Additional coils mitigate elevated defibrillation threshold in right-sided implantable cardioverter defibrillator generator placement: a simulation study.

AIMS: The standard implantable cardioverter defibrillator (ICD) generator (can) is placed in the left pectoral area; however, in certain circumstances, right-sided cans may be required which may increase defibrillation threshold (DFT) due to suboptimal shock vectors. We aim to quantitatively assess whether the potential increase in DFT of right-sided can configurations may be mitigated by alternate positioning of the right ventricular (RV) shocking coil or adding coils in the superior vena cava (SVC) and coronary sinus (CS). METHODS AND RESULTS: A cohort of CT-derived torso models was used to assess DFT of ICD configurations with right-sided cans and alternate positioning of RV shock coils. Efficacy changes with additional coils in the SVC and CS were evaluated. A right-sided can with an apical RV shock coil significantly increased DFT compared to a left-sided can [19.5 (16.4, 27.1) J vs. 13.3 (11.7, 19.9) J, P < 0.001]. Septal positioning of the RV coil led to a further DFT increase when using a right-sided can [26.7 (18.1, 36.1) J vs. 19.5 (16.4, 27.1) J, P < 0.001], but not a left-sided can [12.1 (8.1, 17.6) J vs. 13.3 (11.7, 19.9) J, P = 0.099). Defibrillation threshold of a right-sided can with apical or septal coil was reduced the most by adding both SVC and CS coils [19.5 (16.4, 27.1) J vs. 6.6 (3.9, 9.9) J, P < 0.001, and 26.7 (18.1, 36.1) J vs. 12.1 (5.7, 13.5) J, P < 0.001]. CONCLUSION: Right-sided, compared to left-sided, can positioning results in a 50% increase in DFT. For right-sided cans, apical shock coil positioning produces a lower DFT than septal positions. Elevated right-sided can DFTs may be mitigated by utilizing additional coils in SVC and CS.

Optimization of anti-tachycardia pacing efficacy through scar-specific delivery and minimization of re-initiation: a virtual study on a cohort of infarcted porcine hearts.

AIMS: Anti-tachycardia pacing (ATP) is a reliable electrotherapy to painlessly terminate ventricular tachycardia (VT). However, ATP is often ineffective, particularly for fast VTs. The efficacy may be enhanced by optimized delivery closer to the re-entrant circuit driving the VT. This study aims to compare ATP efficacy for different delivery locations with respect to the re-entrant circuit, and further optimize ATP by minimizing failure through re-initiation. METHODS AND RESULTS: Seventy-three sustained VTs were induced in a cohort of seven infarcted porcine ventricular computational models, largely dominated by a single re-entrant pathway. The efficacy of burst ATP delivered from three locations proximal to the re-entrant circuit (septum) and three distal locations (lateral/posterior left ventricle) was compared. Re-initiation episodes were used to develop an algorithm utilizing correlations between successive sensed electrogram morphologies to automatically truncate ATP pulse delivery. Anti-tachycardia pacing was more efficacious at terminating slow compared with fast VTs (65 vs. 46%, P = 0.000039). A separate analysis of slow VTs showed that the efficacy was significantly higher when delivered from distal compared with proximal locations (distal 72%, proximal 59%), being reversed for fast VTs (distal 41%, proximal 51%). Application of our early termination detection algorithm (ETDA) accurately detected VT termination in 79% of re-initiated cases, improving the overall efficacy for proximal delivery with delivery inside the critical isthmus (CI) itself being overall most effective. CONCLUSION: Anti-tachycardia pacing delivery proximal to the re-entrant circuit is more effective at terminating fast VTs, but less so slow VTs, due to frequent re-initiation. Attenuating re-initiation, through ETDA, increases the efficacy of delivery within the CI for all VTs.

An automated near-real time computational method for induction and treatment of scar-related ventricular tachycardias.

