Delayed afterdepolarization‐induced triggered activity in cardiac purkinje cells mediated through cytosolic calcium diffusion waves

Shah, Chirag; Jiwani, Sohel; Limbu, Bijay; Weinberg, Seth H.; Deo, M. C.

doi:10.14814/phy2.14296

Cited by 3 publications

(3 citation statements)

References 48 publications

(78 reference statements)

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“…Therefore, this study combined network pharmacology with relevant biological experiments to explore the mechanisms of DHI in the treatment of arrhythmia. Ca 2+ plays an irreplaceable role in myocardial excitation-contraction coupling (ECC) [ 45 ], and the disturbance of Ca 2+ regulation in cardiomyocytes may lead to arrhythmias [ 46 ]. At the same time, it has been reported that aconitine-induced arrhythmia is related to intracellular Ca 2+ signaling [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Danhong Injection in the Treatment of Arrhythmia Based on Network Pharmacology, Molecular Docking, and In Vitro Experiments

Yan

et al. 2022

BioMed Research International

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Background. Danhong injection (DHI) is widely used in the treatment of cardiovascular and cerebrovascular diseases, and its safety and effectiveness have been widely recognized and applied in China. However, the potential molecular mechanism of action for the treatment of arrhythmia is not fully understood. Aim. In this study, through network pharmacology and in vitro cell experiments, we explored the active compounds of DHI for the treatment of arrhythmia and predicted the potential targets of the drug to investigate its mechanism of action. Materials and Methods. First, the potential therapeutic effect of DHI on arrhythmia was investigated in an in vitro arrhythmia model using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), in which calcium transients were recorded to evaluate the status of arrhythmia. Next, the active compounds and key targets in the treatment of arrhythmia were identified through network pharmacology and molecular docking, and the key signaling pathways related to the treatment of arrhythmia were analyzed. Furthermore, we used real-time quantitative reverse transcription PCR (qRT–PCR) to verify the expression levels of key genes. Results. Early afterdepolarizations (EADs) were observed during aconitine treatment in hiPSC-CMs, and the proarrhythmic effect of aconitine was partially rescued by DHI, indicating that the antiarrhythmic role of DHI was verified in an in vitro human cardiomyocyte model. To further dissect the underlying molecular basis of this observation, network pharmacology analysis was performed, and the results showed that there were 108 crosstargets between DHI and arrhythmia. Moreover, 30 of these targets, such as AKT1 and HMOX1, were key genes. In addition, the mRNA expression of AKT1 and HMOX1 could be regulated by DHI. Conclusion. DHI can alleviate aconitine-induced arrhythmia in an in vitro model, presumably because of its multitarget regulatory mechanism. Key genes, such as AKT1 and HMOX1, may contribute to the antiarrhythmic role of DHI in the heart.

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Section: Discussionmentioning

confidence: 99%

Mechanism of Danhong Injection in the Treatment of Arrhythmia Based on Network Pharmacology, Molecular Docking, and In Vitro Experiments

Yan

et al. 2022

BioMed Research International

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“…To enable the pacing of the model by an external stimulus of varying frequencies, the spontaneous firing of APs was disabled by decreasing the maximum conductance of I f by 50%. The effects of adrenergic stimulation using isoproterenol were simulated by altering the maximum conductance of five currents as described previously ( Shah et al, 2019 ). Briefly, the conductance of L-type Ca 2+ channel ( I CaL ), Na + /K + pump ( I NaK ), Na + /Ca 2+ exchanger ( I NaCa ), and SR Ca 2+ -ATPase (SERCA) were up-regulated by 100, 30, 30, and 20%, respectively, while I K1 was down-regulated by 20%.…”

