Association with the nonparoxysmal atrial fibrillation duration and outcome of ExTRa Mapping-guided rotor ablation.

Background: Additional ablation strategies after pulmonary vein isolation (PVI) for patients with nonparoxysmal atrial fibrillation (non-PAF) lasting ≥2 years have not been fully effective. This is presumably because of insufficient identification of non-PAF maintenance mechanisms. In this study, we employed a novel online and real-time phase mapping system, ExTRa Mapping, to identify and modulate rotors as one of the non-PAF maintenance mechanisms in patients with non-PAF sustained after PVI. We investigated the relationship between outcomes of ExTRa Mapping-guided rotor ablation (ExTRa-ABL) and non-PAF duration prior to this procedure. Methods: This study consisted of 73 non-PAF patients (63 ± 8 years, non-PAF duration 31 ± 37 months) who underwent the first ExTRa-ABL in patients with non-PAF sustained after completion of PVI. Results: Freedom from non-PAF/atrial tachycardia (AT) recurrence at 12 months after ExTRa-ABL was achieved in 50 (69%) of patients. The non-PAF duration prior to ExTRa-ABL was significantly longer in patients with non-PAF/AT recurrence after ExTRa-ABL compared with those without (56 ± 50 vs. 19 ± 22 months, p = .001). In patients with non-PAF duration of ≤60 months prior to ExTRa-ABL, compared with >60 months, non-PAF/AT-free rate was significantly higher (68.9% vs. 23.1%, p < .001), during the follow-up of 36 ± 18 months. Conclusions: A non-PAF duration of ≤60 months prior to ExTRa-ABL was associated with a better outcome. The effect of ExTRa-ABL was considered to be limited in patients with >60 months of non-PAF duration.

Organization of atrial fibrillation using a pure sodium channel blocker: Implications of rotor ablation therapy.

Background: Rotors are the source of atrial fibrillation (AF). However, the ablation of rotors for persistent AF is challenging. The purpose of this study was to identify the dominant rotor by accelerating the organization of AF using a sodium channel blocker and detecting the rotor's preferential area that governs AF. Methods: Overall, 30 consecutive patients with persistent AF who underwent pulmonary vein isolation and still sustained AF were enrolled. Pilsicainide 50 mg was administered. An online real-time phase mapping system (ExTRa Mapping™) was used to identify the meandering rotors and multiple wavelets in 11 left atrial segments. The time ratio of non-passive activation (%NP) was evaluated as the frequency of rotor activity in each segment. Results: Conduction velocity became slower-from 0.46 ± 0.14 to 0.35 ± 0.14 mm/ms (p = .004)-and the rotational period of the rotor was significantly prolonged-156 ± 21 to 193 ± 28 ms/cycle (p < .001). AF cycle length was prolonged from 169 ± 19 to 223 ± 29 ms (p < .001). A decrease in %NP was observed in seven segments. Additionally, 14 patients had at least one complete passive activation area. Of them, the use of high %NP area ablation resulted in atrial tachycardia and sinus rhythm in two patients each. Conclusions: A sodium channel blocker organized persistent AF. In selective patients with a wide organized area, high %NP area ablation could convert AF into atrial tachycardia or terminate AF.

Effect of pulmonary vein isolation on rotor/multiple wavelet dynamics in persistent atrial fibrillation, association with vagal response and implications for adjunctive ablation.

Persistent atrial fibrillation (PeAF) may develop arrhythmogenic substrates of rotors/multiple wavelets. However, the ways in which pulmonary vein isolation (PVI) affects the dynamics of rotor/multiple wavelets in PeAF patients remain elusive. Real-time phase-mapping (ExTRa mapping, EXT) in the whole left atrium (LA) was performed during PeAF before and after PVI (n = 111). The percentage of time in which rotor/multiple wavelets (phase singularities) was observed during each 5-s phase-mapping recording (non-passive activation ratio, %NP) was measured as an index of its burden. The mapping areas showing %NP ≥ 50% were defined as rotor/multiple-wavelet substrates (RSs). Before PVI, RSs were globally distributed in the LA. After PVI, %NP decreased (< 50%) in many RSs (PVI-modifiable RSs) but remained high (≥ 50%) in some RSs, especially localized in the anterior/septum/inferior regions (PVI-unmodifiable RSs, 2.3 ± 1.0 areas/patient). Before PVI, vagal response (VR) to high-frequency stimulation was observed in 23% of RSs, especially localized in the inferior region. VR disappearance after PVI was more frequently observed in PVI-modifiable RSs (79%) than in PVI-unmodifiable RSs (55%, p < 0.05), suggesting that PVI affects autonomic nerve activities and rotor/multiple wavelet dynamics. PVI-unmodifiable RSs were adjunctively ablated in 104 patients. The 1-year AT/AF-free survival rate was 70% in those with PVI alone (n = 115), and 86% in patients with the adjunctive ablation (log-rank test = 7.65, p < 0.01). PVI suppresses not only ectopic firing but also rotor/multiple wavelets partly via modification of autonomic nerve activities. The adjunctive ablation of PVI-unmodifiable RSs improved the outcome in PeAF patients and might be a novel ablation strategy beyond PVI.

