RESUMO
BACKGROUND: Health information systems (HISs) are continuously targeted by hackers, who aim to bring down critical health infrastructure. This study was motivated by recent attacks on health care organizations that have resulted in the compromise of sensitive data held in HISs. Existing research on cybersecurity in the health care domain places an imbalanced focus on protecting medical devices and data. There is a lack of a systematic way to investigate how attackers may breach an HIS and access health care records. OBJECTIVE: This study aimed to provide new insights into HIS cybersecurity protection. We propose a systematic, novel, and optimized (artificial intelligence-based) ethical hacking method tailored specifically for HISs, and we compared it with the traditional unoptimized ethical hacking method. This allows researchers and practitioners to identify the points and attack pathways of possible penetration attacks on the HIS more efficiently. METHODS: In this study, we propose a novel methodological approach to ethical hacking in HISs. We implemented ethical hacking using both optimized and unoptimized methods in an experimental setting. Specifically, we set up an HIS simulation environment by implementing the open-source electronic medical record (OpenEMR) system and followed the National Institute of Standards and Technology's ethical hacking framework to launch the attacks. In the experiment, we launched 50 rounds of attacks using both unoptimized and optimized ethical hacking methods. RESULTS: Ethical hacking was successfully conducted using both optimized and unoptimized methods. The results show that the optimized ethical hacking method outperforms the unoptimized method in terms of average time used, the average success rate of exploit, the number of exploits launched, and the number of successful exploits. We were able to identify the successful attack paths and exploits that are related to remote code execution, cross-site request forgery, improper authentication, vulnerability in the Oracle Business Intelligence Publisher, an elevation of privilege vulnerability (in MediaTek), and remote access backdoor (in the web graphical user interface for the Linux Virtual Server). CONCLUSIONS: This research demonstrates systematic ethical hacking against an HIS using optimized and unoptimized methods, together with a set of penetration testing tools to identify exploits and combining them to perform ethical hacking. The findings contribute to the HIS literature, ethical hacking methodology, and mainstream artificial intelligence-based ethical hacking methods because they address some key weaknesses of these research fields. These findings also have great significance for the health care sector, as OpenEMR is widely adopted by health care organizations. Our findings offer novel insights for the protection of HISs and allow researchers to conduct further research in the HIS cybersecurity domain.
Assuntos
Inteligência Artificial , Sistemas de Informação em Saúde , Humanos , Registros Eletrônicos de Saúde , Segurança Computacional , SoftwareRESUMO
The endoplasmic reticulum (ER) is responsible for protein synthesis and calcium storage. ER stress, reflected by protein unfolding and calcium handling abnormalities, has been studied as a pathogenic factor in cardiovascular diseases. The aim of this study is to examine the effects of ER stress on mechanical and electrophysiological functions in the heart and explore the underlying molecular mechanisms. A total of 30 rats were randomly divided into control, ER stress inducer (tunicamycin[TN]) and ER stress inhibitor (tunicamycin+4-phenylbutyric acid [4-PBA]) groups. ER stress induction led to significantly systolic and diastolic dysfunction as reflected by maximal increasing/decreasing rate of left intraventricular pressure (±dp/dt), left ventricular peaksystolic pressure(LVSP) and LV end-diastolic pressure(LVEDP). Epicardial mapping performed in vivo revealed reduced conduction velocity and increased conduction heterogeneity associated with the development of spontaneous ventricular tachycardia. Masson's trichrome staining revealed marked fibrosis in the myocardial interstitial and sub-pericardial regions, and thickened epicardium. Western blot analysis revealed increased pro-fibrotic factor transforming growth factor-ß1 (TGF-ß1), decreased mitochondrial biogenesis protein peroxlsome proliferator-activated receptor-γ coactlvator-1α ï¼PGC-1aï¼, and decreased mitochondrial fusion protein mitofusin-2 (MFN2). These changes were associated with mitochondria dysfunction and connexin 43(CX43)translocation to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA. Our study shows that ER stress induction can produce cardiac electrical and mechanism dysfunction as well as structural remodelling. Mitochondrial function alterations are contributed by CX43 transposition to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA.