Section: Methodsmentioning

confidence: 99%

An in silico hiPSC-Derived Cardiomyocyte Model Built With Genetic Algorithm

et al. 2021

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The formulation of in silico biophysical models generally requires optimization strategies for reproducing experimentally observed phenomena. In electrophysiological modeling, robust nonlinear regressive methods are often crucial for guaranteeing high fidelity models. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), though nascent, have proven to be useful in cardiac safety pharmacology, regenerative medicine, and in the implementation of patient-specific test benches for investigating inherited cardiac disorders. This study demonstrates the potency of heuristic techniques at formulating biophysical models, with emphasis on a hiPSC-CM model using a novel genetic algorithm (GA) recipe we proposed. The proposed GA protocol was used to develop a hiPSC-CM biophysical computer model by fitting mathematical formulations to experimental data for five ionic currents recorded in hiPSC-CMs. The maximum conductances of the remaining ionic channels were scaled based on recommendations from literature to accurately reproduce the experimentally observed hiPSC-CM action potential (AP) metrics. Near-optimal parameter fitting was achieved for the GA-fitted ionic currents. The resulting model recapitulated experimental AP parameters such as AP durations (APD50, APD75, and APD90), maximum diastolic potential, and frequency of automaticity. The outcome of this work has implications for validating the biophysics of hiPSC-CMs in their use as viable substitutes for human cardiomyocytes, particularly in cardiac safety pharmacology and in the study of inherited cardiac disorders. This study presents a novel GA protocol useful for formulating robust numerical biophysical models. The proposed protocol is used to develop a hiPSC-CM model with implications for cardiac safety pharmacology.

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“…In contrast to the prominent role of EADs in the initiation of TdP in LQTS, polymorphic VT and VF in CPVT are triggered by delayed afterdepolarizations (DADs) that occur during the diastolic phase of the cardiac cycle due to intracellular calcium overload. DADs are typically caused by the spontaneous release of calcium from the sarcoplasmic reticulum, leading to a depolarizing inward sodium-calcium exchange current (I NCX ) [19].…”

Section: Mechanistic Insights Into the Substrate And Triggers Of Vfmentioning

confidence: 99%

Catheter Ablation for Channelopathies: When Is Less More?

Mehta,

Chandiramani,

Ghosh

et al. 2024

JCM

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Ventricular fibrillation (VF) is a common cause of sudden cardiac death in patients with channelopathies, particularly in the young population. Although pharmacological treatment, cardiac sympathectomy, and implantable cardioverter defibrillators (ICD) have been the mainstay in the management of VF in patients with channelopathies, they are associated with significant adverse effects and complications, leading to poor quality of life. Given these drawbacks, catheter ablation has been proposed as a therapeutic option for patients with channelopathies. Advances in imaging techniques and modern mapping technologies have enabled increased precision in identifying arrhythmia triggers and substrate modification. This has aided our understanding of the underlying pathophysiology of ventricular arrhythmias in channelopathies, highlighting the roles of the Purkinje network and the epicardial right ventricular outflow tract in arrhythmogenesis. This review explores the role of catheter ablation in managing the most common channelopathies (Brugada syndrome, congenital long QT syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia). While the initial results for ablation in Brugada syndrome are promising, the long-term efficacy and durability of ablation in different channelopathies require further investigation. Given the genetic and phenotypic heterogeneity of channelopathies, future studies are needed to show whether catheter ablation in patients with channelopathies is associated with a reduction in VF, and psychological distress stemming from recurrent ICD shocks, particularly relative to other available therapeutic options (e.g., quinidine in high-risk Brugada patients).

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Delayed afterdepolarization‐induced triggered activity in cardiac purkinje cells mediated through cytosolic calcium diffusion waves

Cited by 3 publications

References 48 publications

Mechanism of Danhong Injection in the Treatment of Arrhythmia Based on Network Pharmacology, Molecular Docking, and In Vitro Experiments

Mechanism of Danhong Injection in the Treatment of Arrhythmia Based on Network Pharmacology, Molecular Docking, and In Vitro Experiments

An in silico hiPSC-Derived Cardiomyocyte Model Built With Genetic Algorithm

Catheter Ablation for Channelopathies: When Is Less More?

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