Excessive folic acid intake combined with undernutrition during gestation alters offspring behavior and brain monoamine profiles.

Dietary folic acid augmentation during gestation reduces neurodevelopmental disorder risk in offspring; however, it is still unclear if excessive maternal folic acid intake can impair brain function in offspring. We examined if excessive folic acid intake throughout gestation altered the behavior of male offspring under poor nutrition during early gestation (E5.5-E11.5). Dams were divided into four groups: control (CON, 2 mg folic acid/kg of food), excessive folic acid fortification (FF, 10 mg folic acid/kg of food), undernutrition (UN, 40% food reduction from E5.5-E11.5), and excessive folic acid fortification plus undernutrition (UN-FF). Excess maternal folic acid fortification induced hyperactivity in the open-field and lower anxiety-like behavior in the elevated plus maze at 9 weeks of age. These behavioral changes were accompanied by reduced dopamine in the prefrontal cortex (PFC), norepinephrine in the amygdala, and 5-hydroxytryptamine (5-HT) in the dorsal midbrain (DM), PFC, and amygdala where 5-HT neurons project from the DM. Furthermore, canonical discriminant analysis, including dopamine and DOPAC concentrations in the PFC, norepinephrine concentrations in the PFC, amygdala, and pons, and 5-HT and 5-HIAA concentrations in the amygdala and DM, correctly classified 73.5% of the offspring in CON, FF, UN, and UN-FF groups. The first discriminant function mainly classified groups based on nutritional status, whereas the second function mainly classified groups based on folic acid intake. Our study suggests that combined transformations of brain monoamine profiles by maternal undernutrition and excess folic acid intake is involved in the behavioral alteration of offsprings.

The impact of the atrial wall thickness in normal/mild late-gadolinium enhancement areas on atrial fibrillation rotors in persistent atrial fibrillation patients.

Background: Some of atrial fibrillation (AF) drivers are found in normal/mild late-gadolinium enhancement (LGE) areas, as well as moderate ones. The atrial wall thickness (AWT) has been reported to be important as a possible AF substrate. However, the AWT and degree of LGEs as an AF substrate has not been fully validated in humans. Objective: The purpose of this study was to evaluate the impact of the AWT in normal/mild LGE areas on AF drivers. Methods: A total of 287 segments in 15 persistent AF patients were assessed. AF drivers were defined as non-passively activated areas (NPAs), where rotational activation was frequently observed, and were detected by the novel real-time phase mapping (ExTRa Mapping), mild LGE areas were defined as areas with a volume ratio of the enhancement voxel of 0% to <10%. The AWT was defined as the minimum distance from the manually determined endocardium to the epicardial border on the LGE-MRI. Results: NPAs were found in 20 (18.0%) of 131 normal/mild LGE areas where AWT was significantly thicker than that in the passively activated areas (PAs) (2.5 ± 0.3 vs. 2.2 ± 0.3 mm, p < .001). However, NPAs were found in 41 (26.3%) of 156 moderate LGE areas where AWT was thinner than that of PAs (2.1 ± 0.2 mm vs. 2.23 ± 0.3 mm, p = .02). An ROC curve analysis yielded an optimal cutoff value of 2.2 mm for predicting the presence of an NPA in normal/mild LGE areas. Conclusion: The location of AF drivers in normal/mild LGE areas might be more accurately identified by evaluating AWT.

High accessory pathway conductivity blocks antegrade conduction in Wolff-Parkinson-White syndrome: A simulation study.