Catheter ablation is currently the only curative treatment for scar-related ventricular tachycardias (VTs). However, not only are ablation procedures long, with relatively high risk, but success rates are punitively low, with frequent VT recurrence. Personalized in-silico approaches have the opportunity to address these limitations. However, state-of-the-art reaction diffusion (R-D) simulations of VT induction and subsequent circuits used for in-silico ablation target identification require long execution times, along with vast computational resources, which are incompatible with the clinical workflow. Here, we present the Virtual Induction and Treatment of Arrhythmias (VITA), a novel, rapid and fully automated computational approach that uses reaction-Eikonal methodology to induce VT and identify subsequent ablation targets. The rationale for VITA is based on finding isosurfaces associated with an activation wavefront that splits in the ventricles due to the presence of an isolated isthmus of conduction within the scar; once identified, each isthmus may be assessed for their vulnerability to sustain a reentrant circuit, and the corresponding exit site automatically identified for potential ablation targeting. VITA was tested on a virtual cohort of 7 post-infarcted porcine hearts and the results compared to R-D simulations. Using only a standard desktop machine, VITA could detect all scar-related VTs, simulating activation time maps and ECGs (for clinical comparison) as well as computing ablation targets in 48 minutes. The comparable VTs probed by the R-D simulations took 68.5 hours on 256 cores of high-performance computing infrastructure. The set of lesions computed by VITA was shown to render the ventricular model VT-free. VITA could be used in near real-time as a complementary modality aiding in clinical decision-making in the treatment of post-infarction VTs.

Determining anatomical and electrophysiological detail requirements for computational ventricular models of porcine myocardial infarction.

BACKGROUND: Computational models of the heart built from cardiac MRI and electrophysiology (EP) data have shown promise for predicting the risk of and ablation targets for myocardial infarction (MI) related ventricular tachycardia (VT), as well as to predict paced activation sequences in heart failure patients. However, most recent studies have relied on low resolution imaging data and little or no EP personalisation, which may affect the accuracy of model-based predictions. OBJECTIVE: To investigate the impact of model anatomy, MI scar morphology, and EP personalisation strategies on paced activation sequences and VT inducibility to determine the level of detail required to make accurate model-based predictions. METHODS: Imaging and EP data were acquired from a cohort of six pigs with experimentally induced MI. Computational models of ventricular anatomy, incorporating MI scar, were constructed including bi-ventricular or left ventricular (LV) only anatomy, and MI scar morphology with varying detail. Tissue conductivities and action potential duration (APD) were fitted to 12-lead ECG data using the QRS duration and the QT interval, respectively, in addition to corresponding literature parameters. Paced activation sequences and VT induction were simulated. Simulated paced activation and VT inducibility were compared between models and against experimental data. RESULTS: Simulations predict that the level of model anatomical detail has little effect on simulated paced activation, with all model predictions comparing closely with invasive EP measurements. However, detailed scar morphology from high-resolution images, bi-ventricular anatomy, and personalized tissue conductivities are required to predict experimental VT outcome. CONCLUSION: This study provides clear guidance for model generation based on clinical data. While a representing high level of anatomical and scar detail will require high-resolution image acquisition, EP personalisation based on 12-lead ECG can be readily incorporated into modelling pipelines, as such data is widely available.

An in-silico assessment of efficacy of two novel intra-cardiac electrode configurations versus traditional anti-tachycardia pacing therapy for terminating sustained ventricular tachycardia.

The implanted cardioverter defibrillator (ICD) is an effective direct therapy for the treatment of cardiac arrhythmias, including ventricular tachycardia (VT). Anti-tachycardia pacing (ATP) is often applied by the ICD as the first mode of therapy, but is often found to be ineffective, particularly for fast VTs. In such cases, strong, painful and damaging backup defibrillation shocks are applied by the device. Here, we propose two novel electrode configurations: "bipolar" and "transmural" which both combine the concept of targeted shock delivery with the advantage of reduced energy required for VT termination. We perform an in silico study to evaluate the efficacy of VT termination by applying one single (low-energy) monophasic shock from each novel configuration, comparing with conventional ATP therapy. Both bipolar and transmural configurations are able to achieve a higher efficacy (93% and 85%) than ATP (45%), with energy delivered similar to and two orders of magnitudes smaller than conventional ICD defibrillation shocks, respectively. Specifically, the transmural configuration (which applies the shock vector directly across the scar substrate sustaining the VT) is most efficient, requiring typically less than 1 J shock energy to achieve a high efficacy. The efficacy of both bipolar and transmural configurations are higher when applied to slow VTs (100% and 97%) compared to fast VTs (57% and 29%). Both novel electrode configurations introduced are able to improve electrotherapy efficacy while reducing the overall number of required therapies and need for strong backup shocks.

The Amplitude-Normalized Area of a Bipolar Electrogram as a Measure of Local Conduction Delay in the Heart.

