To predict the safety of a drug at an early stage in its development is a major challenge as there is a lack of in vitro heart models that correlate data from preclinical toxicity screening assays with clinical results. A biophysically detailed computer model of the heart, the virtual heart, provides a powerful tool for simulating drug–ion channel interactions and cardiac functions during normal and disease conditions and, therefore, provides a powerful platform for drug cardiotoxicity screening. In this article, we first review recent progress in the development of theory on drug–ion channel interactions and mathematical modelling. Then we propose a family of biomarkers that can quantitatively characterize the actions of a drug on the electrical activity of the heart at multi‐physical scales including cellular and tissue levels. We also conducted some simulations to demonstrate the application of the virtual heart to assess the pro‐arrhythmic effects of cisapride and amiodarone. Using the model we investigated the mechanisms responsible for the differences between the two drugs on pro‐arrhythmogenesis, even though both prolong the QT interval of ECGs. Several challenges for further development of a virtual heart as a platform for screening drug cardiotoxicity are discussed.Linked ArticlesThis article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23
Cation-doped Bi2Te3 nanoplates were prepared via a cation exchange reaction between a cation solution and a Bi2Te3 nanoplate colloid.
Ischemia in the heart impairs function of the cardiac pacemaker, the sinoatrial node (SAN). However, the ionic mechanisms underlying the ischemia-induced dysfunction of the SAN remain elusive. In order to investigate the ionic mechanisms by which ischemia causes SAN dysfunction, action potential models of rabbit SAN and atrial cells were modified to incorporate extant experimental data of ischemia-induced changes to membrane ion channels and intracellular ion homeostasis. The cell models were incorporated into an anatomically detailed 2D model of the intact SAN-atrium. Using the multi-scale models, the functional impact of ischemia-induced electrical alterations on cardiac pacemaking action potentials (APs) and their conduction was investigated. The effects of vagal tone activity on the regulation of cardiac pacemaker activity in control and ischemic conditions were also investigated. The simulation results showed that at the cellular level ischemia slowed the SAN pacemaking rate, which was mainly attributable to the altered Na-Ca exchange current and the ATP-sensitive potassium current. In the 2D SAN-atrium tissue model, ischemia slowed down both the pacemaking rate and the conduction velocity of APs into the surrounding atrial tissue. Simulated vagal nerve activity, including the actions of acetylcholine in the model, amplified the effects of ischemia, leading to possible SAN arrest and/or conduction exit block, which are major features of the sick sinus syndrome. In conclusion, this study provides novel insights into understanding the mechanisms by which ischemia alters SAN function, identifying specific conductances as contributors to bradycardia and conduction block.
Aiming at the problem of anomalous and non-independent distribution of the image errors in the feature-based visual pose estimation, a method of monocular visual pose estimation based on the uncertainty of noise error established by projection vector is proposed. First, by using the covariance matrix to describe the uncertainty of the feature point direction and integrating the uncertainty of the feature point direction into the pose estimation, characteristic point measurement error with different degrees of directional uncertainty can be adapted that can makes the algorithm robust. Then, by introducing the projection vector and combining the depth information of each feature point to represent the collinearity error, the model nonlinear problem caused by the camera perspective projection can be eliminated that can make the algorithm have global convergence. Finally, we use global convergence theorem to prove the global convergence of the proposed algorithm. The results show that the proposed method has good robustness and convergence while adapting to different degrees of error uncertainty, which can meet practical engineering applications.
The short QT syndrome (SQTS) is associated with shortening of QT interval resulting from an accelerated cardiac repolarization. The SQT1, SQTS variant, results from a gain-of-function N588K-KCNH2 mutation in the rapid delayed rectifier potassium current (I Kr) channels. Since β-Adrenoceptor blocker can block slow delayed rectifier potassium currents (I Ks) and I Kr , we used in silico approach to evaluate carvedilol's effects on SQT1. Mathematical models of human ventricular action potential (AP) developed by ten Tusscher et al. were modified to incorporate a Markov chain formulation of I Kr describing the SQT1 mutant condition. AP models were incorporated into a transmural strand for investigation of QT interval changes. In addition, the simulated I Ks and I Kr inhibition to prolong the QT interval in SQT1 was quantified. The blocking effects of carvedilol on I Ks and I Kr were modelled by using Hill coefficient and IC 50 from literatures (10 μM carvedilol reduced I Kr in Wild Type-and N588K-KCNH2 by 92.8% and 36.0%; it reduced I Ks by 36.5% in both conditions). At single cell level, carvedilol prolonged the AP duration (APD) in SQT1; at strand level, the effects of carvedilol normalized the QT interval in SQT1 from 286 ms to 364 ms. Simulations identified β-Adrenoceptor blocker carvedilol as a potential drug for SQTS treatment.
Experiments mimicking microgravity condition have multiple effects on cardiac electrophysiology. Therefore, based on experimental data of rats with 2-weeks (short term) and 4-weeks (long term) tail suspension, effect of microgravity on action potentials (APs) were simulated by decreasing I CaL and increasing I NaK based on rat endocardial and epicardial models. Additionally, a 1D model was constructed by considering the increasing of connexin 43 under microgravity condition. Simulation results show that I CaL and I NaK changes have similar effect in reducing APD 90 under short term condition, while the inhibition of I CaL is the main factor in reducing APD 90 under long term condition. The simulated pseudo-ECG in both conditions showed a shortened QT interval and depressed of ST phase and T wave as experimental observations. Increased expression of connexin 43 in microgravity condition resulted in a mild increase in conduction velocity. Meanwhile, the vulnerable window in 1D ventricle strand reduced in microgravity condition. Compared with short term microgravity condition, all these changes were more prominent in the long term microgravity condition. In conclusion, this study provides new insight into understanding of impaired cardiac functions in short and long term microgravity conditions during spaceflight.
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