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is characterized by an anomalous accessory pathway (AP) that connects the atrium and ventricles, which can cause abnormal myocardial excitation and cardiac arrhythmias. The morphological and electrophysiological details of the AP remain unclear. The size and conductivity of the AP may affect conduction and WPW syndrome symptoms. METHODS: To clarify this issue, we performed computer simulations of antegrade AP conduction using a simplified wall model. We focused on the bundle size of the AP and myocardial electrical conductivity during antegrade conduction (from the atrium to the ventricle). RESULTS: We found that a thick AP and high ventricular conductivity promoted antegrade conduction, whereas a thin AP is unable to deliver the transmembrane current required for electric conduction. High ventricular conductivity amplifies transmembrane current. These findings suggest the involvement of a source-sink mechanism. Furthermore, we found that high AP conductivity blocked antegrade conduction. As AP conductivity increased, sustained outward transmembrane currents were observed. This finding suggests the involvement of an electrotonic effect. CONCLUSIONS: The findings of our theoretical simulation suggest that AP size, ventricular conductivity, and AP conductivity affect antegrade conduction through different mechanisms. Our findings provide new insights into the morphological and electrophysiological details of the AP.

Heart sound recognition technology based on convolutional neural network.

The mortality rate of heart disease continues to rise each year: developing mechanisms to reduce mortality from heart disease is a top concern in today's society. Heart sound auscultation is a crucial skill used to detect and diagnose heart disease. In this study, we propose a heart sound signal classification algorithm based on a convolutional neural network. The algorithm is based on heart sound data collected in the clinic and from medical books. The heart sound signals were first preprocessed into a grayscale image of 5 seconds. The training samples were then used to train and optimize the convolutional neural network; obtaining a training result with an accuracy of 95.17% and a loss value of 0.23. Finally, the convolutional neural network was used to test the test set samples. The results showed an accuracy of 94.80%, sensitivity of 94.29%, specificity of 95.54%, precision of 93.44%, F1_score of 93.84%, and an AUC of 0.943. Compared with other algorithms, the accuracy and sensitivity of the algorithms were improved. This shows that the method used in this study can effectively classify heart sound signals and could prove useful in assisting heart sound auscultation.

Late-gadolinium enhancement properties associated with atrial fibrillation rotors in patients with persistent atrial fibrillation.

BACKGROUND: A computational model demonstrated that atrial fibrillation (AF) rotors could be distributed in patchy late-gadolinium enhancement (LGE) areas and play an important role in AF drivers. However, this was not validated in humans. OBJECTIVE: The purpose of this study was to evaluate the LGE properties of AF rotors in patients with persistent AF. METHODS: A total of 287 segments in 15 patients with persistent AF (long-standing persistent AF in 9 patients) that underwent AF ablation were assessed. Non-passively activated areas (NPAs), where rotational activation (AF rotor) was frequently observed, were detected by the novel real-time phase mapping (ExTRa Mapping). The properties of the LGE areas were assessed using the LGE heterogeneity and the density which was evaluated by the entropy (LGE-entropy) and the volume ratio of the enhancement voxel (LGE-volume ratio), respectively. RESULTS: NPAs were found in 61 (21%) of 287 segments and were mostly found around the pulmonary vein antrum. A receiver operating characteristic curve analysis yielded an optimal cutoff value of 5.7% and 10% for the LGE-entropy and LGE-volume ratio, respectively. The incidence of NPAs was significantly higher at segments with an LGE-entropy of >5.7 and LGE-volume ratio of >10% than at the other segments (38 [30%] of 126 vs. 23 [14%] of 161 segments; p = .001). No NPAs were found at segments with an LGE-volume ratio of >50% regardless of the LGE-entropy. Of five patients with AF recurrence, NPAs outside the PV antrum were not ablated in three patients and the remaining NPAs were ablated, but their LGE-entropy and LGE-volume ratio were low. CONCLUSION: AF rotors are mostly distributed in relatively weak and much more heterogenous LGE areas.

Spatial phase discontinuity at the center of moving cardiac spiral waves.

