Cardiomyocyte calcium handling in health and disease: Insights from in vitro and in silico studies

Sutanto, Henry; Lyon, Aurore; Lumens, Joost; Schotten, Ulrich; Dobrev, Dobromir; Heijman, Jordi

doi:10.1016/j.pbiomolbio.2020.02.008

Cited by 75 publications

(89 citation statements)

References 263 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The latter then alters excitation-contraction coupling and impairs cardiac contractility. Although more detailed, spatial Ca 2+ -handling models are required to simulate spontaneous SR Ca 2+ -release events [40], in our in-silico study, the Passini human LV model similarly showed an ethanol-dependent reduction of Ca 2+ -transient amplitude (Supplemental Figs. 4-5).…”

Section: The Detrimental Effects Of High Ethanol Concentrationsmentioning

confidence: 78%

“…In addition to direct ion-channel modifications, ethanol can activate intracellular signaling pathways, e.g., through oxidative stress and CaMKII, altering Ca 2+ -handling proteins, including SERCA2a activity and SR Ca 2+ leak, as well as reducing Ca 2+ -transient amplitude and myofilament Ca 2+ sensitivity [13,14]. These Ca 2+ -handling abnormalities may then affect transmembrane ion channels via their Ca 2+dependent regulation [40] and therefore, contribute to ethanol-induced AP changes.…”

Section: Ethanol and Cardiac Ion Channelsmentioning

confidence: 99%

See 1 more Smart Citation

Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses

Sutanto

Cluitmans

Dobrev

et al. 2020

Journal of Molecular and Cellular Cardiology

Self Cite

View full text Add to dashboard Cite

Acute excessive ethyl alcohol (ethanol) consumption alters cardiac electrophysiology and can evoke cardiac arrhythmias, e.g., in 'holiday heart syndrome'. Ethanol acutely modulates numerous targets in cardiomyocytes, including ion channels, Ca 2+-handling proteins and gap junctions. However, the mechanisms underlying ethanol-induced arrhythmogenesis remain incompletely understood and difficult to study experimentally due to the multiple electrophysiological targets involved and their potential interactions with preexisting electrophysiological or structural substrates. Here, we employed cellular-and tissue-level in-silico analyses to characterize the acute effects of ethanol on cardiac electrophysiology and arrhythmogenesis. Acute electrophysiological effects of ethanol were incorporated into human atrial and ventricular cardiomyocyte computer models: reduced I Na , I Ca,L , I to , I Kr and I Kur , dual effects on I K1 and I K,ACh (inhibition at low and augmentation at high concentrations), and increased I NCX and SR Ca 2+ leak. Multiscale simulations in the absence or presence of preexistent atrial fibrillation or heart-failure-related remodeling demonstrated that low ethanol concentrations prolonged atrial action-potential duration (APD) without effects on ventricular APD. Conversely, high ethanol concentrations abbreviated atrial APD and prolonged ventricular APD. High ethanol concentrations promoted reentry in tissue simulations, but the extent of reentry promotion was dependent on the presence of altered intercellular coupling, and the degree, type, and pattern of fibrosis. Taken together, these data provide novel mechanistic insight into the potential proarrhythmic interactions between a preexisting substrate and acute changes in cardiac electrophysiology. In particular, acute ethanol exposure has concentration-dependent electrophysiological effects that differ between atria and ventricles, and between healthy and diseased hearts. Low concentrations of ethanol can have anti-fibrillatory effects in atria, whereas high concentrations promote the inducibility and maintenance of reentrant atrial and ventricular arrhythmias, supporting a role for limiting alcohol intake as part of cardiac arrhythmia management.

show abstract

Section: The Detrimental Effects Of High Ethanol Concentrationsmentioning

confidence: 78%

Section: Ethanol and Cardiac Ion Channelsmentioning

confidence: 99%

Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses

Sutanto

Cluitmans

Dobrev

et al. 2020

Journal of Molecular and Cellular Cardiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…This finding suggests the need for careful consideration of beta-adrenergic stimulation under disease conditions that potentially enlarge the I Ca,L window. Moreover, long-term beta-adrenergic stimulation promotes cardiac remodeling, including hypertrophy, fibrosis, and the downregulation of several ion channels via transcriptional and post-translational modifications, potentially creating a substrate for cardiac arrhythmias (Scheuer, 1999;Dang et al, 2020;Sutanto et al, 2020b). The present study revealed that transient activation of the beta-adrenergic response may be beneficial against drug-induced proarrhythmia and beta-blockers might not be appropriate under such circumstances.…”