Assuntos
Conexina 43/metabolismo , Estresse do Retículo Endoplasmático , Cardiopatias/metabolismo , Coração/fisiopatologia , Mitocôndrias/metabolismo , Animais , Antineoplásicos/farmacologia , Antivirais/toxicidade , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Cardiopatias/patologia , Masculino , Mitocôndrias/patologia , Fenilbutiratos/farmacologia , Ratos , Ratos Sprague-Dawley , Tunicamicina/toxicidadeRESUMO
[This corrects the article DOI: 10.2196/21747.].
RESUMO
BACKGROUND: COVID-19 has challenged the resilience of the health care information system, which has affected our ability to achieve the global goal of health and well-being. The pandemic has resulted in a number of recent cyberattacks on hospitals, pharmaceutical companies, the US Department of Health and Human Services, the World Health Organization and its partners, and others. OBJECTIVE: The aim of this review was to identify key cybersecurity challenges, solutions adapted by the health sector, and areas of improvement needed to counteract the recent increases in cyberattacks (eg, phishing campaigns and ransomware attacks), which have been used by attackers to exploit vulnerabilities in technology and people introduced through changes to working practices in response to the COVID-19 pandemic. METHODS: A scoping review was conducted by searching two major scientific databases (PubMed and Scopus) using the search formula "(covid OR healthcare) AND cybersecurity." Reports, news articles, and industry white papers were also included if they were related directly to previously published works, or if they were the only available sources at the time of writing. Only articles in English published in the last decade were included (ie, 2011-2020) in order to focus on current issues, challenges, and solutions. RESULTS: We identified 9 main challenges in cybersecurity, 11 key solutions that health care organizations adapted to address these challenges, and 4 key areas that need to be strengthened in terms of cybersecurity capacity in the health sector. We also found that the most prominent and significant methods of cyberattacks that occurred during the pandemic were related to phishing, ransomware, distributed denial-of-service attacks, and malware. CONCLUSIONS: This scoping review identified the most impactful methods of cyberattacks that targeted the health sector during the COVID-19 pandemic, as well as the challenges in cybersecurity, solutions, and areas in need of improvement. We provided useful insights to the health sector on cybersecurity issues during the COVID-19 pandemic as well as other epidemics or pandemics that may materialize in the future.
Assuntos
COVID-19/epidemiologia , Segurança Computacional , Gestão da Informação em Saúde/métodos , Gestão da Informação em Saúde/normas , Humanos , Pandemias , SARS-CoV-2/isolamento & purificaçãoRESUMO
BACKGROUND: Short QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD). The SQTS variant 3 is linked to D172N mutation to the KCNJ2 gene that causes a gain-of-function to the inward rectifier potassium channel current (I K1), which shortens the ventricular action potential duration (APD) and effective refractory period (ERP). Pro-arrhythmogenic effects of SQTS have been characterized, but less is known about the possible pharmacological treatment of SQTS. Therefore, in this study, we used computational modeling to assess the effects of amiodarone, class III anti-arrhythmic agent, on human ventricular electrophysiology in SQT3. METHODS: The ten Tusscher et al. model for the human ventricular action potentials (APs) was modified to incorporate I K1 formulations based on experimental data of Kir2.1 channels (including WT, WT-D172N and D172N conditions). The modified cell model was then implemented to construct one-dimensional (1D) and 2D tissue models. The blocking effects of amiodarone on ionic currents were modeled using IC50 and Hill coefficient values from literatures. Effects of amiodarone on APD, ERP and pseudo-ECG traces were computed. Effects of the drug on the temporal and spatial vulnerability of ventricular tissue to genesis and maintenance of re-entry were measured, as well as on the dynamic behavior of re-entry. RESULTS: Amiodarone prolonged the ventricular cell APD and decreased the maximal voltage heterogeneity (δV) among three difference cells types across transmural ventricular wall, leading to a decreased transmural heterogeneity of APD along a 1D model of ventricular transmural strand. Amiodarone increased cellular ERP, prolonged QT interval and decreased the T-wave amplitude. It reduced tissue's temporal susceptibility to the initiation of re-entry and increased the minimum substrate size necessary to sustain re-entry in the 2D tissue. CONCLUSIONS: At the therapeutic-relevant concentration of amiodarone, the APD and ERP at the single cell level were increased significantly. The QT interval in pseudo-ECG was prolonged and the re-entry in tissue was prevented. This study provides further evidence that amiodarone may be a potential pharmacological agent for preventing arrhythmogenesis for SQT3 patients.