BACKGROUND: Precise analysis of cardiac spiral wave (SW) dynamics is essential for effective arrhythmia treatment. Although the phase singularity (PS) point in the spatial phase map has been used to determine the cardiac SW center for decades, quantitative detection algorithms that assume PS as a point fail to trace complex and rapid PS dynamics. Through a detailed analysis of numerical simulations, we examined our hypothesis that a boundary of spatial phase discontinuity induced by a focal conduction block exists around the moving SW center in the phase map. METHOD: In a numerical simulation model of a 2D cardiac sheet, three different types of SWs (short wavelength; long wavelength; and low excitability) were induced by regulating ion channels. Discontinuities of all boundaries among adjacent cells at each instance were evaluated by calculating the phase bipolarity (PB). The total amount of phase transition (PTA) in each cell during the study period was evaluated. RESULTS: Pivoting, drifting, and shifting SWs were observed in the short-wavelength, low-excitability, and long-wavelength models, respectively. For both the drifting and shifting cases, long high-PB edges were observed on the SW trajectories. In all cases, the conduction block (CB) was observed at the same boundaries. These were also identical to the boundaries in the PTA maps. CONCLUSIONS: The analysis of the simulations revealed that the conduction block at the center of a moving SW induces discontinuous boundaries in spatial phase maps that represent a more appropriate model of the SW center than the PS point.

Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome.

Reduced cardiac sodium (Na+) channel current (INa) resulting from the loss-of-function of Na+ channel is a major cause of lethal arrhythmias in Brugada syndrome (BrS). Inspired by previous experimental studies which showed that in heart diseases INa was reduced along with expression changes in Na+ channel within myocytes, we hypothesized that the local decrease in INa caused by the alteration in Na+ channel expression in myocytes leads to the occurrence of phase-2 reentry, the major triggering mechanism of lethal arrhythmias in BrS. We constructed in silico human ventricular myocardial strand and ring models, and examined whether the Na+ channel expression changes in each myocyte cause the phase-2 reentry in BrS. Reducing Na+ channel expression in the lateral membrane of each myocyte caused not only the notch-and-dome but also loss-of-dome type action potentials and slowed conduction, both of which are typically observed in BrS patients. Furthermore, the selective reduction in Na+ channels on the lateral membrane of each myocyte together with spatial tissue heterogeneity of Na+ channel expression caused the phase-2 reentry and phase-2 reentry-mediated reentrant arrhythmias. Our data suggest that the BrS phenotype is strongly influenced by expression abnormalities as well as genetic abnormalities of Na+ channels.

Validation of Intraoperative Catheter Phase Mapping Using a Simultaneous Optical Measurement System in Rabbit Ventricular Myocardium.

BACKGROUND: Recently, an interoperative catheter electrode mapping system, termed ExTRa Mapping (EXT), was developed for precise diagnosis and effective treatment of non-paroxysmal atrial fibrillations (non-PAF). However, the mapping accuracy of EXT is still unclear.Methods and Results:In this study, the reliability of the EXT in comparison with that of high-resolution optical membrane potential mapping was compared. Spiral wave re-entries (SWRs) were induced in the excised rabbit hearts (n=8, 42 episodes). Electrical signals were measured by electrodes on a transparent silicone plate, with the same arrangement as in the clinical catheter, and fluorescence signals were recorded simultaneously across the plate. Based on the phase maps derived by EXT, activation patterns (one-directed propagations: 26, rotational activities: 16) were identified correctly with 95% accuracy (40/42), and the correlation coefficient of the ratio of the non-passive period was 0.95. In the rotational episodes (15), the mean position error of the centers of gravity of the SWR trajectory (2,000 ms) was 2.0 mm. For the one-directional episodes (25), the correlation coefficient of the directions of one-way propagation was 0.99. CONCLUSIONS: The phase map sequence by EXT is consistent with that by the analyses of high-resolution optical mapping. EXT is reliable for analyzing the activation pattern in the region of interest.

Impact of Box Isolation on Rotors and Multiple Wavelets in Persistent Atrial Fibrillation.

BACKGROUND: Additional benefits of posterior left atrial (LA) box isolation (BOXI) over pulmonary vein isolation (PVI) in persistent atrial fibrillation (perAF) have been reported, but the mechanism is still unclear. We evaluated the effects of BOXI on rotors and multiple wavelets in the whole LA.Methods and Results:Twenty patients with perAF (including 12 cases of longstanding perAF) underwent PVI. Real-time phase mapping (ExTRa Mapping) was performed in the whole LA during AF. Subsequently, BOXI was added and re-ExTRa Mapping was performed again at the same site. The nonpassively activated ratio (%NP), the ratio of the form of rotors and multiple wavelets to the recording time, was compared before and after BOXI. After BOXI, the %NP significantly decreased in the anterior wall (from 53±22% to 39±23%, P=0.010), inferior wall (from 51±16% to 34±19%, P=0.001), and LA appendage (from 23±27% to 16±19%, P=0.049). However, there were no significant differences in the septum (49±19% vs. 49±18%, P=0.562) or lateral wall (41±19% vs. 38±15%, P=0.526). CONCLUSIONS: BOXI not only reduced the critical mass for maintenance of AF, but also decreased the rotors and multiple wavelets in the anterior wall, inferior wall and LA appendage during perAF.

