Quantitative cross-species translators of cardiac myocyte electrophysiology: Model training, experimental validation, and applications

Morotti, Stefano; Liu, Caroline; Hegyi, Bence; Ni, Haibo; Iseppe, Alex Fogli; Wang, Lianguo; Pritoni, Marco; Ripplinger, Crystal M.; Bers, Donald M.; Edwards, Andrew G.; Grandi, Eleonora

doi:10.1126/sciadv.abg0927

Cited by 29 publications

(26 citation statements)

References 82 publications

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“…We coupled our well-established model of human atrial cardiomyocyte electrophysiology and Ca 2+ handling (44, 119) with biochemically detailed systems models of CaMKII and βAR/cAMP/PKA signaling pathways (31, 39, 40, 45, 46, 120) to build a novel integrative model of human atrial cardiomyocytes. Each of the modules was updated to recapitulate new and human atrial-specific features.…”

Section: Methodsmentioning

confidence: 99%

“…Namely, we created a new Markovian formulation of I CaL ( SI Appendix, Fig. S16 ) to replace the original Hodgkin-Huxley type model formulation for I CaL in (44, 119), needed to recapitulate the two components of inactivation (54) and describe the channel activity in mode 2 (31, 39, 40). Our new Markov formulation of I CaL reproduces characteristic steady-state activation and inactivation, kinetics, and recovery from inactivation ( SI Appendix, Fig.…”

Section: Methodsmentioning

confidence: 99%

“…The βAR/cAMP/PKA and CaMKII signaling cascade systems models were based on the work of Saucerman and colleagues (40, 45, 46, 120). We incorporated our recent modifications to the systems model of human ventricular cardiomyocytes (39), which incorporated functional signaling effects of PKA on I Na , I to , and I K1 , and added dynamic CaMKII-dependent regulation of on I NaL . Here, we also incorporated for the first time a dynamic description of CaMKII-dependent decrease in the gap junction conductance based on findings reported in (75, 81), and CaMKII-dependent increase in the atrial-predominant I Kur (21).…”

Section: Methodsmentioning

confidence: 99%

“…1). This integrative framework has been previously established for rabbit (40), mouse (31), and human (39,47) ventricular cardiomyocytes, but is currently lacking in contemporary models of human atrial cardiomyocytes (44,(48)(49)(50). In Materials and Methods, we provide detailed descriptions of the model development.…”

Section: Integrative Systems Models Of Electrophysiology Ca 2+ Handli...mentioning

confidence: 99%

“…While these are challenging experimental goals, mechanistic computational modeling of cardiomyocytes has proven instrumental to understand the complex interplay of membrane potential and Ca 2+ -dependent signaling, by not only integrating functional and structural experimental (and clinical) data, but also revealing experimentally unrecognized mechanistic underpinnings of physiological and pathophysiological processes (31,(33)(34)(35)(36). Indeed, extensive previous studies have constructed biochemically detailed models of PKA or CaMKII signaling and integrated these formulations with ventricular electrophysiology and Ca 2+ -signaling models to provide insights into their individual roles in regulating ventricular EC coupling and arrhythmia in health and disease, namely heart failure (31,(37)(38)(39)(40). However, cell ultrastructure, subcellular Ca 2+ -signaling, and EC coupling differ between atrial and ventricular cardiomyocytes (36,(41)(42)(43) and appropriate computational models and studies are conspicuously absent in atrial physiology and pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

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Integrative human atrial modeling unravels interactive PKA and CaMKII signaling as key determinant of atrial arrhythmogenesis

Ni¹,

Morotti²,

Zhang³

et al. 2022

Preprint

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Atrial fibrillation (AF), the most prevalent clinical arrhythmia, is associated with atrial remodeling manifesting as acute and chronic alterations in expression, function, and regulation of atrial electrophysiological and Ca2+-handling processes. These AF-induced modifications crosstalk and propagate across spatial scales creating a complex pathophysiological network, which renders AF resistant to existing pharmacotherapies that predominantly target transmembrane ion channels. Developing innovative therapeutic strategies requires a systems approach to disentangle quantitatively the proarrhythmic contributions of individual AF-induced alterations. Here, we built a novel computational framework for simulating electrophysiology and Ca2+-handling in human atrial cardiomyocytes and tissues, and their regulation by key upstream signaling pathways (i.e., protein kinase A, PKA, and Ca2+/calmodulin-dependent protein kinase II, CaMKII) involved in AF-pathogenesis. Populations of atrial cardiomyocyte models were constructed to determine the influence of subcellular ionic processes, signaling components, and regulatory networks on atrial arrhythmogenesis. Our results reveal a novel synergistic crosstalk between PKA and CaMKII that promotes atrial cardiomyocyte electrical instability and arrhythmogenic triggered activity. Simulations of heterogeneous tissue demonstrate that this cellular triggered activity is further amplified by CaMKII-dependent alterations of tissue properties, further exacerbating atrial arrhythmogenesis. Our analysis positions CaMKII as a key nodal master switch of the adaptive changes and the maladaptive proarrhythmic triggers at the cellular and tissue levels and establishes CaMKII inhibition as potential anti-AF strategy. Collectively, our integrative approach is powerful and instrumental to assemble and reconcile existing knowledge into a systems network for identifying novel anti-AF targets and innovative approaches moving beyond the traditional ion channel-based strategy.Significance statementDespite significant advancement in our understanding of pathological mechanisms and alterations underlying atrial fibrillation (AF), a highly prevalent clinical arrhythmia causing substantial health and socioeconomic burden, development of effective pharmacological therapeutics for AF remains an urgent unmet clinical need. We built a systems framework integrating key processes and their regulatory upstream signaling pathways that are involved in atrial electrophysiology and modified by AF. By simulating populations of single atrial cardiomyocyte models and heterogeneous tissues, our analysis demonstrated synergistic interactions between upstream signaling pathways that promote atrial arrhythmogenesis across spatial scales, added new insight into complex atrial arrhythmia mechanisms, and revealed adaptive and maladaptive alterations caused by AF, thus providing a powerful new tool for identifying innovative therapeutic approaches against AF.

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