Assuntos
Amiodarona/farmacologia , Arritmias Cardíacas/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Modelos Cardiovasculares , Potenciais de Ação/efeitos dos fármacos , Arritmias Cardíacas/metabolismo , Humanos , Canais Iônicos/metabolismoRESUMO
T-wave alternans (TWA) has been used for predicting the risk of malignant cardiac arrhythmias and sudden cardiac death (SCD) in multiple clinical settings; however, possible mechanism(s) underlying the spontaneous transition from cellular alternans reflected by TWA to arrhythmias in impaired repolarization remains unclear. The healthy guinea pig ventricular myocytes under E-4031 blocking IKr (0.1 µM, N = 12; 0.3 µM, N = 10; 1 µM, N = 10) were evaluated using whole-cell patch-clamp. The electrophysiological properties of isolated perfused guinea pig hearts under E-4031 (0.1 µM, N = 5; 0.3 µM, N = 5; 1 µM, N = 5) were evaluated using dual- optical mapping. The amplitude/threshold/restitution curves of action potential duration (APD) alternans and potential mechanism(s) underlying the spontaneous transition of cellular alternans to ventricular fibrillation (VF) were examined. There were longer APD80 and increased amplitude and threshold of APD alternans in E-4031 group compared with baseline group, which was reflected by more pronounced arrhythmogenesis at the tissue level, and were associated with steep restitution curves of the APD and the conduction velocity (CV). Conduction of AP alternans augmented tissue's functional spatiotemporal heterogeneity of regional AP/Ca alternans, as well as the AP/Ca dispersion, leading to localized uni-directional conduction block that spontaneous facilitated the formation of reentrant excitation waves without the need for additional premature stimulus. Our results provide a possible mechanism for the spontaneous transition from cardiac electrical alternans in cellular action potentials and intercellular conduction without the involvement of premature excitations, and explain the increased susceptibility to ventricular arrhythmias in impaired repolarization. In this study, we implemented voltage-clamp and dual-optical mapping approaches to investigate the underlying mechanism(s) for the arrhythmogenesis of cardiac alternans in the guinea pig heart at cellular and tissue levels. Our results demonstrated a spontaneous development of reentry from cellular alternans, arising from a combined actions of restitution properties of action potential duration, conduction velocity of excitation wave and interplay between alternants of action potential and the intracellular Ca handling. We believe this study provides new insights into underlying the mechanism, by which cellular cardiac alternans spontaneously evolves into cardiac arrhythmias.
Assuntos
Nascimento Prematuro , Fibrilação Ventricular , Animais , Cobaias , Feminino , Humanos , Arritmias Cardíacas , Miócitos Cardíacos , Morte Súbita Cardíaca , Potenciais de AçãoRESUMO
RATIONALE: Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are important mechanisms of atrial remodeling, predisposing to the development of atrial fibrillation (AF) in type 2 diabetes mellitus (T2DM). However, the molecular mechanisms underlying these processes especially their interactions have not been fully elucidated. OBJECTIVE: To explore the potential role of ER stress-mitochondrial oxidative stress in atrial remodeling and AF induction in diabetes. METHODS AND RESULTS: Mouse atrial cardiomyocytes (HL-1 cells) and rats with T2DM were used as study models. Significant ER stress was observed in the diabetic rat atria. After treatment with tunicamycin (TM), an ER stress agonist, mass spectrometry (MS) identified several known ER stress and calmodulin proteins, including heat shock protein family A (HSP70) member [HSPA] 5 [GRP78]) and HSPA9 (GRP75, glucose-regulated protein 75). In situ proximity ligation assay indicated that TM led to increased protein expression of the IP3R1-GRP75-VDAC1 (inositol 1,4,5-trisphosphate receptor 1-glucose-regulated protein 75-voltage-dependent anion channel 1) complex in HL-1 cells. Small interfering RNA silencing of GRP75 in HL-1 cells and GRP75 conditional knockout in a mouse model led to impaired calcium transport from the ER to the mitochondria and alleviated mitochondrial oxidative stress and calcium overload. Moreover, GRP75 deficiency attenuated atrial remodeling and AF progression in Myh6-Cre+/Hspa9flox/flox + TM mice. CONCLUSIONS: The IP3R1-GRP75-VDAC1 complex mediates ER stress-mitochondrial oxidative stress and plays an important role in diabetic atrial remodeling.