BACKGROUND: Re-entrant ventricular tachycardia may be non-inducible or haemodynamically compromising, requiring assessment of the electrophysiological properties of the myocardium during sinus rhythm (i.e., substrate mapping). Areas of heart tissue with slow conduction can act as a critical isthmus for re-entrant electrical excitation and are a potential target for ablation therapy. AIM: To develop and validate a novel metric of local conduction delay in the heart, the amplitude-normalized electrogram area (norm_EA). METHODS: A computational model of a propagating mouse action potential was used to establish the impact of altering sodium channel conductance, intracellular conductivity, fibrosis density, and electrode size/orientation on bipolar electrogram morphology. Findings were then validated in experimental studies in mouse and guinea pig hearts instrumented for the recording of bipolar electrograms from a multipolar linear mapping catheter. norm_EA was calculated by integrating the absolute area of a bipolar electrogram divided by the electrogram amplitude. Electrogram metrics were correlated with the local conduction delay during sodium channel block, gap junction inhibition, and acute ischemia. RESULTS: In computational simulations, reducing sodium channel conductance and intracellular conductivity resulted in a decrease in signal amplitude and increase in norm_EA (reflecting a broadening of electrogram morphology). For larger electrodes (3 mm diameter/7.1 mm2 area), the change in norm_EA was essentially linear with the change in local conduction delay. Experimental studies supported this finding, showing that the magnitude of change in norm_EA induced by flecainide (1-4 µM), carbenoxolone (10-50 µM), and low-flow ischemia (25% of initial flow rate) was linearly correlated with the local conduction delay in each condition (r 2 = 0.92). Qualitatively similar effects were observed in guinea pig hearts perfused with flecainide. Increasing fibrosis density in the computational model also resulted in a decrease in signal amplitude and increase in norm_EA. However, this remains to be validated using experimental/clinical data of chronic infarct. CONCLUSION: norm_EA is a quantitative measure of local conduction delay between the electrode pair that generates a bipolar electrogram, which may have utility in electrophysiological substrate mapping of non-inducible or haemodynamically compromising tachyarrhythmia.

Left ventricular endocardial pacing is less arrhythmogenic than conventional epicardial pacing when pacing in proximity to scar.

BACKGROUND: Epicardial pacing increases risk of ventricular tachycardia (VT) in patients with ischemic cardiomyopathy (ICM) when pacing in proximity to scar. Endocardial pacing may be less arrhythmogenic as it preserves the physiological sequences of activation and repolarization. OBJECTIVE: The purpose of this study was to determine the relative arrhythmogenic risk of endocardial compared to epicardial pacing, and the role of the transmural gradient of action potential duration (APD) and pacing location relative to scar on arrhythmogenic risk during endocardial pacing. METHODS: Computational models of ICM patients (n = 24) were used to simulate left ventricular (LV) epicardial and endocardial pacing 0.2-3.5 cm from a scar. Mechanisms were investigated in idealized models of the ventricular wall and scar. Simulations were run with/without a 20-ms transmural APD gradient in the physiological direction and with the gradient inverted. Dispersion of repolarization was computed as a surrogate of VT risk. RESULTS: Patient-specific models with a physiological APD gradient predict that endocardial pacing decreases VT risk (34%; P <.05) compared to epicardial pacing when pacing in proximity to scar (0.2 cm). Endocardial pacing location does not significantly affect VT risk, but epicardial pacing at 0.2 cm compared to 3.5 cm from scar increases it (P <.05). Inverting the transmural APD gradient reverses this trend. Idealized models predict that propagation in the direction opposite to APD gradient decreases VT risk. CONCLUSION: Endocardial pacing is less arrhythmogenic than epicardial pacing when pacing proximal to scar and is less susceptible to pacing location relative to scar. The physiological repolarization sequence during endocardial pacing mechanistically explains reduced VT risk compared to epicardial pacing.

Pacing in proximity to scar during cardiac resynchronization therapy increases local dispersion of repolarization and susceptibility to ventricular arrhythmogenesis.

