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In silico investigation of pro-arrhythmic effects of azithromycin on the human ventricle.

ABSTRACT: The macrolide antibiotic azithromycin (AZM) is widely used for respiratory infections and has been suggested to be a possible treatment for the Coronavirus Disease of 2019 (COVID-19). However, AZM-associated QT interval prolongation and arrhythmias have been reported. Integrated mechanistic information on AZM actions on human ventricular excitation and conduction is lacking. Therefore, this study was undertaken to investigate the actions of AZM on ventricular cell and tissue electrical activity. The O'Hara- Virag-Varro-Rudy dynamic (ORd) model of human ventricular cells was modified to incorporate experimental data on the concentration-dependent actions of AZM on multiple ion channels, including I_Na, I_CaL, I_Kr, I_Ks, I_K1 and I_NaL in both acute and chronic exposure conditions. In the single cell model, AZM prolonged the action potential duration (APD) in a concentration-dependent manner, which was predominantly attributable to I_Kr reduction in the acute condition and potentiated I_NaL in the chronic condition. High concentrations of AZM also increased action potential (AP) triangulation (determined as an increased difference between APD₃₀ and APD₉₀) which is a marker of arrhythmia risk. In the chronic condition, the potentiated I_NaL caused a modest intracellular Na ⁺ concentration accumulation at fast pacing rates. At the 1D tissue level, the AZM-prolonged APD at the cellular level was reflected by an increased QT interval in the simulated pseudo-ECG, consistent with clinical observations. Additionally, AZM reduced the conduction velocity (CV) of APs in the acute condition due to a reduced I_Na, and it augmented the transmural APD dispersion of the ventricular tissue, which is also pro-arrhythmic. Such actions were markedly augmented when the effects of chronic exposure of AZM were also considered, or with additional I_Kr block, as may occur with concurrent use of other medications. This study provides insights into the ionic mechanisms by which high concentrations of AZM may modulate ventricular electrophysiology and susceptibility to arrhythmia.

SUBMITTER: Liu Y

PROVIDER: S-EPMC8213892 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of in silico drug trials in populations of human action potential (AP) models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. In silico drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC50/Hill coefficient). Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarization/depolarization abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca2+-transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Drug-induced changes in silico vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarization reserve (increased Ca2+/late Na+ currents and Na+/Ca2+-exchanger, reduced Na+/K+-pump) are highly vulnerable to drug-induced repolarization abnormalities, while those with reduced inward current density (fast/late Na+ and Ca2+ currents) exhibit high susceptibility to depolarization abnormalities. Repolarization abnormalities in silico predict clinical risk for all compounds with 89% accuracy. Drug-induced changes in biomarkers are in overall agreement across different assays: in silico AP duration changes reflect the ones observed in rabbit QT interval and hiPS-CMs Ca2+-transient, and simulated upstroke velocity captures variations in rabbit QRS complex. Our results demonstrate that human in silico drug trials constitute a powerful methodology for prediction of clinical pro-arrhythmic cardiotoxicity, ready for integration in the existing drug safety assessment pipelines.

Project description:RationaleAtrial fibrillation (AF) and heart failure often coexist, but their interaction is poorly understood. Clinical data indicate that the arrhythmic component of AF may contribute to left ventricular (LV) dysfunction.ObjectiveThis study investigates the effects and molecular mechanisms of AF on the human LV.Methods and resultsVentricular myocardium from patients with aortic stenosis and preserved LV function with sinus rhythm or rate-controlled AF was studied. LV myocardium from patients with sinus rhythm and patients with AF showed no differences in fibrosis. In functional studies, systolic Ca2+ transient amplitude of LV cardiomyocytes was reduced in patients with AF, while diastolic Ca2+ levels and Ca2+ transient kinetics were not statistically different. These results were confirmed in LV cardiomyocytes from nonfailing donors with sinus rhythm or AF. Moreover, normofrequent AF was simulated in vitro using arrhythmic or rhythmic pacing (both at 60 bpm). After 24 hours of AF-simulation, human LV cardiomyocytes from nonfailing donors showed an impaired Ca2+ transient amplitude. For a standardized investigation of AF-simulation, human iPSC-cardiomyocytes were tested. Seven days of AF-simulation caused reduced systolic Ca2+ transient amplitude and sarcoplasmic reticulum Ca2+ load likely because of an increased diastolic sarcoplasmic reticulum Ca2+ leak. Moreover, cytosolic Na+ concentration was elevated and action potential duration was prolonged after AF-simulation. We detected an increased late Na+ current as a potential trigger for the detrimentally altered Ca2+/Na+-interplay. Mechanistically, reactive oxygen species were higher in the LV of patients with AF. CaMKII (Ca2+/calmodulin-dependent protein kinase IIδc) was found to be more oxidized at Met281/282 in the LV of patients with AF leading to an increased CaMKII activity and consequent increased RyR2 phosphorylation. CaMKII inhibition and ROS scavenging ameliorated impaired systolic Ca2+ handling after AF-simulation.ConclusionsAF causes distinct functional and molecular remodeling of the human LV. This translational study provides the first mechanistic characterization and the potential negative impact of AF in the absence of tachycardia on the human ventricle.

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In silico investigation of pro-arrhythmic effects of azithromycin on the human ventricle.

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