Assuntos
Remodelamento Atrial , Diabetes Mellitus Tipo 2 , Animais , Cálcio/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Glucose/metabolismo , Proteínas de Choque Térmico HSP70 , Receptores de Inositol 1,4,5-Trifosfato/genética , Proteínas de Membrana , Camundongos , Estresse Oxidativo , Ratos , Tunicamicina , Canal de Ânion 1 Dependente de Voltagem/metabolismoRESUMO
T-wave alternans (TWA) reflects every-other-beat alterations in the morphology of the electrocardiogram ST segment or T wave in the setting of a constant heart rate, hence, in the absence of heart rate variability. It is believed to be associated with the dispersion of repolarization and has been used as a non-invasive marker for predicting the risk of malignant cardiac arrhythmias and sudden cardiac death as numerous studies have shown. This review aims to provide up-to-date review on both experimental and simulation studies in elucidating possible mechanisms underlying the genesis of TWA at the cellular level, as well as the genesis of spatially concordant/discordant alternans at the tissue level, and their transition to cardiac arrhythmia. Recent progress and future perspectives in antiarrhythmic therapies associated with TWA are also discussed.
RESUMO
BACKGROUND: The Intelligent Medical Diagnosis System (IMDS) has been targeted by the cyber attackers, who aim to damage the Healthcare Critical National Infrastructure (CNI). This research is motivated by the recent cyber attacks happened worldwide that have resulted in the compromise of medical diagnosis records. This study was conducted to demonstrate how the IMDS could be attacked and diagnosis records compromised (i.e. heart disease) and suggest a list of security defence strategies to prevent against such attacks. METHODS: This research developed an IMDS simulation platform by implementing the OpenEMR system. A Cardiac Diagnosis Component is then added to the IMDS. The IMDS is fed with the ECG data (retrieved from the PhysioNet/Computing in Cardiology Challenge 2017). This research then launched systematic ethical hacking, which was tailored to target IMDS diagnosis records. The systematic hacking was based on the NIST ethical hacking method and followed an attack pathway, starting from identifying the entry points of the medical websites, then propagating to gain access to the server, with the ultimate aim of modifying the heart disease diagnosis records. RESULTS: The hacking was successful. Four major vulnerabilities (i.e. broken authentication, broken access control, security misconfiguration and using components with known vulnerabilities) were identified in the simulated IMDS and the cardiac diagnosis records were compromised. This research then proposed a list of security defence strategies to prevent such attacks at each possible attacking points along the attacking pathway. CONCLUSIONS: This research demonstrated a systematic ethical hacking to the IMDS, identified four major vulnerabilities and proposed the security defence pathways. It provided novel insights into the protection of IMDS and will benefit researchers in the community to conduct further research in security defence of IMDS.