BACKGROUND: Cardiac resynchronization therapy (CRT) increases the risk of ventricular tachycardia (VT) in patients with ischemic cardiomyopathy (ICM) when the left ventricular (LV) epicardial lead is implanted in proximity to scar. OBJECTIVE: The purpose of this study was to determine the mechanisms underpinning this risk by investigating the effects of pacing on local electrophysiology (EP) in relation to scar that provides a substrate for VT in ICM patients undergoing CRT. METHODS: Imaging data from ICM patients (n = 24) undergoing CRT were used to create patient-specific LV anatomic computational models including scar morphology. Simulations of LV epicardial pacing at 0.2-4.5 cm from the scar were performed using EP models of chronic infarct and heart failure (HF). Dispersion of repolarization and the vulnerable window were computed as surrogates for VT risk. RESULTS: Simulations predict that pacing in proximity to scar (0.2 cm) compared to more distant pacing to a scar (4.5 cm) significantly (P <.01) increased dispersion of repolarization in the vicinity of the scar and widened (P <.01) the vulnerable window, increasing the likelihood of unidirectional block. Moreover, slow conduction during HF further increased dispersion (∼194%). Analysis of variance and post hoc tests show significantly (P <.01) reduced repolarization dispersion when pacing ≥3.5 cm from the scar compared to pacing at 0.2 cm. CONCLUSION: Increased dispersion of repolarization in the vicinity of the scar and widening of the vulnerable window when pacing in proximity to scar provides a mechanistic explanation for VT induction in ICM-CRT with lead placement proximal to scar. Pacing 3.5 cm or more from scar may avoid increasing VT risk in ICM-CRT patients.

Modeling the Electrophysiological Properties of the Infarct Border Zone.

Ventricular arrhythmias (VA) in patients with myocardial infarction (MI) are thought to be associated with structural and electrophysiological remodeling within the infarct border zone (BZ). Personalized computational models have been used to investigate the potential role of the infarct BZ in arrhythmogenesis, which still remains incompletely understood. Most recent models have relied on experimental data to assign BZ properties. However, experimental measurements vary significantly resulting in different computational representations of this region. Here, we review experimental data available in the literature to determine the most prominent properties of the infarct BZ. Computational models are then used to investigate the effect of different representations of the BZ on activation and repolarization properties, which may be associated with VA. Experimental data obtained from several animal species and patients with infarct show that BZ properties vary significantly depending on disease's stage, with the early disease stage dominated by ionic remodeling and the chronic stage by structural remodeling. In addition, our simulations show that ionic remodeling in the BZ leads to large repolarization gradients in the vicinity of the scar, which may have a significant impact on arrhythmia simulations, while structural remodeling plays a secondary role. We conclude that it is imperative to faithfully represent the properties of regions of infarction within computational models specific to the disease stage under investigation in order to conduct in silico mechanistic investigations.

Fibrosis Microstructure Modulates Reentry in Non-ischemic Dilated Cardiomyopathy: Insights From Imaged Guided 2D Computational Modeling.

Aims: Patients who present with non-ischemic dilated cardiomyopathy (NIDCM) and enhancement on late gadolinium magnetic resonance imaging (LGE-CMR), are at high risk of sudden cardiac death (SCD). Further risk stratification of these patients based on LGE-CMR may be improved through better understanding of fibrosis microstructure. Our aim is to examine variations in fibrosis microstructure based on LGE imaging, and quantify the effect on reentry inducibility and mechanism. Furthermore, we examine the relationship between transmural activation time differences and reentry. Methods and Results: 2D Computational models were created from a single short axis LGE-CMR image, with 401 variations in fibrosis type (interstitial, replacement) and density, as well as presence or absence of reduced conductivity (RC). Transmural activation times (TAT) were measured, as well as reentry incidence and mechanism. Reentries were inducible above specific density thresholds (0.8, 0.6 for interstitial, replacement fibrosis). RC reduced these thresholds (0.3, 0.4 for interstitial, replacement fibrosis) and increased reentry incidence (48 no RC vs. 133 with RC). Reentries were classified as rotor, micro-reentry, or macro-reentry and depended on fibrosis micro-structure. Differences in TAT at coupling intervals 210 and 500ms predicted reentry in the models (sensitivity 89%, specificity 93%). A sensitivity analysis of TAT and reentry incidence showed that these quantities were robust to small changes in the pacing location. Conclusion: Computational models of fibrosis micro-structure underlying areas of LGE in NIDCM provide insight into the mechanisms and inducibility of reentry, and their dependence upon the type and density of fibrosis. Transmural activation times, measured at the central extent of the scar, can potentially differentiate microstructures which support reentry.