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

Abstract

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, Ca and Na handling, contraction, and energetics that lead to rhythm derangements. The Ca /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.

Cardiomyocyte Na+ and Ca2+ mishandling drives vicious cycle involving CaMKII, ROS, and ryanodine receptors

“…Impairments in cardiomyocyte Na + and Ca 2+ handling are characteristic of HF and contribute to contractile dysfunction and arrhythmias [45,54,68]. In our HF rabbit model, [Na + ] i was found to be 3 mmol/L higher than in control [8].…”

“…Furthermore, reactive oxygen species (ROS) are increased by CaMKII [49], and elevated [Na + ] i and intracellular [Ca 2+ ] ([Ca 2+ ] i ) [7], which in turn further stimulate CaMKII [11] and RyR leak [50]. Thus, these pathological changes in HF are connected via a vicious cycle of positive feedback reinforcing systolic and diastolic dysfunction and arrhythmia mechanisms [18,45,68] (see Fig. 1).…”

Intracellular Na+ Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis

“… Reparameterization of the Kharche et al model of the murine SAM. ( A ) Experimental (top panels) and simulated (bottom panels) voltage-dependence of peak I CaL [ 24 ], peak I to [ 25 ], and I f availability [ 26 ]. ( B ) Parameter scaling factors yielded by the global optimization process aimed at minimizing the differences between average measured and simulated AP characteristics (shown in the schematic in the inset).…”

“…[Na + ] i has emerged as a key regulator of cardiac excitation-contraction coupling in ventricular and atrial myocytes [ 14 , 15 , 16 ], in that it controls not only cardiac inotropy by affecting the ability of NCX to extrude Ca 2+ , but also affects cardiac excitability and AP duration by modulating voltage-gated Na + channels [ 17 , 18 ] and electrogenic NKA and NCX currents [ 19 , 20 , 21 ]. Indeed, in ventricular myocytes from HF rabbits and patients, excessive Na + accumulation limits NCX-mediated Ca 2+ extrusion, possibly leading to diastolic dysfunction and increased propensity for Ca 2+ -induced triggered arrhythmias [ 20 , 21 , 22 , 23 , 24 , 25 ]. Unlike [Ca 2+ ] i , which shows large changes from ~100 nM to ~1 µM within each cardiac cycle (i.e., a few hundreds of milliseconds) [ 26 ], the balance between Na + influx and efflux mechanisms results in a relatively stable [Na + ] i from beat to beat, with changes requiring many seconds to minutes.…”