Assuntos
Segurança Computacional , HumanosRESUMO
AIMS: The Intelligence Medical Diagnosis System (IMDS) has been targeted by the cyber terrorists, who aim to destroy the Critical National Infrastructure (CNI). This paper is motivated by the most recent incidents happened worldwide and have resulted in the compromise of diagnosis results. This study was undertaken to show how the IMDS could be attacked and diagnosis results compromised and present a set of cyber defense strategies to prevent against such attacks. METHODS AND RESULTS: This study used the ECGs data from the PhysioNet/Computing in Cardiology (CinC) Challenge 2017. We fed the data into our IMDS and launched a series of ethical hacking, which is specifically tailored to target IMDS. We proposed a set of cyber security strategies to prevent such compromise. We tested the effectiveness of our cyber defense strategies using an experiment. The results showed that the strategies were effective in protecting the IMDS diagnosis results from being compromised. CONCLUSIONS: This study provides novel insights into the protection of IMDS and concludes that our cyber defense strategies can protect IMDS from being compromised by Brute Force and SQL Injection attacks.
Assuntos
Segurança Computacional , Informática Médica , Sistemas Computadorizados de Registros MédicosRESUMO
Due to the inevitable drawbacks of the implantable electrical pacemaker, the biological pacemaker was believed to be an alternative therapy for heart failure. Previous experimental studies have shown that biological pacemaker could be produced by genetically manipulating non-pacemaking cardiac cells by suppressing the inward rectifier potassium current (IK1) and expressing the hyperpolarization- activated current (If). However, the role of If in such bio-engineered pacemaker is not clear. In this study, we simulated the action potential of biological pacemaker cells by manipulating If-IK1 parameters (i.e., inhibiting IK1 as well as incorporating If) to analyze possible mechanisms by which different If densities control pacemaking action potentials. Our simulation results showed different pacing mechanism between the bioengineered pacemaking cells with and without If. In addition, it was shown that a greater If density might result in a slower pacing frequency, and excessive of it might produce an early-afterdepolarizations-like action potential due to a sudden release of calcium from sarcoplasmic reticulum into the cytoplasm. This study indicated that when IK1 was significantly suppressed, incorporating If may not enhance the pacing ability of biological pacemaker, but lead to abnormal dynamics of intracellular ionic concentration, increasing risks of dysrhythmia in the heart.
Assuntos
Potenciais de Ação , Marca-Passo Artificial , Nó Sinoatrial , Bioengenharia , Relógios Biológicos , Cálcio , Humanos , Modelos Biológicos , Retículo SarcoplasmáticoRESUMO
AIMS: Short QT syndrome (SQTS) arises due to gene mutations leading to accelerated ventricular repolarization, and increased risk of cardiac arrhythmias and sudden cardiac death (SCD). The SQT1, SQT2 and SQT3 variants of the SQTS result from inherited gain-of-function mutations (e.g. N588K, V307L and D172N, respectively) to potassium channels. However, the effective management of SQTS remains a challenge, and is incompletely understood. In this study, computational modelling was used to investigate pharmacotherapeutic effects of selected class I drug quinidine on SQT1, SQT2 and SQT3 variants. METHODS AND RESULTS: The biophysically-detailed Stewart et al. model of Purkinje fibre cell action potentials and the ten Tusscher et al. model of ventricular cell action potentials were coupled together into a heterogeneous two-dimensional (2D) tissue model. Previously validated IKr, IKs and IK1 channel formulations for SQT1, SQT2 and SQT3 were incorporated in ventricular cell and tissue models. The channel-blocking effects of quinidine on ionic currents were modelled by using Hill coefficient and IC50 values from the literature. At the 10 µM concentration tested in this study, quinidine effectively prolonged the action potential duration (APD) under all the SQT1, SQT2 and SQT3 conditions. In 2D simulations, quinidine prolonged the ventricular repolarization process and prolonged the QT intervals under all SQTS variants conditions. CONCLUSIONS: Our findings provide a rational basis for the pursuit of pharmacotherapeutic agent quinidine in the treatment of all SQTS variants.