Section: Beta-adrenergic Activation Reduces the Apd And Modulates Thementioning

confidence: 68%

“…Palpitation, which is commonly associated with the activation of beta-adrenergic response, has been reported to be the main symptom of COVID-19 (Nishiga et al, 2020). Altogether, these processes may increase the propensity for cardiac arrhythmias by altering cardiomyocyte Ca 2+ -handling and modulating ion-channel properties (Figure 1; Sutanto et al, 2020b).…”

Section: Introductionmentioning

confidence: 99%

Beta-Adrenergic Receptor Stimulation Modulates the Cellular Proarrhythmic Effects of Chloroquine and Azithromycin

Sutanto

Heijman

2020

Front. Physiol.

Self Cite

View full text Add to dashboard Cite

The antimalarial drug, chloroquine (CQ), and antimicrobial drug, azithromycin (AZM), have received significant attention during the COVID-19 pandemic. Both drugs can alter cardiac electrophysiology and have been associated with drug-induced arrhythmias. Meanwhile, sympathetic activation is commonly observed during systemic inflammation and oxidative stress (e.g., in SARS-CoV-2 infection) and may influence the electrophysiological effects of CQ and AZM. Here, we investigated the effect of beta-adrenergic stimulation on proarrhythmic properties of CQ and AZM using detailed in silico models of ventricular electrophysiology. Concentration-dependent alterations in ion-channel function were incorporated into the Heijman canine and O'Hara-Rudy human ventricular cardiomyocyte models. Single and combined drug effects on action-potential (AP) properties were analyzed using a population of 1,000 models accommodating inter-individual variability. Sympathetic stimulation was simulated by increasing pacing rate and experimentally validated isoproterenol (ISO)-induced changes in ion-channel function. In the canine ventricular model at 1 Hz pacing, therapeutic doses of CQ and AZM (5 and 20 μM, respectively) individually prolonged AP duration (APD) by 33 and 13%. Their combination produced synergistic APD prolongation (+161%) with incidence of proarrhythmic early afterdepolarizations in 53.5% of models. Increasing the pacing frequency to 2 Hz shortened APD and together with 1 μM ISO counteracted the drug-induced APD prolongation. No afterdepolarizations occurred following increased rate and simulated application of ISO. Similarly, CQ and AZM individually prolonged APD by 43 and 29% in the human ventricular cardiomyocyte model, while their combination prolonged APD by 76% without causing early afterdepolarizations. Consistently, 1 μM ISO at 2 Hz pacing counteracted the drug-induced APD prolongation. Increasing the I Ca,L window current produced afterdepolarizations, which were exacerbated by ISO. In both models, reduced extracellular K + reduced the repolarization reserve and increased drug effects. In conclusion, CQ-and AZM-induced proarrhythmia is promoted by conditions with reduced repolarization reserve. Sympathetic stimulation limits drug-induced APD prolongation, suggesting the potential importance of heart rate and autonomic status monitoring in particular conditions (e.g., COVID-19).

show abstract

“…As extensively discussed in Chapter 2, calcium is a key regulator of cardiac electromechanical function that interacts with many proteins and signaling molecules to regulate excitation-contraction coupling (335). Calcium enters the cardiomyocyte through L-type calcium channels (LTCC), triggering a more abundant calcium release from the sarcoplasmic reticulum (SR) through a process called calcium-induced calcium release (CICR).…”

Section: Introductionmentioning

confidence: 99%

Integrative computational modeling of calcium handling and cardiac arrhythmias

Sutanto¹

Self Cite

View full text Add to dashboard Cite

Cardiomyocyte calcium handling in health and disease: Insights from in vitro and in silico studies

Cited by 75 publications

References 263 publications

Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses

Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses

Beta-Adrenergic Receptor Stimulation Modulates the Cellular Proarrhythmic Effects of Chloroquine and Azithromycin

Integrative computational modeling of calcium handling and cardiac arrhythmias

Contact Info

Product

Resources

About