Individual Contributions of Cardiac Ion Channels on Atrial Repolarization and Reentrant Waves: A Multiscale In-Silico Study

The excitation, contraction, and relaxation of an atrial cardiomyocyte are maintained by the activation and inactivation of numerous cardiac ion channels. Their collaborative efforts cause time-dependent changes of membrane potential, generating an action potential (AP), which is a surrogate marker of atrial arrhythmias. Recently, computational models of atrial electrophysiology emerged as a modality to investigate arrhythmia mechanisms and to predict the outcome of antiarrhythmic therapies. However, the individual contribution of atrial ion channels on atrial action potential and reentrant arrhythmia is not yet fully understood. Thus, in this multiscale in-silico study, perturbations of individual atrial ionic currents (INa, Ito, ICaL, IKur, IKr, IKs, IK1, INCX and INaK) in two in-silico models of human atrial cardiomyocyte (i.e., Courtemanche-1998 and Grandi-2011) were performed at both cellular and tissue levels. The results show that the inhibition of ICaL and INCX resulted in AP shortening, while the inhibition of IKur, IKr, IKs, IK1 and INaK prolonged AP duration (APD). Particularly, in-silico perturbations (inhibition and upregulation) of IKr and IKs only minorly affected atrial repolarization in the Grandi model. In contrast, in the Courtemanche model, the inhibition of IKr and IKs significantly prolonged APD and vice versa. Additionally, a 50% reduction of Ito density abbreviated APD in the Courtemanche model, while the same perturbation prolonged APD in the Grandi model. Similarly, a strong model dependence was also observed at tissue scale, with an observable IK1-mediated reentry stabilizing effect in the Courtemanche model but not in the Grandi atrial model. Moreover, the Grandi model was highly sensitive to a change on intracellular Ca2+ concentration, promoting a repolarization failure in ICaL upregulation above 150% and facilitating reentrant spiral waves stabilization by ICaL inhibition. Finally, by incorporating the previously published atrial fibrillation (AF)-associated ionic remodeling in the Courtemanche atrial model, in-silico modeling revealed the antiarrhythmic effect of IKr inhibition in both acute and chronic settings. Overall, our multiscale computational study highlights the strong model-dependent effects of ionic perturbations which could affect the model’s accuracy, interpretability, and prediction. This observation also suggests the need for a careful selection of in-silico models of atrial electrophysiology to achieve specific research aims.

The Grapefruit Flavonoid Naringenin Inhibits Multiple Cardiac Ion Channels

Drinking fresh grapefruit juice is associated with a significant prolongation of the QT segment on the electrocardiogram (ECG) in healthy volunteers. Among the prominent flavonoids contained in citrus fruits, the flavanone naringenin is known to be a blocker of the human ether-a-go-go related gene (hERG) potassium channel. We hypothesized that naringenin could interfere with other major ion channels shaping the cardiac ventricular action potential (AP). To this end, we examined the effects of naringenin on the seven currents comprising the Comprehensive in vitro Pro-Arrhythmia (CiPA) panel for early arrhythmogenic risk assessment in drug discovery and development. We used automated patch-clamp of human ion channels heterologously expressed in mammalian cell lines to evaluate half-maximal inhibitory concentrations (IC50). Naringenin blocked all CiPA currents tested with IC50 values in the 30 µM – 100 µM concentration-range. The rank-order of channel sensitivity was the following: hERG > Kir2.1 > NaV1.5 late > NaV1.5 peak > KV7.1 > KV4.3 > CaV1.2. This multichannel inhibitory profile of naringenin suggests exercising caution when large amounts of grapefruit juice or other citrus juices enriched in this flavanone are drunk in conjunction with QT prolonging drugs or by carriers of congenital long QT syndromes.

Structure and predictors of repolarization disorders in patients with severe COVID-19 infection

