Response to the letter from Warren et al.

Takanari, Hiroki; Fontes, Magda S.C.; Heyden, Marcel A G van der; Vos, Marc A.; Veen, Toon A.B. van

doi:10.1093/cvr/cvx200

“…The discrepant outcomes of the cellular studies mentioned above await explanation and resolution. The controversy regarding the regulation of cardiac excitability by CaMKII signaling pathway has recently translated to the intact heart level (74,86) and could, at least in part, be due to off-target effects of the drugs used in whole heart experiments. However, taken together, our previous (85,86) and current findings show that inhibition of CaMKII by KN93, inhibition of calmodulin (upstream regulator of CaMKII) with W7, and inhibition of PKA with H89 produce qualitatively similar pattern of conduction depression in the rabbit heart, with the epicenter of the effect in the basal RV approximately corresponding to the RVOT.…”

Section: Discussionmentioning

confidence: 99%

Conduction in the right and left ventricle is differentially regulated by protein kinases and phosphatases: implications for arrhythmogenesis

Av

¹

,

Torres

²

,

Cawley

³

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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The “stress” kinases cAMP-dependent protein kinase (PKA) and calcium/calmodulin-dependent protein kinase II (CaMKII), phosphorylate the Na+ channel Nav1.5 subunit to regulate its function. However, how the channel regulation translates to ventricular conduction is poorly understood. We hypothesized that the stress kinases positively and differentially regulate conduction in the right (RV) and the left (LV) ventricles. We applied the CaMKII blocker KN93 (2.75 μM), PKA blocker H89 (10 μM), and broad-acting phosphatase blocker calyculin (30 nM) in rabbit hearts paced at a cycle length (CL) of 150-8,000 ms. We used optical mapping to determine the distribution of local conduction delays (inverse of conduction velocity). Control hearts exhibited constant and uniform conduction at all tested CLs. Calyculin (15-min perfusion) accelerated conduction, with greater effect in the RV (by 15.3%) than in the LV (by 4.1%; P < 0.05). In contrast, both KN93 and H89 slowed down conduction in a chamber-, time-, and CL-dependent manner, with the strongest effect in the RV outflow tract (RVOT). Combined KN93 and H89 synergistically promoted conduction slowing in the RV (KN93: 24.7%; H89: 29.9%; and KN93 + H89: 114.2%; P = 0.0016) but not the LV. The progressive depression of RV conduction led to conduction block and reentrant arrhythmias. Protein expression levels of both the CaMKII-δ isoform and the PKA catalytic subunit were higher in the RVOT than in the apical LV ( P < 0.05). Thus normal RV conduction requires a proper balance between kinase and phosphatase activity. Dysregulation of this balance due to pharmacological interventions or disease is potentially proarrhythmic. NEW & NOTEWORTHY We show that uniform ventricular conduction requires a precise physiological balance of the activities of calcium/calmodulin-dependent protein kinase II (CaMKII), PKA, and phosphatases, which involves region-specific expression of CaMKII and PKA. Inhibiting CaMKII and/or PKA activity elicits nonuniform conduction depression, with the right ventricle becoming vulnerable to the development of conduction disturbances and ventricular fibrillation/ventricular tachycardia.

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“…Indeed, the CaMKII-induced functional decoupling decreased conduction velocity in our simulations, which should reduce wavelength of excitation thereby promoting reentry. However, we acknowledge that opposing effects of acute CaM/CaMKII inhibition on ventricular conduction velocity have been reported (75,81,(109)(110)(111). Due to the extensive targets of CaMKII involved in determining conduction velocity, the exact action of CaMKII on Cx remains to be resolved.…”

Section: Limitations and Future Directionsmentioning

confidence: 96%

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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Integrative human atrial modelling unravels interactive protein kinase A and Ca2+/calmodulin-dependent protein kinase II signalling as key determinants of atrial arrhythmogenesis

Ni

¹

,

Morotti

²

,

Zhang

³

et al. 2023

Cardiovascular Research

View full text Add to dashboard Cite

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- and PKA-dependent alterations of tissue properties, further exacerbating atrial arrhythmogenesis. Our analysis reveals potential mechanisms by which the stress-associated adaptive changes turn into maladaptive proarrhythmic triggers at the cellular and tissue levels and identifies potential anti-AF targets. 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.

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Response to the letter from Warren et al.

Cited by 3 publications

References 12 publications

Conduction in the right and left ventricle is differentially regulated by protein kinases and phosphatases: implications for arrhythmogenesis

Conduction in the right and left ventricle is differentially regulated by protein kinases and phosphatases: implications for arrhythmogenesis

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

Integrative human atrial modelling unravels interactive protein kinase A and Ca2+/calmodulin-dependent protein kinase II signalling as key determinants of atrial arrhythmogenesis

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