Successful modulation of atrial fibrillation drivers anchoring to fibrotic tissue after box isolation using an online real-time phase mapping system: ExTRa Mapping.

A 41-year-old man with persistent atrial fibrillation (AF) underwent radiofrequency (RF) catheter ablation using an online real-time phase mapping system: ExTRa Mapping. Box isolation could not terminate AF. Subsequently, RF applications on nonpassively activated areas (NPAs), where rotational activations were frequently observed, at the posterior bottom of left atrium outside of box lesion could convert AF to common atrial flutter. Of interest, the NPA near the posterior bottom were located on the patchy fibrotic tissue area assessed by the late-gadolinium enhancement magnetic resonance imaging. This indicated the possibility of the critical AF rotor meandering through the fibrotic tissue area.

Systematic expression analysis of genes related to generation of action potentials in human iPS cell-derived cardiomyocytes.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a valuable tool to characterize the pharmacology and toxic effects of drugs on heart cells. In particular, hiPSC-CMs can be used to identify drugs that generate arrhythmias. However, it is unclear whether the expression of genes related to generation of CM action potentials differs between hiPSC-CM cell lines and the mature human heart. To address this, we obtained accurate gene expression profiles of commercially available hiPSC-CM cell lines with quantitative real time RT-PCR analysis. Expression analysis of ten cardiac proteins important for generation of action potentials and three cardiac proteins important for muscle contractility was performed using GAPDH for normalization. Comparison revealed large variations in expression levels among hiPSC-CM cell lines and between hiPSC-CMs and normal human heart. In general, gene expression in hiPSC-CM cell lines was more similar to an immature, stem-like cell than a mature cardiomyocyte from human heart samples. These results provide quantitative information about differences in gene expression between hiPSC-CM cell lines, essential for interpreting pharmacology experiments. Our approach can be used as an experimental guideline for future research on gene expression in hiPSC-CMs.

A de novo gain-of-function KCND3 mutation in early repolarization syndrome.

BACKGROUND: Early repolarization syndrome (ERS) is characterized by J-point elevation on electrocardiograms and ventricular fibrillation (VF). Early repolarization arises from augmentation of the transmural electrical gradient in the cardiac action potential; therefore, the transient outward potassium current (Ito) has been regarded as a key candidate current for elucidating the mechanism of ERS. KCND3 encoding Kv4.3, an α-subunit of the Ito channel, is considered as one of target genes. OBJECTIVE: The purpose of this study was to search for novel KCND3 mutations associated with ERS and to clarify the pathogenesis. METHODS: We performed genetic screening for 11 unrelated probands with ERS and analyzed the electrophysiological properties of detected mutations by patch-clamp methods. RESULTS: A novel de novo KCND3 heterozygous mutation, Gly306Ala (c.917g>c), was found in 1 proband. The proband was a 12-year-old boy, who suffered VF storm and showed significant J-point elevation in multiple leads. Intravenous isoproterenol and subsequent administration of quinidine were effective in preventing VF recurrence and restored the J-point elevation. In electrophysiological analysis, cultured cells expressing mutant Kv4.3 showed significantly increased current densities, slow inactivation, and slow recovery from inactivation compared to wild type. Extracellular application of quinidine significantly restored the inactivation time course in mutant Kv4.3. A simulation study confirmed the relationship between the novel KCND3 mutation and early repolarization on electrocardiograms. CONCLUSION: A novel KCND3 heterozygous mutation was found to be associated with ERS. The pathogenesis can be explained by the increased Ito. Genetic screening for KCND3 could be useful for understanding the pathogenesis and selecting effective treatment.

Not all rotors, effective ablation targets for nonparoxysmal atrial fibrillation, are included in areas suggested by conventional indirect indicators of atrial fibrillation drivers: ExTRa Mapping project.

Background: Effects of nonparoxysmal atrial fibrillation (non-PAF) ablation targeting complex fractionated atrial electrogram (CFAE) areas and/or low voltage areas (LVAs) are still controversial. Methods and Results: A recently developed online real-time phase mapping system (ExTRa Mapping) was used to conduct LVA mapping and simultaneous ExTRa and CFAE mapping in 28 non-PAF patients after pulmonary vein isolation (PVI). Nonpassively activated areas, in the form of meandering rotors and/or multiple wavelets assumed to contain non-PAF drivers, partly overlapped with CFAE/LVAs but not always coincided with them. Conclusion: Real-time rotor imaging, rather than conventional indirect indicators only, might be very useful for detecting non-PAF drivers.