Assuntos
Antiarrítmicos , Arritmias Cardíacas/tratamento farmacológico , Quinidina , Potenciais de Ação , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Coração , Ventrículos do Coração , Humanos , Modelos Biológicos , Quinidina/farmacologia , Quinidina/uso terapêuticoRESUMO
AIMS: The short QT syndrome (SQTS) is a rare genetic disorder associated with arrhythmias and sudden cardiac death (SCD). The SQTI and SQT3, SQTS variants, result from gain-of-function mutations (N588K and D172N, respectively) in the KCNH2-encoded and KCNJ2-encoded potassium channels, in which treatment with potassium channel blocking agents has demonstrated some efficacy. This study used in silico modelling to gain mechanistic insights into the actions of anti-malarial drug chloroquine (CQ) in the setting of SQTI and SQT3. METHODS AND RESULTS: The ten Tusscher et al. human ventricle model was modified to a Markov chain formulation of $I_{J}$Assuntos
Arritmias Cardíacas
, Potenciais de Ação
, Cloroquina
, Eletrocardiografia
, Sistema de Condução Cardíaco
, Humanos
RESUMO
AIMS: Short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias. SQT1 variant (linked to the rapid delayed rectifier potassium channel current, IKr) of SQTS, results from an inactivation-attenuated, gain-of-function mutation (N588K) in the KCNH2-encoded potassium channels. Pro-arrhythmogenic effects of SQT1 have been well characterized, but less is known about the possible pharmacological antiarrhythmic treatment of SQT1. Therefore, this study aimed to assess the potential effects of E-4031, disopyramide and quinidine on SQT1 using a mathematical model of human ventricular electrophysiology. METHODS: The ten Tusscher et al. biophysically detailed model of the human ventricular action potential (AP) was modified to incorporate IKr Markov chain (MC) formulations based on experimental data of the kinetics of the N588K mutation of the KCNH2-encoded subunit of the IKr channels. The modified ventricular cell model was then integrated into one-dimensional (1D) strand, 2D regular and realistic tissues with transmural heterogeneities. The channel-blocking effect of the drugs on ion currents in healthy and SQT1 cells was modeled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values from literatures. Effects of drugs on cell AP duration (APD), effective refractory period (ERP) and pseudo-ECG traces were calculated. Effects of drugs on the ventricular temporal and spatial vulnerability to re-entrant excitation waves were measured. Re-entry was simulated in both 2D regular and realistic ventricular tissue. RESULTS: At the single cell level, the drugs E-4031 and disopyramide had hardly noticeable effects on the ventricular cell APD at 90% repolarization (APD90), whereas quinidine caused a significant prolongation of APD90. Quinidine prolonged and decreased the maximal transmural AP heterogeneity (δV); this led to the decreased transmural heterogeneity of APD across the 1D strand. Quinidine caused QT prolongation and a decrease in the T-wave amplitude, and increased ERP and decreased temporal susceptibility of the tissue to the initiation of re-entry and increased the minimum substrate size necessary to prevent re-entry in the 2D regular model, and further terminated re-entrant waves in the 2D realistic model. Quinidine exhibited significantly better therapeutic effects on SQT1 than E-4031 and disopyramide. CONCLUSIONS: The simulated pharmacological actions of quinidine exhibited antiarrhythmic effects on SQT1. This study substantiates a causal link between quinidine and QT interval prolongation in SQT1 and suggests that quinidine may be a potential pharmacological agent for treating SQT1 patients.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Disopiramida/farmacologia , Piperidinas/farmacologia , Piridinas/farmacologia , Quinidina/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Linhagem Celular , Disopiramida/uso terapêutico , Canal de Potássio ERG1/genética , Eletrocardiografia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Modelos Biológicos , Piperidinas/uso terapêutico , Polimorfismo de Nucleotídeo Único , Piridinas/uso terapêutico , Quinidina/uso terapêuticoRESUMO
