A High Fidelity Transmural Anisotropic Ventricular Tissue Model Function to Investigate the Interaction Mechanisms of Drug: An In-Silico Model for Pharmacotherapy

A high fidelity transmural anisotropic ventricular tissue model consisting of endocardial, mid myocardial, and epicardial myocytes were configured to investigate drug interaction, such as Hydroxychloroquine (HCQ), under hypoxia conditions without and with pro-arrhythmic comorbidity like hypokalemia in (a) ventricular tissue b) its arrhythmogenesis for different dosages and (b) two different pacing sequences (Normal and tachycardiac). In-silico ventricular modeling indicates HCQ has an insignificant effect on hypoxia with and without comorbidities, except in the combination of mild hypoxia with moderate hypokalemia condition and severe hypoxia with mild hypokalemia where it initiated a re-entrant arrhythmia. Secondly, incorporating drug dosage variations indicates the 10 μM HCQ created PVCs for all settings except in severe hypoxia conditions where re-entrant arrhythmia occurred. In addition to the dosage of HCQ utilized for treatment, the pacing protocol also influences the appearance of re-entrant arrhythmia only for severe hypoxia with 10 μM HCQ dosage alone. For all other conditions, including tachycardiac pacing protocol, no arrhythmia occurred. These findings infer that the arrhythmic fatality rate due to HCQ treatment for hypoxia can be effectively alleviated by subtly altering or personalizing the dosage of HCQ and aid in the treatment of hypoxia-induced symptoms caused by COVID.

Altered ventricular torsion and transmural patterns of myocyte relaxation precede heart failure in aging F344 rats

The purpose of this study was to identify and explain changes in ventricular and cellular function that contribute to aging-associated cardiovascular disease in aging F344 rats. Three groups of female F344 rats, aged 6, 18, and 22 mo, were studied. Echocardiographic measurements in isoflurane-anesthetized animals showed an increase in peak left ventricular torsion between the 6- and the 18-mo-old groups that was partially reversed in the 22-mo-old animals ( P < 0.05). Epicardial, midmyocardial, and endocardial myocytes were subsequently isolated from the left ventricles of each group of rats. Unloaded sarcomere shortening and Ca2+ transients were then measured in these cells ( n = >75 cells for each of the nine age-region groups). The decay time of the Ca2+ transient and the time required for 50% length relaxation both increased with age but not uniformly across the three regions ( P < 0.02). Further analysis revealed a significant shift in the transmural distribution of these properties between 18 and 22 mo of age, with the largest changes occurring in epicardial myocytes. Computational modeling suggested that these changes were due in part to slower Ca2+ dissociation from troponin in aging epicardial myocytes. Subsequent biochemical assays revealed a >50% reduction in troponin I phosphoprotein content in 22-mo-old epicardium relative to the other regions. These data suggest that between 18 and 22 mo of age (before the onset of heart failure), F344 rats display epicardial-specific myofilament-level modifications that 1) break from the progression observed between 6 and 18 mo and 2) coincide with aberrant patterns of cardiac torsion.

Ionic mechanisms of cellular electrical and mechanical abnormalities in Brugada syndrome

The Brugada syndrome (BrS) is a right ventricular (RV) arrhythmia that is responsible for up to 12% of sudden cardiac deaths. The aims of our study were to determine the cellular mechanisms of the electrical abnormality in BrS and the potential basis of the RV contractile abnormality observed in the syndrome. Tetrodotoxin was used to reduce cardiac Na+ current ( INa) to mimic a BrS-like setting in canine ventricular myocytes. Moderate reduction (<50%) of INa with tetrodotoxin resulted in all-or-none repolarization in a fraction of RV epicardial myocytes. Dynamic clamp and modeling show that reduction of INa shifts the action potential (AP) duration-transient outward current ( Ito) density curve to the left and has a biphasic effect on AP duration. In the presence of a large Ito, INa reduction either prolongs or collapses the AP, depending on the exact density of Ito. These repolarization changes reduce Ca2+ influx and sarcoplasmic reticulum load, resulting in marked attenuation of myocyte contraction and Ca2+ transient in RV epicardial myocytes. We conclude that INa reduction alters repolarization by reducing the threshold for Ito-induced all-or-none repolarization. These cellular electrical changes suppress myocyte excitation-contraction coupling and contraction and may be a contributing factor to the contractile abnormality of the RV wall in BrS.

Transmural heterogeneity of repolarization and Ca2+ handling in a model of mouse ventricular tissue

Mouse hearts have a diversity of action potentials (APs) generated by the cardiac myocytes from different regions. Recent evidence shows that cells from the epicardial and endocardial regions of the mouse ventricle have a diversity in Ca2+ handling properties as well as K+ current expression. To examine the mechanisms of AP generation, propagation, and stability in transmurally heterogeneous tissue, we developed a comprehensive model of the mouse cardiac cells from the epicardial and endocardial regions of the heart. Our computer model simulates the following differences between epicardial and endocardial myocytes: 1) AP duration is longer in endocardial and shorter in epicardial myocytes, 2) diastolic and systolic intracellular Ca2+ concentration and intracellular Ca2+ concentration transients are higher in paced endocardial and lower in epicardial myocytes, 3) Ca2+ release rate is about two times larger in endocardial than in epicardial myocytes, and 4) Na+/Ca2+ exchanger rate is greater in epicardial than in endocardial myocytes. Isolated epicardial cells showed a higher threshold for stability of AP generation but more complex patterns of AP duration at fast pacing rates. AP propagation velocities in the model of two-dimensional tissue are close to those measured experimentally. Simulations show that heterogeneity of repolarization and Ca2+ handling are sustained across the mouse ventricular wall. Stability analysis of AP propagation in the two-dimensional model showed the generation of Ca2+ alternans and more complex transmurally heterogeneous irregular structures of repolarization and intracellular Ca2+ transients at fast pacing rates.