). Alterations in impulse conduction include slowing of conduction and increase in spatial AP duration (APD) heterogeneity (right)

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