OBJECTIVE: Short QT syndrome (SQTS) is an inherited cardiac channelopathy, but at present little information is available on its pharmacological treatment. SQT3 variant (linked to the inward rectifier potassium current I K1) of SQTS, results from a gain-of-function mutation (Kir2.1 D172N) in the KCNJ2-encoded channels, which is associated with ventricular fibrillation (VF). Using biophysically-detailed human ventricular computer models, this study investigated the potential effects of quinidine, disopyramide, and E-4031 on SQT3. APPROACH: The ten Tusscher et al model of human ventricular myocyte action potential (AP) was modified to recapitulate the changes in I K1 due to heterozygous and homozygous forms of the D172N mutation. Wild-type (WT) and mutant WT-D172N and D172N formulations were incorporated into one-dimensional (1D) and 2D tissue models with transmural heterogeneities. Effects of drugs on channel-blocking activity were modelled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values. Effects of drugs on AP duration (APD), effective refractory period (ERP) and QT interval of pseudo-ECGs were quantified, and both temporal and spatial vulnerability to re-entry was measured. Re-entry was simulated in the 2D ventricular tissue. MAIN RESULTS: At the single cell level, the drugs quinidine, disopyramide, and E-4031 prolonged APD at 90% repolarization (APD90), and decreased maximal transmural voltage heterogeneity (δV); this caused the decreased transmural dispersion of APD90. Quinidine prolonged the QT interval and decreased the T-wave amplitude. Furthermore, quinidine increased ERP and reduced temporal vulnerability and increased spatial vulnerability, resulting in a reduced susceptibility to arrhythmogenesis in SQT3. In the 2D tissue, quinidine was effective in terminating and preventing re-entry associated with the heterozygous D172N condition. Quinidine exhibited significantly better therapeutic effects on SQT3 than disopyramide and E-4031. SIGNIFICANCE: This study substantiates a causal link between quinidine and QT interval prolongation in SQT3 Kir2.1 mutations and highlights possible pharmacological agent quinidine for treating SQT3 patients.
Assuntos
Arritmias Cardíacas/tratamento farmacológico , Disopiramida/farmacologia , Sistema de Condução Cardíaco/anormalidades , Cardiopatias Congênitas/tratamento farmacológico , Ventrículos do Coração/efeitos dos fármacos , Modelos Biológicos , Piperidinas/farmacologia , Piridinas/farmacologia , Quinidina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Disopiramida/uso terapêutico , Sistema de Condução Cardíaco/patologia , Sistema de Condução Cardíaco/fisiopatologia , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/fisiopatologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Quinidina/uso terapêuticoRESUMO
A gain-of-function KCNJ2 D172N mutation in KCNJ2-encoded Kir2.1 channels underlies one form of short QT syndrome (SQT3), which is associated with increased susceptibility to arrhythmias and sudden death. Anti-malarial drug chloroquine was reported as an effective inhibitor of Kir2.1 channels. Using biophysically-detailed human ventricle computer models, this study assessed the effects of chloroquine on SQT3. The ten Tusscher et al. model of human ventricular cell action potential was modified to recapitulate functional changes in the inward rectifier K+ current (IK1) due to heterozygous and homozygous forms of the D172N mutation. Mutant formulations were incorporated into multi-scale models. The blocking effects of chloroquine on ionic currents were modelled using IC50 and Hill coefficient values from literatures. Effects of chloroquine on action potential duration (APD), effective refractory period (ERP) and pseudo-ECGs were quantified. It was shown that chloroquine caused a dose-dependent reduction in IK1, prolonged APD, and decreased the maximum voltage heterogeneity. Chloroquine prolonged QT interval and declined the T-wave amplitude. Although chloroquine reduced tissue's temporal vulnerability, it increased the minimum substrate size necessary for sustaining re-entry. The actions of chloroquine decreased arrhythmia risk, due to the reduced tissue vulnerability, prolonged ERP and wavelength of re-entrant excitation waves, which in combination prevented and terminated re-entry in the tissue models. In conclusion, the results of this study provide new evidence that the anti-arrhythmic effects of chloroquine on SQT3 and, by extension, to the possibility that chloroquine may be a potential therapeutic agent for SQT3 treatment.
RESUMO
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.
Assuntos
Cardiotoxicidade , Avaliação Pré-Clínica de Medicamentos/métodos , Coração/efeitos dos fármacos , Testes de Toxicidade/métodos , Animais , HumanosRESUMO
Bradycardia is found to be a complication during catecholaminergic polymorphic ventricular tachycardia in which calcium leak plays a pivotal role. In this computational study, we determined the effects of sarcoplasmic reticulum calcium leak on the function of sino-atrial node and ventricular model cells.