Modelling Torsade de Pointes arrhythmias in vitro in 3D human iPS cell-engineered heart tissue.

Torsade de Pointes (TdP) is a lethal arrhythmia that is often drug-induced, thus there is an urgent need for development of models to test or predict the drug sensitivity of human cardiac tissue. Here, we present an in vitro TdP model using 3D cardiac tissue sheets (CTSs) that contain a mixture of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and non-myocytes. We simultaneously monitor the extracellular field potential (EFP) and the contractile movement of the CTSs. Upon treatment with IKr channel blockers, CTSs exhibit tachyarrhythmias with characteristics of TdP, including both a typical polymorphic EFP and meandering spiral wave re-entry. The TdP-like waveform is predominantly observed in CTSs with the cell mixture, indicating that cellular heterogeneity and the multi-layered 3D structure are both essential factors for reproducing TdP-like arrhythmias in vitro. This 3D model could provide the mechanistic detail underlying TdP generation and means for drug discovery and safety tests.

Overexpression of KCNJ2 in induced pluripotent stem cell-derived cardiomyocytes for the assessment of QT-prolonging drugs.

Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes hold great potentials to predict pro-arrhythmic risks in preclinical cardiac safety screening, although the hiPSC cardiomyocytes exhibit rather immature functional and structural characteristics, including spontaneous activity. Our physiological characterization and mathematical simulation showed that low expression of the inward-rectifier potassium (IK1) channel is a determinant of spontaneous activity. To understand impact of the low IK1 expression on the pharmacological properties, we tested if transduction of hiPSC-derived cardiomyocytes with KCNJ2, which encodes the IK1 channel, alters pharmacological response to cardiac repolarization processes. The transduction of KCNJ2 resulted in quiescent hiPSC-derived cardiomyocytes, which need pacing to elicit action potentials. Significant prolongation of paced action potential duration in KCNJ2-transduced hiPSC-derived cardiomyocytes was stably measured at 0.1 µM E-4031, although the same concentration of E-4031 ablated firing of non-treated hiPSC-derived cardiomyocytes. These results in single cells were confirmed by mathematical simulations. Using the hiPSC-derived cardiac sheets with KCNJ2-transduction, we also investigated effects of a range of drugs on field potential duration recorded at 1 Hz. The KCNJ2 overexpression in hiPSC-derived cardiomyocytes may contribute to evaluate a part of QT-prolonging drugs at toxicological concentrations with high accuracy.

Significance of integrated in silico transmural ventricular wedge preparation models of human non-failing and failing hearts for safety evaluation of drug candidates.

INTRODUCTION: To evaluate the usefulness of in silico assay in predicting drug-induced QTc prolongation and ventricular proarrhythmia, we describe in this study 2-dimensional transmural ventricular wedge preparation model (2D model) of non-failing (non-FH) and failing hearts (FH) based on O'Hara-Rudy dynamic model of human ventricular myocytes. METHODS: Using the prepared 2D model, we simulated ventricular action potential and recorded electrocardiogram for the non-FH and FH. The FH model was constructed based on differences in mRNA, protein, and/or current levels of ion channels between non-diseased heart and failing heart. To simulate the effects of selected drugs, we incorporated changes in ion channel conductance depending on the IC50 value and Hill coefficient at unbound drug blood concentrations. RESULTS: Dofetilide concentration-dependently induced QTc prolongation at therapeutic concentration in the 2D model of both non-FH and FH. The QTc prolongation in FH was longer than that in non-FH. These findings are consistent with previously reported clinical data. At supratherapeutic concentration 20nM, dofetilide induced Torsade de Pointes-like arrhythmia in the 2D non-FH model. In contrast, the single ventricular myocyte model did not quantitatively reproduce experimental data due to lack of electrotonic interaction. The simulated QTc change induced by six drugs examined in the IQ-CSRC prospective study was almost equivalent to that recorded in drug-treated healthy volunteers. DISCUSSION: Our 2D model with or without heart failure faithfully reproduced drug-induced QT prolongation and ventricular arrhythmias, suggesting that the in silico approach is a powerful tool for predicting cardiac safety of drug candidates at preclinical stage.