Background COVID-19 infection can adversely affect the function of cardiac ion channels, leading to changes of the properties of conductivity and repolarization, which increases arrhythmogenesis. Purpose To determine the features of the structure and predictors of repolarization disorders in the patients with severe COVID-infection. Methods 133 patients with severe COVID-19 infection were examined, who were in the intensive care unit of the clinical hospital No. 1 in our city in the period from April to December 2020 and as a result of treatment with improved health were discharged from the hospital. Among them there were 65 (48.9%) men and 68 (51.1%) women (X2=0.068, p=0.79). The age of patients ranged from 24 to 90 years, averaging 61.38±12.96 years. Middle-aged and elderly patients were dominated at age structure (p=0.001). The total duration of staying in the hospital was 18.9±9.12 days. The duration of staying in the intensive care unit was 8.32±6.91 days. Statistical processing of the obtained data was performed using the statistical software package SPSS 12.0 for Windows. Results ECG analysis showed that most of the patients had various ischemic changes and/or myocardial repolarization disorders – in 119 (89.5%) patients. Thus, inversion of the T wave was registered – in 91 (68.4%), signs of early ventricular repolarization – in 14 (10.5%), elevation of ST segment – in 6 (4.5%), depression of ST segment – in 54 (40.6%), pathological Q wave – in 9 (6.8%). In turn, signs of an overload of a left ventricle (LV) – in 27 (20,3%), signs of an overload of a right ventricle (RV) – in 8 (6,0%), a sign of SIQIIITIII – in 7 (5,3%), prolongation of QT interval – in 6 (4.5%) patients, respectively. Also signs of LV hypertrophy – in 45 (33.8%), signs of RV hypertrophy – in 12 (9.0%), the presence of p-pulmonale – in 6 (4.5%), p-mitrale – in 7 (5.3%) patients, respectively. Predictors of ischemic changes and/or repolarization disorders in the patients with severe COVID infection are: a decrease of glomerular filtration rate (GFR) <60 ml/min/1.73 m2 – r=0.580, p=0.006; time of hospitalization r=−0,204, p=0,02; elderly patients – r=0,184; p=0.02. Conclusions The prevalence of ischemic changes and/or myocardial repolarization disorders according to ECG data is 89.5%. Presence of inversion of T wave (68.4%) and depression of ST segment (40.6%) were dominated in the structure of ischemic changes and/or myocardial repolarization disorders. Their predictors are: decrease of GFR <60 ml/min/1.73 m2; time of hospitalization; elderly patients. FUNDunding Acknowledgement Type of funding sources: None.

Antiepileptic Drug Tiagabine Does Not Directly Target Key Cardiac Ion Channels Kv11.1, Nav1.5 and Cav1.2

Tiagabine is an antiepileptic drug used for the treatment of partial seizures in humans. Recently, this drug has been found useful in several non-epileptic conditions, including anxiety, chronic pain and sleep disorders. Since tachycardia—an impairment of cardiac rhythm due to cardiac ion channel dysfunction—is one of the most commonly reported non-neurological adverse effects of this drug, in the present paper we have undertaken pharmacological and numerical studies to assess a potential cardiovascular risk associated with the use of tiagabine. A chemical interaction of tiagabine with a model of human voltage-gated ion channels (VGICs) is described using the molecular docking method. The obtained in silico results imply that the adverse effects reported so far in the clinical cardiological of tiagabine could not be directly attributed to its interactions with VGICs. This is also confirmed by the results from the isolated organ studies (i.e., calcium entry blocking properties test) and in vivo (electrocardiogram study) assays of the present research. It was found that tachycardia and other tiagabine-induced cardiac complications are not due to a direct effect of this drug on ventricular depolarization and repolarization.

Impact of Medical Castration on Malignant Arrhythmias in Patients With Prostate Cancer

Background Medical castration, gonadotropin‐releasing hormone agonists, and antiandrogens have been widely applied as a treatment for prostate cancer. Sex steroid hormones influence cardiac ion channels. However, few studies have examined the proarrhythmic properties of medical castration. Methods and Results This study included 149 patients who underwent medical castration using gonadotropin‐releasing hormones with/without antiandrogen for prostate cancer. The changes in the ECG findings during the therapy and associations of the electrocardiographic findings with malignant arrhythmias were studied. The QT and corrected QT (QTc) intervals prolonged during the therapy compared with baseline (QT, 394±32 to 406±39 ms [ P <0.001]; QTc, 416±27 to 439±31 ms [ P <0.001]). The QTc interval was prolonged in 119 (79.9%) patients during the therapy compared with baseline. In 2 (1.3%) patients who had no structural heart disease, torsade de pointes (TdP) and ventricular fibrillation (VF) occurred ≥6 months after starting the therapy. In patients with TdP/VF, the increase in the QTc interval from the pretreatment value was >80 ms. However, in patients without TdP/VF, the prevalence of an increase in the QTc interval from the pretreatment value of >50 ms was 11%, and an increase in the QTc interval from the pretreatment value >80 ms was found in only 4 (3%) patients. Conclusions Medical castration prolongs the QT/QTc intervals in most patients with prostate cancer, and it could cause TdP/VFs even in patients with no risk of QT prolongation before the therapy. An increase in the QTc interval from the pretreatment value >50 ms might become a predictor of TdP/VF. Much attention should be paid to the QTc interval throughout all periods of medical castration to prevent malignant arrhythmias.

The Link Between Sex Hormones and Susceptibility to Cardiac Arrhythmias: From Molecular Basis to Clinical Implications

It is well-known that gender is an independent risk factor for some types of cardiac arrhythmias. For example, males have a greater prevalence of atrial fibrillation and the Brugada Syndrome. In contrast, females are at increased risk for the Long QT Syndrome. However, the underlying mechanisms of these gender differences have not been fully identified. Recently, there has been accumulating evidence indicating that sex hormones may have a significant impact on the cardiac rhythm. In this review, we describe in-depth the molecular interactions between sex hormones and the cardiac ion channels, as well as the clinical implications of these interactions on the cardiac conduction system, in order to understand the link between these hormones and the susceptibility to arrhythmias.